Aripiprazole Oral

Aripiprazole is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia).^{[1][2][3][9][89][91][93]} Aripiprazole also is used orally for the treatment of bipolar I disorder,^{[1][67][90][139]} as an adjunct to antidepressants for the acute treatment of major depressive disorder,^[1][85] for the acute treatment of irritability associated with autistic disorder,^{[1][109][110]} and for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome).^[1][124] Short-acting (immediate-release) aripiprazole injection (Abilify^®; no longer commercially available in the US) has been used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia.^{[1][86][87][88]} Extended-release aripiprazole injection (Abilify Maintena^®) is used IM for the treatment of schizophrenia and maintenance treatment of bipolar I disorder.^{[118][120][121]} Extended-release aripiprazole lauroxil injection (Aristada^®; available as prefilled syringes in 441-mg, 662-mg, 882-mg, and 1064-mg strengths) is used IM for the treatment of schizophrenia;^[119][122] the 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) is used IM in combination with oral aripiprazole for the initiation of extended-release aripiprazole lauroxil therapy for the treatment of schizophrenia.^[147]

Aripiprazole tablets with sensor (Abilify MyCite^®) is part of a digital ingestion tracking system intended to provide objective data on drug ingestion.^[139][146] (See Tablets with Sensor under Administration: Oral Administration, in Dosage and Administration and also see Description: Aripiprazole Tablets with Sensor.) The ability of the system to improve patient compliance or help guide aripiprazole dosage adjustments has not been established.^[139][146] The manufacturer states that the use of Abilify MyCite^® to track drug ingestion in ''real time'' or during an emergency is not recommended because detection of tablet ingestion may be delayed or may not occur.^[139][146] Abilify MyCite^® is used orally for the treatment of schizophrenia, for the treatment of bipolar I disorder, and as an adjunct to antidepressants for the treatment of major depressive disorder.^[139]

Psychotic Disorders

Aripiprazole is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia).^{[1][2][3][9][89][91][93][118][119][120][121][122][139][147]} Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse.^[28] Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.^[28] Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.^{[28][70][71][72][115]}

Schizophrenia

Aripiprazole is used orally for the acute and maintenance treatment of schizophrenia.^{[1][2][3][9][89][91][93][139]} In addition, extended-release formulations of aripiprazole (Abilify Maintena^®) and aripiprazole lauroxil (Aristada^®, Aristada Initio^®) are used IM for the treatment of schizophrenia.^{[118][119][120][121][122][147]} Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors.^[28][68] Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment.^[28][68] The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms.^[28] Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition).^[28] Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.^[28]

Short-term efficacy of oral aripiprazole monotherapy in the acute treatment of schizophrenia in adults was evaluated in 5 placebo-controlled studies of 4 and 6 weeks' duration principally in acutely relapsed, hospitalized patients who predominantly met DSM-III/IV criteria for schizophrenia.^[1][2][3][9] Four of the 5 studies were able to distinguish aripiprazole from placebo, but the smallest study did not.^[1] In the 4 positive studies, assessment of improvement in manifestations of schizophrenia was based on results of psychiatric rating scales, including the Positive and Negative Syndrome Scale (PANSS), the PANSS positive subscale, the PANSS negative subscale, and the Clinical Global Impressions (CGI) scale.^[1][2][3][9] Aripiprazole generally was found to be superior to placebo in improving both positive and negative manifestations in acute exacerbations of schizophrenia in these 4 studies.^[1][2][3][9] Efficacy of 10-, 15-, 20-, and 30-mg daily dosages of aripiprazole was established in 2 studies for each dosage; however, there was no evidence that higher dosages offered any therapeutic advantage over lower dosages in these studies.^[1] Active controls (haloperidol or risperidone) were used in addition to placebo controls in 3 of these studies, but study design did not allow for comparison between aripiprazole and the active controls.^{[1][2][3][8][9]} An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.^[1]

In a longer-term study, adult inpatients or outpatients who met DSM-IV criteria for schizophrenia and who were, by history, symptomatically stable on other antipsychotic agents for at least 3 months were discontinued from those other agents and randomized to receive either oral aripiprazole 15 mg daily or placebo for up to 26 weeks of observation for relapse in the double-blind phase.^[1] Relapse was based on results of the CGI-Improvement and PANSS psychiatric rating scales.^[1] Patients receiving aripiprazole experienced a significantly longer time to relapse over the subsequent 26 weeks compared with those receiving placebo.^[1] In addition, pooled data from 2 double-blind, multicenter studies in acutely ill patients with schizophrenia in whom therapy with aripiprazole or haloperidol was continued for 52 weeks demonstrated a substantially higher rate of symptomatic remission across 52 weeks in the aripiprazole-treated patients compared with the haloperidol-treated patients; improved tolerability with aripiprazole may have contributed to the higher overall remission rates observed in this pooled analysis.^[93]

Short-term efficacy of oral aripiprazole in the acute treatment of schizophrenia in adolescents 13-17 years of age was evaluated in a double-blind, placebo-controlled trial of 6 weeks' duration in 302 outpatients who met DSM-IV criteria for schizophrenia and had a PANSS total score of 70 or more at baseline.^[1][75][91] Patients were randomized to receive a fixed dosage of aripiprazole 10 mg daily or 30 mg daily or to receive placebo.^[1][75][91] Both dosages of aripiprazole were found to be superior to placebo in reducing the PANSS total score, which was the primary efficacy measure; the 10-mg daily dosage also demonstrated superiority over placebo on the PANSS negative subscale score at the study end point.^[1][75][91] However, the 30-mg daily dosage failed to demonstrate superiority over the 10-mg daily dosage.^[1] The drug was generally well tolerated.^[91]

Short-term efficacy of the extended-release IM formulation of aripiprazole (Abilify Maintena^®) in the treatment of schizophrenia in adults was established in a multicenter, double-blind, placebo-controlled study of 12 weeks' duration in acutely relapsed inpatients who met DSM-IV-TR criteria for schizophrenia and who were experiencing an acute psychotic episode.^[118][120] Patients in this study were randomized to receive IM injections of extended-release aripiprazole (400 mg) or placebo every 4 weeks.^[118][120] Patients receiving extended-release IM aripiprazole were also given oral aripiprazole (10-20 mg daily) for 14 days beginning on the day of the first injection to provide therapeutic plasma concentrations, which may take longer to achieve in some patients; patients who received placebo injections were given placebo tablets for the first 14 days.^[120] The IM dosage of extended-release aripiprazole could be adjusted down to 300 mg and increased back to 400 mg on a one-time basis.^[118][120] The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 10).^[118][120] Patients treated with extended-release IM aripiprazole injection demonstrated substantially greater improvement in mean PANSS total scores compared with those receiving placebo.^[118][120]

In a longer-term maintenance study, adults who met DSM-IV-TR criteria for schizophrenia and who were receiving at least one antipsychotic agent were treated with open-label oral aripiprazole for 4-6 weeks followed by extended-release aripiprazole (Abilify Maintena^®) 400 mg IM once every 4 weeks with oral aripiprazole continued for the first 2 weeks after the initial injection.^[118][121] The IM extended-release aripiprazole dosage could be adjusted down to 300 mg based on tolerability and increased back to 400 mg on a one-time basis.^[118][121] Patients who remained stable on the extended-release IM injection for at least 12 weeks were then randomized either to continue receiving extended-release IM aripiprazole at the same dosage or to receive placebo injection IM every 4 weeks for up to 52 weeks and observed for relapse in the double-blind withdrawal phase.^[118][121] The primary efficacy measure was the time from randomization to relapse, and patients who received extended-release IM aripiprazole had a substantially longer time to relapse than those who received placebo.^[118][121]

Efficacy of extended-release aripiprazole lauroxil IM injection (Aristada^®) in the treatment of schizophrenia was established, in part, based on extrapolation of efficacy data from clinical trials with oral aripiprazole.^[119] In addition, efficacy was established in a multicenter, double-blind, placebo-controlled, fixed-dose study of 12 weeks' duration in adults who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute exacerbation or relapse.^[119][122] Patients were randomized to receive extended-release aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo by IM injection every 4 weeks.^[119][122] After establishing tolerability to oral aripiprazole, patients concomitantly received oral aripiprazole 15 mg daily (if randomized to aripiprazole) or placebo for the first 3 weeks.^[119][122] The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 12).^[119][122] At the study end point, both dosages of extended-release aripiprazole lauroxil injection resulted in substantially greater improvement in the PANSS total score compared with placebo.^[119][122] Substantial improvements in the PANSS total score were evident as early as day 8 with extended-release aripiprazole lauroxil therapy and continued through the end of the treatment period.^[119][122] The secondary efficacy end point was the Clinical Global Impression-Improvement (CGI-I) score on day 85.^[119][122] Both groups of patients receiving extended-release aripiprazole lauroxil therapy demonstrated substantially better CGI-I scores compared with the placebo group.^[119][122] An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, race, or body weight.^[119]

Aripiprazole tablets with sensor (Abilify MyCite^®) is part of a digital ingestion tracking system intended to provide objective data on drug ingestion.^[139][146] (See Tablets with Sensor under Administration: Oral Administration, in Dosage and Administration and also see Description: Aripiprazole Tablets with Sensor.) The usability (i.e., ease of use, helpfulness) of this digital ingestion tracking system was evaluated in a multicenter, open-label study in 67 adults with a primary diagnosis of schizophrenia.^[144] Patients who had been stabilized on oral aripiprazole therapy were switched to the same dosage of aripiprazole tablets with sensor (Abilify MyCite^®) for 8 weeks.^[144] Patients received training at baseline and weekly as needed for the first 3 weeks then were instructed to change the wearable sensor and pair it with their mobile device independently or with the assistance of a caregiver weekly for the next 5 weeks.^[144] The majority of patients in this study were male (74.6%) and black or African-American (76.1%), and 70.1% had mild disease (i.e., Clinical Global Impression-Severity [CGI-S] score of 3) and a higher range of function (indicated by relatively high mean scores on the Instrumental Activities of Daily Living and Personal and Social Performance scales).^[144] Forty-nine patients (73.1%) completed the 8-week study; by the end of the study period or at the time of withdrawal from the study, 55.2% of patients were able to apply and pair a wearable sensor with their mobile device independently and 82.1% completed the tasks independently or with minimal assistance (as rated by a clinician using a standardized scale).^[144] Of the 60 patients who rated the ease of use and helpfulness of the digital ingestion tracking system at the end of study or at the time of withdrawal from the study, 78% reported that they were somewhat satisfied to extremely satisfied with the digital ingestion tracking system, 70% rated the system as at least somewhat helpful in management of their condition, 77% rated the system as at least somewhat helpful in improving discussions with their healthcare provider, and 65% rated the system as somewhat easy to extremely easy to use.^[144]

Although the efficacy of oral aripiprazole as maintenance therapy in pediatric patients with schizophrenia has not been systematically evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.^[1]

If aripiprazole is used for extended periods as maintenance therapy for schizophrenia, the need for continued therapy should be reassessed periodically.^[1] (See Dosage and Administration: Dosage and see also Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial.^[28] The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.^[28] Conventional antipsychotic agents may be considered first-line therapy in patients who have been treated successfully in the past with or who prefer conventional agents.^[28] The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.^[28]

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Bipolar Disorder

Aripiprazole is used orally as monotherapy or as an adjunct to either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features.^{[1][67][90][139]} The drug also is used orally as monotherapy or as adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder.^{[112][125][127][129][139]} Extended-release aripiprazole injection (Abilify Maintena^®) is used IM as monotherapy for the maintenance treatment of bipolar I disorder.^[118][140] According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).^[68]

Efficacy of oral aripiprazole monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 4 short-term (i.e., 3 weeks' duration), placebo-controlled trials in hospitalized adults who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes.^[1][67] These studies included patients with or without psychotic features and 2 of the studies also included patients with or without a rapid cycling course.^[1][67] The principal rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).^[1][67] The main secondary rating instrument used in these trials was the Clinical Global Impression-Bipolar (CGI-BP) scale.^[1][67] In these trials, aripiprazole 15-30 mg once daily (with an initial dosage of 15 mg daily in 2 studies and an initial dosage of 30 mg daily in the other 2 studies) was found to be superior to placebo in the reduction of the Y-MRS total score and the CGI-BP Severity of Illness score (mania).^[1][67] In the 2 studies with an initial aripiprazole dosage of 15 mg daily, 48 and 44% of patients were receiving 15 mg daily at the study end point; in the 2 studies with an initial dosage of 30 mg daily, 86 and 85% of patients were receiving 30 mg daily at end point.^[1][67]

Aripiprazole is used orally as monotherapy for the acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in pediatric patients 10-17 years of age.^[1] Efficacy of aripiprazole in the acute treatment of manic and mixed episodes has been demonstrated in a double-blind, placebo-controlled study of 4 weeks' duration in pediatric outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes (with or without psychotic features) and who had Y-MRS scores of 20 or greater at baseline.^[1] Patients in this study received aripiprazole 10 mg daily, aripiprazole 30 mg daily, or placebo.^[1] Aripiprazole was initiated at a dosage of 2 mg daily, then titrated to 5 mg daily after 2 days, and to the target dosage of 10 mg daily in 5 days or 30 mg daily in 13 days.^[1] Both dosages of aripiprazole were found to be superior to placebo in the reduction of the Y-MRS total score from baseline to week 4.^[1]

Efficacy of oral aripiprazole as an adjunct to lithium or valproate in the treatment of acute manic and mixed episodes has been demonstrated in a placebo-controlled study of 6 weeks' duration in adult outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed type (with or without psychotic features).^[1][90] Patients initially received open-label lithium (dosage producing a serum lithium concentration of 0.6-1 mEq/L) or valproate (dosage producing a serum valproic acid concentration of 50-125 mcg/mL) monotherapy for 2 weeks during the lead-in phase.^[1][90] At the end of 2 weeks, patients demonstrating an inadequate response to lithium or valproate were randomized to receive either aripiprazole (15 mg daily or increased to 30 mg daily as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate during the 6-week, placebo-controlled phase.^[1][90] Patients who received adjunctive aripiprazole with lithium or valproate demonstrated greater reductions in the Y-MRS total score and the CGI-BP Severity of Illness score (mania) compared with patients who received adjunctive placebo with lithium or valproate.^[1][90]

The use of oral aripiprazole as an adjunct to lithium or valproate in the acute treatment of manic or mixed episodes associated with bipolar I disorder has not been evaluated in the pediatric population.^[1] However, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.^[1]

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate.^[69] For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.^[69] For further information on the management of bipolar disorder, see Uses: Bipolar Disorder, in Lithium Salts 28:28.

Efficacy of oral aripiprazole as monotherapy for the maintenance treatment of bipolar I disorder was evaluated in a 26-week, double-blind, placebo-controlled trial in patients with a recent manic or mixed episode who had been stabilized on open-label aripiprazole monotherapy (15-30 mg daily); patients who maintained clinical response with the drug for at least 6 weeks were randomized to either continue aripiprazole at the same dosage or be switched to placebo and monitored for manic or depressive relapse.^{[1][125][139]} In this study, time to relapse to any mood episode, particularly manic episode, was substantially longer and there were fewer manic relapses among patients receiving aripiprazole than in those receiving placebo.^{[1][125][127][139]} There were no differences between aripiprazole and placebo in time to relapse to depressive or mixed episodes^[125][127] or in the number of depressive episodes.^[1][139] A 74-week extension of the study also found that time to relapse to any mood episode, particularly manic episode, was substantially longer with aripiprazole than placebo at 100 weeks of treatment;^[126][127] however, the design and interpretation of these study findings suggesting aripiprazole's efficacy in the maintenance therapy of bipolar disorder have been criticized (i.e., insufficient duration to demonstrate prophylactic efficacy, use of an ''enriched'' patient sample consisting of aripiprazole responders, abrupt discontinuance of aripiprazole in patients randomized to placebo, and low study completion rate).^[127] Time to relapse to depressive episode was not substantially different between treatment groups during the 74-week extension phase.^[126][127]

Oral aripiprazole as adjunctive maintenance therapy in adults with bipolar I disorder was evaluated in a double-blind, placebo-controlled trial in patients with a recent manic or mixed episode.^{[1][112][139]} Patients in this study had received lithium or valproate therapy for at least 2 weeks, and those with an inadequate response to the mood stabilizer also received adjunctive aripiprazole therapy (10-30 mg daily) and were maintained on the combined regimen for at least 12 weeks.^{[1][112][139]} Patients who maintained clinical response with aripiprazole and a mood stabilizer during this period were randomized to either continue aripiprazole or be switched to placebo (combined with lithium or valproate therapy) and monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks.^{[1][112][139]} Patients receiving adjunctive aripiprazole therapy with lithium or valproate experienced a significant delay in time to relapse to any mood episode compared with those receiving placebo plus lithium or valproate,^{[1][112][139]} particularly for relapse to manic episode; no difference between the treatment groups was observed for time to relapse to depressive episode.^[112]

Efficacy of extended-release IM aripiprazole injection (Abilify Maintena^®) as monotherapy for the maintenance treatment of bipolar I disorder has been established in a randomized, double-blind, placebo-controlled withdrawal study of 52 weeks' duration in adults with bipolar I disorder.^[118][140] This study included patients currently experiencing a manic episode and who had experienced at least 1 prior manic or mixed episode with manic symptoms necessitating treatment (e.g., hospitalization, mood stabilizer, antipsychotic agent) who were converted to oral aripiprazole monotherapy over 4-6 weeks.^[118][140] Patients successfully converted to oral aripiprazole monotherapy or patients already receiving oral aripiprazole monotherapy continued receiving the drug orally for a stabilization phase of 2-8 weeks at a target dosage of 15-30 mg daily, and those who remained stable were subsequently converted to extended-release aripiprazole 400 mg IM once every 4 weeks for 12-28 weeks.^[118][140] Oral aripiprazole was continued for the first 2 weeks after the initial injection during the stabilization phase.^[118][140] Patients who remained stable on the extended-release IM injection for at least 8 consecutive weeks were then randomized either to continue receiving extended-release IM aripiprazole at the same dosage or placebo for up to 52 weeks during the double-blind withdrawal phase.^[118][140] The monthly IM aripiprazole dosage could be adjusted down to 300 mg based on tolerability and increased back to 400 mg on a one-time basis.^[118][140] The primary efficacy measure was the time from randomization to recurrence of any mood episode, which was defined as hospitalization for any mood episode; Y-MRS total score 15 or higher; Montgomery-Asberg Depression Rating Scale (MADRS) total score 15 or higher; CGI-BP scale overall score over 4; worsening of bipolar I disorder; withdrawal from the study because of lack of efficacy, adverse event, or worsening disease; clinical worsening with the need for addition of a mood stabilizer, antidepressant, or antipsychotic agent, and/or increase in benzodiazepine dosage above the highest permitted dosage (i.e., exceeding 2 mg of lorazepam or equivalent per day); or active suicidality.^[118][140] Patients who received extended-release IM aripiprazole had a substantially longer time to recurrence of any mood episode than those who received placebo.^[118][140] Time to recurrence of manic or mixed episodes was substantially longer in patients receiving extended-release IM aripiprazole compared with those receiving placebo; no difference between the treatment groups was observed for time to relapse to depressive episodes.^[118]

Major Depressive Disorder

Aripiprazole is used orally as an adjunct to antidepressants for the treatment of major depressive disorder.^[1][85][139] The adjunctive efficacy of aripiprazole has been demonstrated in 2 short-term, double-blind, placebo-controlled trials of 6 weeks' duration in adults who met DSM-IV criteria for major depressive disorder and who had an inadequate response to previous antidepressant therapy (1-3 courses) in the current episode and who had also demonstrated an inadequate response during a prospective treatment period to 8 weeks of antidepressant therapy with extended-release paroxetine, extended-release venlafaxine, fluoxetine, escitalopram, or sertraline.^[1][85][139] The primary instrument used for assessing depressive symptoms was the MADRS, a 10-item clinician-rated scale used to assess the degree of depressive symptomatology.^[1][85][139] The principal secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life, and family life), with each item scored from 0 (not at all) to 10 (extreme).^[1][85][139] In both of these trials, aripiprazole was found to be superior to placebo in reducing mean MADRS total scores; aripiprazole was also superior to placebo in reducing the mean SDS score in one study.^[1][85][139] Patients in both trials initially received an aripiprazole dosage of 5 mg daily; subsequent dosage adjustments, based on efficacy and tolerability, could be made in 5-mg increments 1 week apart.^[1][85][139] Allowable aripiprazole dosages were 2, 5, 10, and 15 mg daily; patients who were not receiving the potent cytochrome P-450 (CYP) isoenzyme 2D6 inhibitors fluoxetine and paroxetine could also receive 20 mg daily.^[1][85][139]

An analysis of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race.^[1][139] With regard to gender, a smaller mean reduction in the MADRS total score was observed in males than in females.^[1][139]

Irritability Associated with Autistic Disorder

Aripiprazole is used orally for the acute treatment of irritability associated with autistic disorder.^{[1][109][110]} Efficacy of aripiprazole was established in 2 double-blind, placebo-controlled trials of 8 weeks' duration in pediatric patients 6-17 years of age who met DSM-IV criteria for autistic disorder and demonstrated behaviors such as aggression towards others, self-injurious behavior, quickly changing moods, or a combination of these behaviors.^{[1][109][110]} Over 75% of the enrolled patients were under 13 years of age.^{[1][109][110]} The primary instruments used for assessing clinical efficacy were the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale.^{[1][109][110]} The primary outcome measure in both trials was the change from baseline to end point in the irritability subscale of the ABC (ABC-I).^{[1][109][110]} In one of the trials, 98 children and adolescents with autistic disorder received flexible daily dosages of aripiprazole ranging from 2-15 mg daily, starting at 2 mg daily with increases allowed up to 15 mg daily based on clinical response, or placebo.^[1][110] In this trial, aripiprazole improved scores on both the ABC-I subscale and on the CGI-I scale compared with placebo.^[1][110] The mean daily dosage of aripiprazole at the end of the 8-week treatment period was approximately 9 mg daily.^[1]

In the other trial, 218 children and adolescents with autistic disorder received one of 3 fixed dosages of aripiprazole (5, 10, or 15 mg daily) or placebo.^[1][109] Aripiprazole therapy was started at 2 mg daily and was increased to 5 mg daily after 1 week.^[1][109] After the second week, the dosage was increased to 10 mg daily for patients in the 10- and 15-mg daily dosage arms; after the third week, the dosage was increased to 15 mg daily in the 15-mg daily treatment arm.^[1][109] Patients receiving all 3 aripiprazole dosages in this study demonstrated improved ABC-I subscale and CGI-I scores compared with placebo.^[1][109]

Tourette's Syndrome

Aripiprazole is used orally for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome).^[1][124] Efficacy of aripiprazole was established in 2 controlled trials (one 8-week and one 10-week) in pediatric patients who met DSM-IV criteria for Tourette's disorder and who had a total tic score (TTS) of at least 20-22 on the Yale Global Tic Severity Scale (YGTSS).^[1][124] The YGTSS is a fully validated scale that measures current tic severity.^[1] The primary outcome measure in both trials was the change from baseline to end point in the TTS on the YGTSS (YGTSS TTS).^[1][124] Over 65% of the enrolled patients were under 13 years of age.^[1]

In the 8-week, placebo-controlled, fixed-dose trial, 133 patients 7-17 years of age were randomized to receive high-dose aripiprazole (target daily dosage of 10 mg for patients weighing less than 50 kg and 20 mg for those weighing 50 kg or more), low-dose aripiprazole (target daily dosage of 5 mg for those weighing less than 50 kg and 10 mg for those weighing 50 kg or more), or placebo.^[1] Aripiprazole was initiated at 2 mg daily and increased to 5 mg after 2 days with subsequent increases of 5 mg on day 7 and weekly thereafter when the target dosage was 10 mg daily or higher.^[1] Patients receiving aripiprazole in both the high-dose and low-dose groups demonstrated substantially improved scores on the YGTSS TTS compared with patients receiving placebo.^[1]

In the 10-week, placebo-controlled, flexible-dose study, which was conducted in Korea, 61 patients 6-18 years of age with Tourette's syndrome were randomized to receive flexible daily dosages of aripiprazole, starting at 2 mg daily with increases allowed up to 20 mg daily based on clinical response, or placebo.^[1][124] The aripiprazole-treated patients in this study demonstrated substantially improved scores on the YGTSS TTS compared with patients receiving placebo.^[1][124] The mean daily dosage of aripiprazole at the end of the 10-week treatment period was approximately 6.5 mg daily.^[1]

For further information on Tourette's syndrome, including clinical manifestations, diagnosis, and management of the disorder, see Uses: Tourette's Syndrome, in Pimozide 28:16.08.92.

Agitation Associated with Schizophrenia or Bipolar Mania

Aripiprazole has been used IM for the acute management of agitation associated with schizophrenia or bipolar disorder, manic or mixed, in patients for whom treatment with aripiprazole is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).^{[1][86][87][88]} However, immediate-release aripiprazole IM injection (Abilify^®) has been discontinued by the manufacturer and is no longer commercially available in the US.^[141]

Administration

Aripiprazole is administered orally^[1][139] or by IM injection.^[118] Aripiprazole lauroxil is administered only by IM injection.^[119][147]

Patients receiving aripiprazole should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.^{[1][76][77][78]} (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Oral Administration

Aripiprazole conventional tablets, tablets with sensor (Abilify MyCite^®), orally disintegrating tablets, and oral solution are administered orally once daily without regard to meals.^[1][139]

Orally Disintegrating Tablets

Patients receiving aripiprazole orally disintegrating tablets should be instructed not to remove a tablet from the blister package until just prior to dosing.^[1] The tablet should not be pushed through the foil, since this may damage the tablet.^[1] With dry hands, the blister package should be peeled open to expose a tablet.^[1] The tablet should then be removed and placed on the tongue, where it rapidly disintegrates in saliva.^[1] The manufacturer recommends that the orally disintegrating tablets be taken without liquid; however, they may be taken with liquid, if necessary.^[1] Aripiprazole orally disintegrating tablets should not be split.^[1]

Tablets with Sensor

Aripiprazole is available as part of a digital ingestion tracking system comprised of the following components: aripiprazole tablets embedded with an ingestible event marker sensor (IEM; Abilify MyCite^®); a wearable sensor (MyCite^® patch), which detects the signal from the IEM sensor after ingestion and transmits data to a compatible mobile device (i.e., a smart phone); a software application (app) for compatible mobile devices (e.g., smart phones; MyCite^® App), which displays information for the patient; and a web-based portal for healthcare professionals and caregivers.^[139]

Prior to initial patient use of the Abilify MyCite^® system, use of the combination product and its components (patch, app, portal) should be facilitated.^[139] Clinicians should ensure that patients are capable and willing to use a mobile device (e.g., smart phone) and the software application (app).^[139] Before using any component of the system, clinicians should instruct patients to download the mobile software application and follow all the instructions for use and to ensure that the software is compatible with their specific mobile device.^[139]

Aripiprazole tablets with sensor are administered orally once daily without regard to meals; tablets with sensor should be swallowed whole and not divided, crushed, or chewed.^[139]

Prior to use of the software application, the patient's mobile device should be powered on and Bluetooth^® enabled.^[139] The accompanying wearable sensor should be applied when prompted by the mobile software application; the application will instruct patients to apply and remove the sensor correctly.^[139] Patients should confirm that their mobile device is paired with the wearable sensor prior to use; the mobile software application will display a status icon on the mobile device to indicate that the wearable sensor is properly adhered and functioning.^[139] For further information, clinicians and patients may refer to the information provided in the product packaging as well as the instructions for use within the mobile software application.^[139]

Most ingestions of aripiprazole tablets with sensor will be detected within 30 minutes following ingestion; however, it may take up to 2 hours for the smart phone application and web portal to detect the ingestion of the tablet with sensor.^[139] In some cases, ingestion of the tablet with sensor may not be detected.^[139] If the tablet with sensor is not detected following ingestion, the dose should not be repeated.^[139]

The wearable sensor should be applied topically to the left side of the body just above the lower edge of the rib cage.^[139] Application to areas where the skin is scraped, cracked, inflamed, or irritated or areas overlapping the area of the most recently removed wearable sensor should be avoided.^[139] The wearable sensor should be changed weekly or sooner as needed; the mobile software application will remind patients when to change the sensor.^[139] Patients should be instructed keep the sensor in place while showering, swimming, or exercising.^[139] However, the sensor should be removed before undergoing magnetic resonance imaging (MRI) and replaced with a new sensor as soon as possible following the procedure.^[139] If skin irritation occurs, the wearable sensor should be removed.^[139] (See Skin Irritation associated with Abilify MyCite^® Wearable Sensor under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

IM Administration

Clinicians should be aware that there are several different IM formulations of aripiprazole with different indications, dosages, and dosing frequencies.^{[1][118][119][147]} A short-acting, immediate-release IM formulation of aripiprazole (Abilify®) has been used for agitation associated with schizophrenia and bipolar mania, but is no longer commercially available in the US.^[1][141] The extended-release IM formulation of aripiprazole (Abilify Maintena®) is available in 300- and 400-mg vials and prefilled syringes and is used for the treatment of schizophrenia and maintenance monotherapy of bipolar I disorder.^[118] The extended-release IM formulation of aripiprazole lauroxil (Aristada®) is available in 441-, 662-, 882-, and 1064-mg prefilled syringes and is used for the treatment of schizophrenia.^[119]

Extended-release aripiprazole lauroxil injection also is available in 675-mg prefilled syringes (Aristada Initio®), which are used IM as a single dose to initiate treatment of schizophrenia or to re-initiate therapy following a missed dose; this formulation is not intended for repeated dosing.^[147]

Aristada Initio® is not interchangeable with Aristada® because of their different pharmacokinetic profiles.^[147]

Extended-release aripiprazole injection and extended-release aripiprazole lauroxil injection are administered only by IM injection by a healthcare professional.^{[1][118][119][147]} Extended-release aripiprazole injection (Abilify Maintena^®) is administered monthly.^[118] The 441- and 662-mg doses of extended-release aripiprazole lauroxil injection (Aristada^®) are administered monthly, the 882-mg dose may be administered every month or every 6 weeks, and the 1064-mg dose is administered every 2 months.^[119] Extended-release aripiprazole lauroxil injection available in 675-mg prefilled syringes (Aristada Initio^®) is used as a single dose only and is not intended for repeated dosing.^[147]

The manufacturers state that tolerability with oral aripiprazole therapy should be established prior to initiating IM therapy with extended-release formulations of the drug.^{[118][119][147]}

Extended-release Aripiprazole Injection

Extended-release aripiprazole injection (Abilify Maintena^®) is administered by deep IM injection monthly into the deltoid or gluteal muscle.^[118] The manufacturer states that at least 26 days should elapse between doses.^[118] Each injection should be administered only by IM injection by a healthcare professional.^[118]

Aripiprazole extended-release IM injection must be reconstituted with sterile water for injection prior to administration.^[118] The drug is commercially available in 2 types of kits that contain aripiprazole lyophilized powder in either single-use vials or prefilled dual-chamber syringes with all the components required for reconstitution and administration (e.g., sterile water for injection diluent, needles, syringes).^[118] Because the entire contents of the prefilled syringe should be administered following reconstitution, only vials of the drug should be used for dosages smaller than 300 mg (e.g., for the 160- and 200-mg dosage adjustments recommended in patients concurrently receiving certain cytochrome P-450 [CYP] isoenzyme inhibitors or inducers; see Dosage and Administration: Special Populations).^[118] Kits containing prefilled dual-chamber syringes should be stored below 30°C and not frozen; the syringe should be protected from light by storing in the original package until the time of use.^[118] Kits containing single-use vials should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.^[118] The manufacturer's instructions for use should be consulted for specific information on the preparation, reconstitution, and administration of aripiprazole extended-release injection using these single-use kits.^[118]

Following reconstitution, the prefilled syringe or vial should be shaken vigorously for 20 or 30 seconds, respectively, to ensure a uniform suspension.^[118] The reconstituted suspension should be inspected visually for particulate matter and discoloration prior to administration; the suspension should appear to be a uniform, homogeneous suspension that is opaque and milky-white in color.^[118] If using vials, the appropriate dose of aripiprazole should be drawn from the vial into the syringe supplied by the manufacturer and injected immediately.^[118] If a vial of reconstituted suspension is not administered immediately, the vial should be shaken vigorously for at least 60 seconds to resuspend the drug; reconstituted suspension should not be stored in a syringe.^[118] If using prefilled syringes, the entire contents of the prefilled syringe should be injected immediately following reconstitution; the manufacturer states that the contents of the prefilled syringe should be administered within 30 minutes of reconstitution.^[118]

Extended-release aripiprazole should be administered slowly by deep IM injection into the deltoid or gluteal muscle using the appropriate length needle (based on body type and injection site) supplied by the manufacturer.^[118] Injection sites should be rotated between the 2 deltoid or gluteal muscles.^[118] Following IM administration, the injection site should not be massaged.^[118]

Extended-release Aripiprazole Lauroxil Injection

Both formulations of extended-release aripiprazole lauroxil injectable suspension (Aristada^® and Aristada Initio^®) are administered by IM injection into the deltoid (441- and 675-mg doses only) or gluteal muscle (441-, 662-, 675-, 882-, or 1064-mg doses).^[119][147] The 441-, 662-, and 882-mg doses are administered monthly; the 882-mg dose also may be administered every 6 weeks; and the 1064-mg dose is administered every 2 months.^[119] The manufacturer states that if a dose of Aristada^® is given earlier than the scheduled time, at least 14 days should elapse between doses.^[119] Each injection should be administered only by IM injection by a healthcare professional.^[119][147]

Extended-release aripiprazole lauroxil injection in 675-mg prefilled syringes (Aristada Initio^®) is used only as a single dose to initiate treatment of schizophrenia or to re-initiate therapy following a missed dose; this formulation is not intended for repeated dosing.^[147] Aristada Initio® is not interchangeable with Aristada® because of their different pharmacokinetic profiles.^[147]

Aripiprazole lauroxil injectable suspension (Aristada^® and Aristada Initio^®) is commercially available in a kit containing the drug in a prefilled syringe and safety needles for IM injection.^[119][147] The kit should be stored at room temperature.^[119][147] Prior to use, the prefilled syringe should be tapped at least 10 times to dislodge any material that may have settled.^[119][147] The syringe should then be shaken vigorously for at least 30 seconds to ensure a uniform suspension.^[119][147] If the drug is not administered within 15 minutes, the syringe should be shaken again for 30 seconds.^[119][147]

The entire contents of the syringe should be administered rapidly and continuously by IM injection into either the deltoid (for 441- and 675-mg doses only) or gluteal muscle (for 441-, 662-, 675-, 882-, and 1064-mg doses) using the appropriate length needle supplied by the manufacturer.^[119][147] The manufacturer states that the longer needles provided should be used in patients with a larger amount of subcutaneous tissue over the injection site muscle.^[119][147] Concurrent administration of the 2 different aripiprazole lauroxil injection formulations (Aristada Initio^® and Aristada^®) in the same muscle should be avoided.^[147]

For patients receiving aripiprazole lauroxil injection 441 mg monthly, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 6 weeks; however, if the time elapsed since the last injection exceeds 6 weeks, but not 7 weeks, oral aripiprazole should be given for 7 days, and if the time elapsed since the last injection exceeds 7 weeks, oral aripiprazole should be given for 21 days.^[119] In patients receiving aripiprazole lauroxil injection 662 mg monthly, 882 mg monthly, or 882 mg every 6 weeks, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 8 weeks; however, if the time elapsed since the last injection exceeds 8 weeks, but not 12 weeks, oral aripiprazole should be given for 7 days, and if the time elapsed since the last injection exceeds 12 weeks, oral aripiprazole should be given for 21 days.^[119] In patients receiving aripiprazole lauroxil injection 1064 mg every 2 months, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 10 weeks; however, if the time elapsed since the last injection exceeds 10 weeks, but not 12 weeks, oral aripiprazole should be given for 7 days, and if the time elapsed since the last injection exceeds 12 weeks, oral aripiprazole should be given for 21 days.^[119] The dosage of oral aripiprazole supplementation should be the same as when the patient started receiving aripiprazole lauroxil injection.^[119] (See IM Dosage of Aripiprazole Lauroxil under Dosage: Schizophrenia, in Dosage and Administration.)

Dosage

Aripiprazole oral solution may be given at the same dose on a mg-per-mg basis as the tablet strengths of the drug up to a dose of 25 mg.^[1] However, if the oral solution is used in patients who were receiving aripiprazole 30 mg as tablets, a dose of 25 mg of the oral solution should be used.^[1]

Conventional tablets and orally disintegrating tablets of aripiprazole are bioequivalent; therefore, dosing for the orally disintegrating tablets is the same as for the conventional tablets.^[1]

Dosage of aripiprazole lauroxil is expressed in terms of aripiprazole lauroxil.^[119][147]

Extended-release aripiprazole lauroxil (Aristada^®) doses of 441, 662, 882, and 1064 mg correspond to aripiprazole doses of 300, 450, 600, and 724 mg, respectively.^[119]

Schizophrenia

Oral Dosage

For the management of schizophrenia in adults, the recommended initial and target dosage of aripiprazole is 10 or 15 mg orally once daily.^[1][139] Although dosages ranging from 10-30 mg daily administered as conventional tablets were effective in clinical trials,^[1] the manufacturer states that dosages exceeding 10-15 mg daily did not result in greater efficacy.^[1][139] The maximum recommended dosage is 30 mg daily.^[139] Because steady-state plasma concentrations of aripiprazole and dehydro-aripiprazole, its active metabolite, may not be attained for 2 weeks, dosage adjustments generally should be made at intervals of not less than 2 weeks.^[1][139]

For the management of schizophrenia in adolescents 13-17 years of age, the recommended target dosage of aripiprazole is 10 mg orally once daily.^[1] Therapy was initiated in a dosage of 2 mg once daily in these patients, with subsequent titration to 5 mg once daily after 2 days and to the target dosage of 10 mg once daily after 2 additional days.^[1][75][91] The manufacturer recommends that any subsequent dosage increases be made in 5-mg, once-daily increments.^[1] Although aripiprazole dosages of 10 and 30 mg once daily administered as conventional tablets have been studied in adolescents, the 30-mg daily dosage was not found to be more effective than the 10-mg daily dosage.^[1][75][91]

The optimum duration of oral aripiprazole therapy in patients with schizophrenia currently is not known, but maintenance therapy with aripiprazole 15 mg once daily as conventional tablets has been shown to be effective in preventing relapse for up to 26 weeks in adults.^[1] In addition, a combined analysis of data from 2 double-blind, multicenter studies indicates that maintenance therapy with the drug may be effective for up to 52 weeks in adults.^[2][9][10]

Although the efficacy of oral aripiprazole as maintenance therapy in pediatric patients with schizophrenia has not been systematically evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.^[1]

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence.^[28] Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent.^[28] In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.^[28]

The manufacturer states that the need for continued therapy with the drug should be reassessed periodically.^[1]

There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotic agents to aripiprazole or concerning concomitant administration with other antipsychotic agents.^[1] Immediate discontinuance of the previous antipsychotic agent may be acceptable in some patients with schizophrenia, and more gradual discontinuance may be most appropriate for other patients.^[1] In all patients, the period of overlapping antipsychotic administration should be minimized.^[1]

IM Dosage of Aripiprazole (Abilify Maintena®)

In patients who have never received aripiprazole, the manufacturer recommends that tolerability with oral aripiprazole be established prior to initiating IM therapy with extended-release aripiprazole injection (Abilify Maintena^®).^[118] Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.^[118]

For the treatment of schizophrenia in adults, the recommended dosage of extended-release aripiprazole injection (Abilify Maintena^®) is 400 mg administered by IM injection every month (no sooner than 26 days following the previous injection).^[118] In patients experiencing adverse effects, a reduction in dosage to 300 mg every month may be considered.^[118]

To maintain therapeutic antipsychotic concentrations during initiation of therapy with extended-release aripiprazole injection, oral aripiprazole at a dosage of 10-20 mg daily or another oral antipsychotic agent (for patients already stable on another oral antipsychotic agent and known to tolerate aripiprazole) should be given after the first IM injection of extended-release aripiprazole and continued for 14 days.^[118]

If a dose of extended-release aripiprazole injection is missed, the next dose should be administered as soon as possible.^[118] Supplementation with oral aripiprazole may be required depending on the time elapsed.^[118] If the second or third doses are missed, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 5 weeks; however, if the time elapsed since the last injection exceeds 5 weeks, supplementation with oral aripiprazole should be given for 14 days with the next administered injection.^[118] If the fourth or subsequent doses are missed, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 6 weeks; however, if the time elapsed since the last injection exceeds 6 weeks, supplementation with oral aripiprazole should be given for 14 days with the next administered injection.^[118]

IM Dosage of Aripiprazole Lauroxil (Aristada®)

In patients who have never received aripiprazole, the manufacturer recommends that tolerability with oral aripiprazole therapy be established prior to initiating IM therapy with extended-release aripiprazole lauroxil (Aristada^®).^[119] Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.^[119]

For the treatment of schizophrenia in adults, extended-release aripiprazole lauroxil injection (Aristada^®) may be initiated at a dosage of 441, 662, or 882 mg every month; 882 mg every 6 weeks; or 1064 mg every 2 months by IM injection.^[119] Oral aripiprazole should be administered with the first IM injection of aripiprazole lauroxil and continued for 21 days.^[119]

For patients established on oral aripiprazole 10 mg daily, the recommended IM dosage of extended-release aripiprazole lauroxil is 441 mg every month.^[119]

For patients established on oral aripiprazole 15 mg daily, the recommended IM dosage of extended-release aripiprazole lauroxil is 662 mg every month, 882 mg every 6 weeks, or 1064 mg every 2 months.^[119]

For patients established on oral aripiprazole 20 mg or higher daily, the recommended IM dosage of extended-release aripiprazole lauroxil is 882 mg every month.^[119]

Subsequent dosage adjustments may be made if needed.^[119] If dosage adjustments are required, the manufacturer states that the pharmacokinetics and prolonged-release characteristics of extended-release aripiprazole lauroxil injection should be considered when making dosage and dosing interval adjustments.^[119]

If a dose of aripiprazole lauroxil injection is missed, the next dose should be administered as soon as possible.^[119] Supplementation with oral aripiprazole and/or a 675-mg IM dose of extended-release aripiprazole lauroxil (Aristada Initio^®) may be required depending on the dosage and the time elapsed (see Tables 1 and 2).^[119][147]

Dosage of oral aripiprazole supplementation should be same as when patient began extended-release aripiprazole lauroxil therapy.\[119 \]

IM Dosage of Aripiprazole Lauroxil (Aristada Initio®)

In patients who have never received aripiprazole, the manufacturer recommends that tolerability with oral aripiprazole therapy be established prior to initiating IM therapy with extended-release aripiprazole lauroxil (Aristada Initio^®).^[147] Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.^[147]

The 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) is only used as a single dose to initiate aripiprazole lauroxil therapy or as a single dose to reinitiate therapy following a missed dose of extended-release aripiprazole lauroxil injection (Aristada^®).^[147] The 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) is not used for repeated dosing of the drug.^[147]

For the initiation of aripiprazole lauroxil therapy for the treatment of schizophrenia in adults and after establishing tolerability with oral aripiprazole, the first IM injection of aripiprazole lauroxil (Aristada^®; 441 mg, 662 mg, 882 mg, or 1064 mg) may be administered in conjunction with both one 675-mg IM injection of aripiprazole lauroxil (Aristada Initio^®) into the deltoid or gluteal muscle (this dosage is equivalent to 459 mg of aripiprazole) and one 30-mg dose of oral aripiprazole.^[147]

The first dosage of aripiprazole lauroxil (Aristada^®) may be administered on the same day as Aristada Initio^® or up to 10 days thereafter.^[147] Clinicians should avoid injecting both IM formulations of aripiprazole lauroxil concurrently into the same deltoid or gluteal muscle.^[147]

For re-initiation of aripiprazole lauroxil (Aristada^®) therapy following a missed dose, the next injection of aripiprazole lauroxil (Aristada^®) should be administered as soon as possible.^[147] Depending on the time elapsed since the last Aristada^® injection, the next Aristada^® injection may be supplemented as recommended in Table 2.^[147]

Bipolar Disorder

Oral Dosage

For the acute management of manic and mixed episodes associated with bipolar I disorder in adults, the recommended initial aripiprazole dosage is 15 mg given orally once daily as monotherapy or 10-15 mg given orally once daily as adjunctive therapy with lithium or valproate.^[1][139] The recommended target dosage of aripiprazole is 15 mg daily whether the drug is given as monotherapy or as adjunctive therapy with lithium or valproate.^[1][139] Based on clinical response, the dosage can be increased to the maximum recommended dosage of 30 mg daily.^[1][139] Safety of aripiprazole dosages exceeding 30 mg daily has not been established in clinical trials.^[1]

For the acute management of manic and mixed episodes associated with bipolar I disorder in pediatric patients 10-17 years of age, the recommended initial aripiprazole dosage when given as monotherapy is 2 mg orally once daily, with subsequent titration to 5 mg once daily after 2 days and to the target dosage of 10 mg once daily after 2 additional days.^[1] The recommended dosage when aripiprazole is given as adjunctive therapy with lithium or valproate is the same as that for monotherapy.^[1] Subsequent increases in the daily dosage of aripiprazole, if necessary, should be made in 5-mg increments.^[1] In pediatric clinical studies, oral aripiprazole dosages of 10 and 30 mg daily were effective.^[1]

IM Dosage of Aripiprazole

In patients who have never received aripiprazole, the manufacturer recommends that tolerability with oral aripiprazole be established prior to initiating IM therapy with extended-release aripiprazole injection (Abilify Maintena^®).^[118] Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.^[118]

For the maintenance treatment of bipolar I disorder in adults, the recommended dosage of extended-release aripiprazole injection (Abilify Maintena^®) is 400 mg administered by IM injection every month (no sooner than 26 days following the previous injection).^[118] In patients experiencing adverse effects, a reduction in dosage to 300 mg every month may be considered.^[118]

To maintain therapeutic antipsychotic concentrations during initiation of therapy with extended-release aripiprazole injection, oral aripiprazole at a dosage of 10-20 mg daily or another oral antipsychotic agent (for patients already stable on another oral antipsychotic agent and known to tolerate aripiprazole) should be given after the first IM injection of extended-release aripiprazole and continued for 14 days.^[118]

If a dose of extended-release aripiprazole injection is missed, the next dose should be administered as soon as possible.^[118] Supplementation with oral aripiprazole may be required depending on the time elapsed.^[118] If the second or third doses are missed, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 5 weeks; however, if the time elapsed since the last injection exceeds 5 weeks, supplementation with oral aripiprazole should be given for 14 days with the next administered injection.^[118] If the fourth or subsequent doses are missed, supplementation with oral aripiprazole is not required if the time elapsed since the last injection does not exceed 6 weeks; however, if the time elapsed since the last injection exceeds 6 weeks, supplementation with oral aripiprazole should be given for 14 days with the next administered injection.^[118]

Major Depressive Disorder

For adjunctive management of major depressive disorder in adults already receiving an antidepressant, the manufacturer recommends an initial aripiprazole dosage of 2-5 mg orally once daily for acute treatment.^[1][139] Subsequent dosage adjustments of up to 5 mg daily should occur gradually at intervals of at least 1 week; the recommended dosage range is 2-15 mg once daily.^[1][139] The maximum recommended dosage is 15 mg daily.^[139] Efficacy of the drug was established within a dosage range of 2-15 mg daily in clinical studies; mean maintenance dosage in these studies was approximately 11 mg daily.^[1][139]

The manufacturer states that if aripiprazole is used for maintenance therapy, the need for continued therapy with the drug should be reassessed periodically.^[1][139]

Irritability Associated with Autistic Disorder

For the treatment of irritability associated with autistic disorder in pediatric patients 6-17 years of age, efficacy of oral aripiprazole was established within a dosage range of 5-15 mg daily in clinical studies.^{[1][109][110]} Dosing should be initiated at 2 mg daily, then increased to 5 mg daily, with subsequent increases to 10 mg daily or 15 mg daily, if necessary.^[1] Dosage increases should be gradual, at intervals of at least 1 week.^[1]

The manufacturer states that the need for continued therapy with the drug should be reassessed periodically.^[1]

Tourette's Syndrome

For the treatment of Tourette's syndrome in pediatric patients 6-18 years of age, the recommended dosage range of oral aripiprazole is 5-20 mg once daily.^[1]

In pediatric patients weighing less than 50 kg, therapy should be initiated at 2 mg once daily, then increased to the recommended target dosage of 5 mg once daily after 2 days.^[1] In patients who do not achieve optimal control of tics, the dosage may be increased to 10 mg once daily.^[1] Dosage adjustments should be made gradually at intervals of at least 1 week.^[1]

In pediatric patients weighing 50 kg or more, therapy should be initiated at 2 mg once daily for 2 days and then increased to 5 mg once daily for 5 days, with a recommended target dosage of 10 mg once daily on day 8.^[1] In patients who do not achieve optimal control of tics, the dosage may be increased up to 20 mg once daily.^[1] Dosage adjustments should be made gradually in increments of 5 mg daily at intervals of at least 1 week.^[1]

The manufacturer states that the need for continued maintenance therapy with aripiprazole should be reassessed periodically.^[1]

Special Populations

No dosage adjustment is necessary in patients with renal or hepatic impairment or in geriatric patients.^{[1][95][118][119]} In addition, no dosage adjustment is recommended based on gender, race, or smoking status.^{[1][118][119]}

Pharmacogenomics and Poor CYP2D6 Metabolizer Phenotype

Patients who are known poor metabolizers of cytochrome P-450 isoenzyme 2D6 (CYP2D6) should receive one-half (50%) of the usual oral aripiprazole dosage.^[1] Such patients who are also taking a potent CYP3A4 inhibitor should receive 25% of the usual oral aripiprazole dosage.^[1] (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Dosage adjustment is not necessary when oral aripiprazole is used as adjunctive treatment of major depressive disorder.^[1]

The manufacturer of aripiprazole extended-release injection (Abilify Maintena^®) recommends a dosage of 300 mg every month in patients who are poor CYP2D6 metabolizers.^[118] In such patients who are also receiving a potent CYP3A4 inhibitor for longer than 14 days, a dosage of 200 mg every month is recommended.^[118]

Dosage of extended-release aripiprazole lauroxil injection (Aristada^®) in patients who are poor CYP2D6 metabolizers should be based on the patient's established oral aripiprazole dosage.^[119] In such patients receiving a concomitant potent CYP3A4 inhibitor for longer than 2 weeks, dosage should be reduced to 441 mg every month; in patients already receiving 441 mg every month, no dosage adjustment is necessary, if tolerated.^[119] If the potent CYP3A4 inhibitor is used for less than 2 weeks, this dosage adjustment is not necessary.^[119] No further dosage adjustment is necessary in patients who are poor CYP2D6 metabolizers receiving a concomitant potent CYP2D6 inhibitor.^[119]

Extended-release aripiprazole lauroxil injection (Aristada Initio^®) is only available in a single strength (675 mg) in a single-dose prefilled syringe; therefore, dosage adjustments in patients who are poor CYP2D6 metabolizers are not possible.^[147] Use of this extended-release formulation should therefore be avoided in patients who are poor CYP2D6 metabolizers.^[147]

Drugs Affecting Hepatic Microsomal Enzymes

In patients receiving concomitant therapy with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole) or potent CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine), dosage of oral aripiprazole should be reduced to 50% of the usual dosage, except when oral aripiprazole is used in the adjunctive treatment of major depressive disorder.^[1] Dosage adjustment is not necessary when oral aripiprazole is used as adjunctive treatment of major depressive disorder.^[1]

In patients receiving concomitant therapy with potent CYP3A4 or CYP2D6 inhibitors for longer than 14 days, dosage of extended-release aripiprazole injection (Abilify Maintena^®) should be reduced from 400 mg to 300 mg every month, or from 300 mg to 200 mg every month.^[118] In such patients, dosage of extended-release aripiprazole lauroxil injection (Aristada^®) should be reduced to the next available lower strength; in patients tolerating the 441-mg dosage, dosage reduction is not necessary.^[119] A dosage of 882 mg every 6 weeks or 1064 mg every 2 months should be reduced to 441 mg every 4 weeks.^[119] If the potent CYP3A4 or 2D6 inhibitor is used for less than 14 days, dosage adjustment of extended-release aripiprazole or aripiprazole lauroxil injection is not necessary.^[118][119]

In patients receiving concomitant therapy with potent CYP3A4 inhibitors and potent CYP2D6 inhibitors, oral aripiprazole dosage should be reduced to 25% of the usual dosage, except when aripiprazole is used in the adjunctive treatment of major depressive disorder.^[1] Dosage adjustment is not necessary when oral aripiprazole is used as adjunctive treatment of major depressive disorder.^[1]

In patients receiving concomitant therapy with potent CYP3A4 inhibitors and potent CYP2D6 inhibitors for longer than 14 days, dosage of extended-release aripiprazole injection (Abilify Maintena^®) should be reduced from 400 mg to 200 mg every month, or from 300 mg to 160 mg every month.^[118] In such patients tolerating the 441-mg dosage of extended-release aripiprazole lauroxil injection (Aristada^®), dosage adjustment is not necessary; however, the manufacturer states that concomitant therapy with potent CYP2D6 inhibitors and potent CYP3A4 inhibitors for longer than 2 weeks should be avoided in patients receiving 662-, 882-, or 1064-mg dosages of extended-release aripiprazole lauroxil injection.^[119] If such therapy is used for less than 14 days, dosage adjustment of extended-release aripiprazole or aripiprazole lauroxil injection is not necessary.^[118][119]

Dosage of oral aripiprazole should be reduced to 25% of the usual dosage in patients receiving aripiprazole concurrently with a combination of potent, moderate, or weak inhibitors of CYP3A4 and CYP2D6 (e.g., a potent CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor).^[1] The oral aripiprazole dosage may then be adjusted based on clinical response.^[1] (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Aripiprazole dosages should be increased back to the original dosage when the CYP2D6 and/or CYP3A4 inhibitor is discontinued.^[1][118]

In patients receiving potent CYP3A4 inducers (e.g., carbamazepine, rifampin), dosage of oral aripiprazole should be doubled over 1-2 weeks of concomitant therapy.^[1] When the CYP3A4 inducer is discontinued, the dosage should be reduced back to the original dosage over 1-2 weeks.^[1] (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

The manufacturer recommends avoiding use of potent CYP3A4 inducers for longer than 14 days in patients receiving extended-release aripiprazole injection (Abilify Maintena^®).^[118]

In patients receiving extended-release aripiprazole lauroxil injection (Aristada^®), if a potent CYP3A4 inducer is used for longer than 2 weeks, dosage of aripiprazole lauroxil should be increased from 441 mg to 662 mg every month; dosage adjustment is not necessary in patients receiving 662-, 882-, or 1064-mg dosages.^[119] If a potent CYP3A4 inducer is used for less than 2 weeks, dosage adjustment is not necessary.^[119]

Extended-release aripiprazole lauroxil injection (Aristada Initio^®) is only available in a single strength (675 mg); therefore, dosage adjustments in patients receiving potent CYP3A4 inhibitors, potent CYP2D6 inhibitors, or potent CYP3A4 inducers are not possible.^[147] Use of this extended-release formulation of the drug should be avoided in such patients.^[147] (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Contraindications

Known hypersensitivity to aripiprazole; hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis.^{[1][118][119][139][147]} (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.^{[1][73][113][118][119]} Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.^{[73][118][119]} Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.^{[73][118][119]} Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.^{[73][118][119]} Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear.^{[28][113][118][119]}

The manufacturers state that aripiprazole is not approved for the treatment of patients with dementia-related psychosis.^{[1][118][119]} If the clinician elects to treat such patients with aripiprazole, patients should be assessed for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.^[1] (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.^{[1][76][77][78][79]} This risk may persist until clinically important remission occurs.^[1][77] Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.^{[1][76][77][78]} However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.^[1][77] Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.^[1][76][77] An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.^[1][76][77]

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.^{[1][76][77][78]} Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.^[1][77][78]

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.^[1][77][78] Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.^[1][77] FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.^[1][77]

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.^[1][77] Therefore, patients with depressive symptoms should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).^[1][77]

Aripiprazole is not approved for use in treating depression in the pediatric population.^[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Sensitivity Reactions

Allergic and sensitivity reactions (e.g., anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, photosensitivity, rash, oropharyngeal spasm) have been reported in patients receiving aripiprazole.^{[1][118][119]} (See Cautions: Contraindications.)

Other Warnings and Precautions

Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis

An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with oral aripiprazole in several placebo-controlled studies (2 flexible-dose studies and one fixed-dose study).^[1][118] A statistically significant dose-response relationship for adverse cerebrovascular events was observed in patients receiving oral aripiprazole in the fixed-dose study.^[1][118] The manufacturers state that aripiprazole is not approved for the treatment of patients with dementia-related psychosis.^{[1][118][119]} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Potential for Dosing and Medication Errors

Medication errors, including substitution and dispensing errors, may occur between the 2 different extended-release IM formulations of aripiprazole lauroxil (e.g., Aristada Initio^® and Aristada^®).^[147]

Aristada Initio^® is for single-dose administration only.^[147] Aristada Initio^® should not be substituted for Aristada^® because of their different pharmacokinetic profiles.^[147]

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including rare cases associated with aripiprazole therapy.^{[1][99][100][101][118][119]} (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Because use of antipsychotic agents, including aripiprazole, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements),^{[1][96][97][118][119]} aripiprazole should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.^{[1][118][119]} Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.^{[1][118][119]} In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.^{[1][118][119]}

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months.^[28] If signs and symptoms of tardive dyskinesia appear in an aripiprazole-treated patient, aripiprazole discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.^{[1][118][119]} For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.^{[1][118][119]} While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.^{[1][118][119]} (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents.^[1] Hyperglycemia has been reported in patients treated with aripiprazole.^[1] In short- and longer-term clinical trials in adult and pediatric patients, clinically important differences between oral aripiprazole and placebo in mean change from baseline to end point in fasting glucose concentrations were not observed.^[1] While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents.^{[1][26][27][64]}

Patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be periodically monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.^[1] Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.^[1] (See Advice to Patients.) In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.^[1]

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications, in Clozapine 28:16.08.04.

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents; however, aripiprazole generally does not appear to adversely affect the lipid profile in patients receiving the drug.^[1] Pooled data from short- and longer-term clinical studies in adult and pediatric patients indicate no clinically important differences from baseline to end point in the proportion of patients with changes in fasting/nonfasting total cholesterol, fasting triglycerides, fasting low-density lipoprotein (LDL)-cholesterol, and fasting/nonfasting high-density lipoprotein (HDL)-cholesterol between aripiprazole-treated patients and those receiving placebo.^[1]

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy.^[1] Clinical monitoring of weight is recommended in patients receiving aripiprazole.^[1]

In an analysis of 13 placebo-controlled monotherapy studies in adults primarily with schizophrenia or bipolar disorder, mean weight gain in aripiprazole-treated patients was 0.3 kg compared with a loss of 0.1 kg in those receiving placebo (with a median exposure of 21-25 days); at 24 weeks, patients receiving aripiprazole or placebo lost an average of 1.5 or 0.2 kg, respectively.^[1] In 2 placebo-controlled trials in pediatric patients with schizophrenia or bipolar disorder, mean weight gain was 1.6 kg in patients receiving oral aripiprazole and 0.3 kg in those receiving placebo (with a median exposure of 42-43 days); at 24 weeks, mean weight gain was 5.8 and 1.4 kg in aripiprazole- and placebo-treated patients, respectively.^[1]

For additional information on metabolic effects associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Warnings/Precautions: Other Warnings and Precautions, in Cautions.

Pathological Gambling and Other Compulsive Behaviors

Serious impulse-control and compulsive behaviors, particularly pathological gambling, have been reported rarely in adult and pediatric patients treated with aripiprazole.^{[1][118][119][123][132][134][135][136][137][138][139][148]} In May 2016, FDA reported that a total of 184 cases of impulse-control problems associated with aripiprazole use have been identified since November 2002; most of these cases (89%) involved pathological gambling.^[123] Other impulse-control and compulsive behaviors reported less frequently than gambling include compulsive or binge eating, compulsive spending or shopping, and compulsive sexual behaviors.^{[123][136][138][139]} The majority of patients in these cases had no history of compulsive behaviors and experienced the uncontrollable urges only after beginning treatment with aripiprazole.^[123][137] Impulse-control symptoms may also be associated with the underlying disorder.^{[1][118][119][139][148]} The results of a large pharmacoepidemiologic study suggest that patients with bipolar disorder who are receiving aripiprazole have a higher risk of gambling compared with patients with bipolar disorder who are not receiving aripiprazole.^[148] In some, but not all, cases, these uncontrollable urges reportedly stopped within days to weeks when the aripiprazole dosage was reduced or the drug was discontinued; recurrence of compulsive behaviors following rechallenge with the drug has been reported.^{[1][118][119][123][134][136][137][138][139]}

Aripiprazole-associated compulsive behaviors may result in harm to the patient or others if not recognized.^{[1][118][119][139]} Because patients may not recognize such behaviors as abnormal, clinicians should specifically ask patients or caregivers whether any new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges have developed during treatment with the drug.^{[1][118][119][123][139]} If a patient develops new or increased impulsive or compulsive behaviors while receiving aripiprazole, consideration should be given to reducing the dosage or discontinuing the drug.^{[1][118][119][123][137][139]} (See Advice to Patients.)

Orthostatic Hypotension

Orthostatic hypotension and associated adverse effects (e.g., postural dizziness, syncope, tachycardia) have been reported in patients receiving oral or IM aripiprazole and IM aripiprazole lauroxil, perhaps because of the drug's α₁-adrenergic blocking activity.^{[1][118][119]} The risk of orthostatic hypotension generally appears to be greatest during initiation of therapy and dosage titration.^[119] The drug should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy), as well as in patients who are antipsychotic naive.^[1][119] In such patients, the manufacturer of extended-release IM aripiprazole lauroxil states that use of a lower initial dosage of the drug and monitoring of vital signs should be considered.^[119]

Falls

Aripiprazole therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.^{[1][118][119][139]} For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.^{[1][118][119][139]}

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including aripiprazole.^{[1][102][103][118][119]} Agranulocytosis also has been reported.^{[1][118][119]}

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.^{[1][102][103][118][119]} Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.^[1] Aripiprazole should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.^{[1][118][119]}

Patients with clinically significant neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.^{[1][118][119]} In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), aripiprazole should be discontinued and the leukocyte count monitored until recovery occurs.^{[1][118][119]} Lithium has reportedly been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.^{[102][118][119]}

Seizures

As with other antipsychotic agents, aripiprazole may cause seizures.^[1] Seizures have occurred in 0.1% of adult and pediatric patients (6-18 years of age) treated with oral aripiprazole.^[1] Aripiprazole should be used with caution in patients with a history of seizures or other conditions that may lower the seizure threshold; conditions that lower the seizure threshold may be more prevalent in geriatric patients 65 years of age or older.^{[1][118][119]}

Cognitive and Motor Impairment

Like other antipsychotic agents, aripiprazole potentially may impair judgment, thinking, or motor skills.^{[1][118][119]} In short-term clinical trials, somnolence (including sedation) was reported in 11% of adults treated with oral aripiprazole compared with 6% of those receiving placebo.^[1] In pediatric patients 6-17 years of age, somnolence (including sedation) was reported in 24% of aripiprazole-treated patients compared with 6% of those receiving placebo.^[1] (See Advice to Patients.)

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.^{[1][118][119]} The manufacturers recommend appropriate caution when aripiprazole is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).^{[1][118][119]}

Suicide

Attendant risk with psychotic illnesses, bipolar disorder, and major depressive disorder; high-risk patients should be closely supervised.^[1] Aripiprazole should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.^[1] (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents, including aripiprazole.^{[1][118][119]} Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.^[1] Aripiprazole should be used with caution in patients at risk for aspiration pneumonia.^{[1][118][119]} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each aripiprazole 10- or 15-mg orally disintegrating tablet contains aspartame, which is metabolized in the GI tract to provide about 1.12 or 1.68 mg of phenylalanine, respectively, following oral administration.^{[1][80][81][82][83][84]} Aripiprazole conventional tablets and oral solution do not contain aspartame.^[1][145]

Skin Irritation associated with Abilify MyCite® Wearable Sensor

Symptoms of skin irritation (e.g., rash, pruritus, skin discoloration) may occur at the application site of the wearable sensor (MyCite^® patch).^[139][144] In clinical studies, 12.4% of the patients receiving aripiprazole tablets with sensor experienced rashes at the site of wearable sensor placement.^[139] If skin irritation occurs, the manufacturer states that the wearable sensor should be removed.^[139]

Specific Populations

Pregnancy

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.^{[1][106][107][108][118][119]} Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.^{[1][106][107][108][111][118][119]} Neonates exhibiting such symptoms should be monitored.^[108] The complications have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required intensive care unit support and prolonged hospitalization.^{[1][106][107][108][118][119]} For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/atypicalantipsychotic/.^{[1][118][119]}

Lactation

Aripiprazole is distributed into milk in humans.^{[1][111][118][119]} However, data are insufficient to determine the amount present in human milk, the effects of the drug on breast-fed infants, or the effects on milk production.^[118][119] Because of the potential for serious adverse reactions to aripiprazole in nursing infants, the manufacturer of aripiprazole tablets states that a decision should be made whether to discontinue nursing or the drug, taking into consideration the importance of the drug to the woman.^[1] The manufacturers of extended-release IM formulations of aripiprazole and aripiprazole lauroxil state that the benefit of aripiprazole therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant resulting from exposure to the drug or from the underlying maternal condition.^[118][119]

Pediatric Use

Safety and efficacy of aripiprazole tablets with sensor have not been established in pediatric patients.^[139]

Safety and efficacy of oral aripiprazole have not been established in pediatric patients with major depressive disorder.^[1]

Safety and efficacy of extended-release IM formulations of aripiprazole and aripiprazole lauroxil have not been evaluated in pediatric patients younger than 18 years of age.^[118][119]

Safety and efficacy of oral aripiprazole for the acute management of schizophrenia in pediatric patients 13-17 years of age have been established in a placebo-controlled study of 6 weeks' duration.^[1][91] Although the efficacy of oral aripiprazole for maintenance treatment of schizophrenia in pediatric patients has not been systematically evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.^[1] (See Schizophrenia under Uses: Psychotic Disorders.)

Safety and efficacy of oral aripiprazole monotherapy for the acute management of bipolar mania in pediatric patients 10-17 years of age have been established in a placebo-controlled study of 4 weeks' duration.^[1]

The efficacy of oral aripiprazole as an adjunct to lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar disorder in pediatric patients has not been systematically evaluated.^[1] However, efficacy can be extrapolated from adult data in addition to pharmacokinetic comparisons of aripiprazole between adult and pediatric populations.^[1]

Safety and efficacy of oral aripiprazole for the treatment of irritability associated with autistic disorder have been established in 2 placebo-controlled clinical trials of 8 weeks' duration in pediatric patients 6-17 years of age.^{[1][109][110]} Efficacy of the drug as maintenance therapy for irritability associated with autistic disorder was not established in a longer-term, placebo-controlled relapse prevention trial in pediatric patients 6-17 years of age.^[1][133]

Safety and efficacy of oral aripiprazole for the treatment of Tourette's syndrome have been established in one 8-week, placebo-controlled trial in pediatric patients 7-17 years of age and one 10-week, placebo-controlled trial in pediatric patients 6-18 years of age.^[1][124] Efficacy of the drug as maintenance therapy in pediatric patients with Tourette's syndrome has not been systematically evaluated.^[1] (See Uses: Tourette's Syndrome.)

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients 10-17 years of age are similar to those in adults after correcting for differences in body weight.^[1]

Mean weight gain of 1.6 kg was reported in pediatric patients with schizophrenia or bipolar disorder receiving oral aripiprazole compared with a gain of 0.3 kg in those receiving placebo in 2 short-term studies.^[1] After 24 weeks of therapy, the mean change from baseline in body weight in the aripiprazole-treated patients was 5.8 kg compared with 1.4 kg in placebo recipients.^[1] Similar gains in weight were observed in short-term studies in pediatric patients with irritability associated with autistic disorder and Tourette's syndrome.^[1]

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants).^[1][77] However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.^[79] No suicides occurred in these pediatric trials.^[1][77][79] These findings should be carefully considered when assessing potential benefits and risks of aripiprazole in a child or adolescent for any clinical use.^{[1][77][78][79]} (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

In clinical studies, approximately 8% of over 13,000 patients treated with oral aripiprazole were 65 years of age or older and approximately 6% were 75 years of age or older.^[1] Experience from placebo-controlled trials with oral aripiprazole in patients with schizophrenia, bipolar mania, or major depressive disorder who are 65 years of age and older is insufficient to determine whether they respond differently than younger adults.^[1]

The manufacturer of oral and extended-release IM formulations of aripiprazole states that dosage adjustment is not necessary in geriatric patients on the basis of age alone.^[1][118] The manufacturer of extended-release IM aripiprazole lauroxil states that the safety and efficacy of the drug have not been evaluated in patients older than 65 years of age and makes no specific dosage recommendations for geriatric patients.^[119]

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{[1][73][113][118][119]} In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with aripiprazole in placebo-controlled studies.^[1] Aripiprazole is not approved for the treatment of dementia-related psychosis.^[1] (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions and see also Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)^[1] For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.^[1][76][77] (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Pharmacogenomics and Poor CYP2D6 Metabolizers

Because higher concentrations of aripiprazole have been observed in poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 than in normal CYP2D6 metabolizers, dosage adjustment of the drug is recommended in patients known to be poor metabolizers of CYP2D6.^{[1][118][119]} Approximately 8% of Caucasians and 3-8% of Blacks/African Americans cannot metabolize CYP2D6 substrates and are classified as poor CYP2D6 metabolizers.^{[1][118][119]} (See Pharmacogenomics and Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 10% or more of adults receiving oral aripiprazole in clinical trials include nausea,^[1] vomiting,^[1] constipation,^[1] headache,^[1] dizziness,^[1] akathisia,^[1] anxiety,^[1] insomnia,^[1] and restlessness.^[1]

Adverse effects occurring in 10% or more of pediatric patients receiving oral aripiprazole in clinical trials include somnolence,^[1] headache,^[1] vomiting,^[1] extrapyramidal disorder,^[1] fatigue,^[1] increased appetite,^[1] insomnia,^[1] nausea,^[1] nasopharyngitis,^[1] and increased weight.^[1]

In clinical trials with aripiprazole tablets with sensor and other components of the digital ingestion tracking system (Abilify MyCite^®), skin rash localized at the application site of the wearable sensor (patch) was reported in 12.4% of patients.^[139] Other symptoms of skin irritation (e.g., pruritus, skin discoloration) have also been reported.^[144]

Adverse effects occurring in 5% or more of adults receiving extended-release IM aripiprazole injection (Abilify Maintena^®) for schizophrenia in clinical trials and at an incidence at least twice that for placebo include increased weight,^[118] akathisia,^[118] injection site pain,^[118] and sedation.^[118]

In patients receiving extended-release IM aripiprazole lauroxil injection (Aristada^®) in clinical trials, akathisia was the only adverse effect that occurred in 5% of more of patients and at an incidence at least twice that for placebo.^[119][122] Other extrapyramidal adverse effects (e.g., parkinsonism, dystonia) and injection site reactions (e.g., pain) were reported in 5-7% and 4-5% of patients in the clinical trials, respectively.^[119][122]

Drugs Affecting Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inducers (e.g., carbamazepine, rifampin), CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole), or CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine): Potential pharmacokinetic interaction (altered aripiprazole metabolism); dosage adjustment generally is recommended.^{[1][105][118]} (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration: Special Populations.)

Inhibitors or inducers of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1: Pharmacokinetic interaction is unlikely.^[1]

Ketoconazole and Other CYP3A4 Inhibitors

Concurrent oral administration of aripiprazole and ketoconazole, a potent CYP3A4 inhibitor, substantially increased peak serum concentrations and area under the plasma concentration-time curve (AUC) values of aripiprazole and its active metabolite, dehydro-aripiprazole.^[1] Concomitant use of aripiprazole with other potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) would also be expected to result in substantially increased systemic exposure to aripiprazole.^[1]

Except when used in the adjunctive treatment of major depressive disorder, dosage of oral aripiprazole should be reduced by 50% when used concurrently with potent CYP3A4 inhibitors.^[1] IM dosages of extended-release aripiprazole (Abilify Maintena^®) and aripiprazole lauroxil (Aristada^®) should be reduced when used concurrently with potent CYP3A4 inhibitors for longer than 14 days.^[118][119] When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the aripiprazole dosage should be increased.^[1] Use of the 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) should be avoided in patients receiving potent CYP3A4 inhibitors.^[147] (See Dosage and Administration: Special Populations.)

Quinidine and Other CYP2D6 Inhibitors

Concurrent oral administration of aripiprazole and quinidine, a potent CYP2D6 inhibitor, substantially increased the AUC of aripiprazole but decreased the AUC of its active metabolite, dehydro-aripiprazole.^[1] Concomitant use of aripiprazole with other potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) would also be expected to result in substantially increased systemic exposure to aripiprazole.^[1]

Except when used in the adjunctive treatment of major depressive disorder, dosage of oral aripiprazole should be reduced by 50% when used concurrently with potent CYP2D6 inhibitors.^[1] IM dosages of extended-release aripiprazole (Abilify Maintena^®) and aripiprazole lauroxil (Aristada^®) should be reduced when used concurrently with potent CYP2D6 inhibitors for longer than 14 days.^[118][119] When the potent CYP2D6 inhibitor is withdrawn from combined therapy, the aripiprazole dosage should be increased.^[1] Use of the 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) should be avoided in patients receiving potent CYP2D6 inhibitors.^[147] (See Dosage and Administration: Special Populations.)

Carbamazepine and Other CYP3A4 Inducers

Concurrent administration of aripiprazole and carbamazepine, a potent CYP3A4 inducer, substantially decreased peak plasma concentrations and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole.^{[1][105][118][119]} Concomitant use of aripiprazole with other potent CYP3A4 inducers (e.g., rifampin) may result in substantially decreased systemic exposure to aripiprazole.^[1]

Oral aripiprazole dosage should be doubled over 1-2 weeks of concurrent use with potent CYP3A4 inducers.^[1] Concurrent use of CYP3A4 inducers and extended-release aripiprazole injection (Abilify Maintena^®) should be avoided since aripiprazole concentrations may fall below therapeutic concentrations.^[118] The 441-mg dose of extended-release aripiprazole lauroxil (Aristada^®) should be increased to 662 mg when used concurrently with potent CYP3A4 inducers for longer than 2 weeks; dosage adjustment is not required in patients receiving 662-, 882-, or 1064-mg doses of the drug.^[119] When the potent CYP3A4 inducer is withdrawn from combined therapy, the aripiprazole dosage should be reduced to the original dosage over 1-2 weeks.^[1] Use of the 675-mg strength of extended-release aripiprazole lauroxil injection (Aristada Initio^®) should be avoided in patients receiving potent CYP3A4 inducers.^[147] (See Dosage and Administration: Special Populations.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 2C9, 2C19, 2D6, and 3A4: Clinically important pharmacokinetic interaction is unlikely; dosage adjustment is not necessary.^{[1][118][119]}

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); aripiprazole should be used with caution in patients concurrently receiving drugs with anticholinergic activity.^{[1][118][119]} (See Body Temperature Regulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hypotensive Agents

Potential pharmacologic interaction (additive hypotensive effects due to α-adrenergic antagonism); aripiprazole should be used with caution in patients receiving hypotensive agents.^{[1][118][119][139]} During concomitant use, blood pressure should be monitored and antihypertensive dosage(s) adjusted accordingly.^{[1][118][119][139]}

Lorazepam and Other Benzodiazepines

Clinically important pharmacokinetic changes have not been reported during concurrent administration of lorazepam and aripiprazole.^{[1][118][119]} The manufacturers state that routine dosage adjustment of aripiprazole or lorazepam is not necessary when the drugs are concurrently administered.^[1][118] However, increased sedative and orthostatic hypotensive effects have been reported in patients receiving these drugs in combination.^{[1][118][119]} If aripiprazole therapy in conjunction with a benzodiazepine is considered necessary, the patient should be carefully monitored for excessive sedation and orthostatic hypotension and dosage of the drug(s) adjusted, if necessary.^{[1][118][119]} (See Orthostatic Hypotension and see also Cognitive and Motor Impairment under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Alcohol

Concomitant administration of ethanol and oral aripiprazole in healthy individuals did not have clinically important effects on gross motor skills or stimulus response compared with administration of ethanol with placebo.^[118] The manufacturer of the extended-release IM formulation of aripiprazole (Abilify Maintena^®) states that alcohol should be avoided during therapy.^[118] The manufacturers of other commercially available formulations of aripiprazole and aripiprazole lauroxil do not provide specific recommendations concerning alcohol use in the prescribing information for the drugs.^[1][119]

Dextromethorphan

Clinically important pharmacokinetic interaction is unlikely.^{[1][118][119]} Dosage adjustment of dextromethorphan (a CYP2D6 and CYP3A4 substrate) is not necessary when administered concomitantly with aripiprazole.^{[1][118][119][139]}

Escitalopram

Concurrent administration of aripiprazole 10 mg orally daily for 14 days in healthy individuals did not substantially alter the steady-state pharmacokinetics of 10 mg daily of escitalopram, a CYP2C19 and CYP3A4 substrate.^[1][104] Dosage adjustment of escitalopram is not necessary when administered concurrently with aripiprazole.^[1]

Famotidine

Concomitant use of aripiprazole and famotidine may result in decreased peak plasma concentrations and systemic exposure of aripiprazole and its active metabolite, dehydro-aripiprazole; however, a clinically important pharmacokinetic interaction between the drugs appears unlikely.^[1][139] No dosage adjustment of aripiprazole is necessary when administered concurrently with famotidine.^[1][139]

Fluoxetine, Paroxetine, and Sertraline

A population pharmacokinetic analysis in patients with major depressive disorder did not demonstrate substantial changes in the pharmacokinetics of fluoxetine, paroxetine, or sertraline (dosed to steady state) following the addition of aripiprazole therapy.^{[1][104][118][119]} Therefore, dosage adjustment of fluoxetine, paroxetine, and sertraline is not necessary in patients concomitantly receiving aripiprazole therapy.^{[1][118][119]}

However, fluoxetine and paroxetine are potent inhibitors of CYP2D6 and the manufacturer recommends that oral aripiprazole dosage be reduced to one-half the usual dosage in patients receiving concomitant therapy with potent inhibitors of CYP2D6, including fluoxetine and paroxetine.^[1] When fluoxetine or paroxetine is withdrawn from combined therapy with aripiprazole, the aripiprazole dosage should be increased back to the original dosage.^[1] When adjunctive aripiprazole is concurrently administered to patients with major depressive disorder receiving fluoxetine or paroxetine, aripiprazole should be given without dosage adjustment.^[1] (See Dosage and Administration: Special Populations.)

Lamotrigine

Combined aripiprazole and lamotrigine therapy appears to be well tolerated in patients with bipolar disorder.^[92] Pharmacokinetic interaction is unlikely; no dosage adjustment of lamotrigine is necessary when aripiprazole is administered concurrently.^[1][92]

Lithium

Clinically important pharmacokinetic interaction is unlikely; no dosage adjustment of aripiprazole or lithium is necessary during concurrent administration.^[1]

Omeprazole

Clinically important pharmacokinetic interaction is unlikely; dosage adjustment of omeprazole is not necessary when administered concurrently with aripiprazole.^[1]

Valproate

Clinically important pharmacokinetic interaction is unlikely; no dosage adjustment of aripiprazole or valproate is necessary during concurrent administration.^[1]

Venlafaxine

Concurrent administration of oral aripiprazole (10-20 mg daily for 14 days) in healthy individuals did not substantially alter the steady-state pharmacokinetics of venlafaxine and O-desmethylvenlafaxine following 75 mg daily of extended-release venlafaxine, a CYP2D6 substrate.^[1][104] Dosage adjustment of venlafaxine is not necessary during concurrent use of aripiprazole.^[1]

Warfarin

Concurrent administration of aripiprazole did not substantially affect warfarin pharmacokinetics, suggesting a lack of a clinically important effect of aripiprazole on CYP2C9 and CYP2C19 metabolism.^[1] Warfarin dosage adjustment is not necessary when administered concurrently with aripiprazole.^[1]

Aripiprazole is a quinolinone derivative^[2][5] antipsychotic agent that differs chemically from other currently available antipsychotic agents (e.g., butyrophenones, phenothiazines)^{[2][3][4][5][6][7]} and has been referred to as an atypical or second-generation antipsychotic agent.^{[1][2][7][28][89][98]} The exact mechanism of action of aripiprazole in schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, Tourette's syndrome, and agitation associated with schizophrenia or bipolar mania has not been fully elucidated but, like that of other drugs with efficacy in these conditions (e.g., olanzapine, risperidone, ziprasidone), may involve the drug's activity at dopamine D₂ and serotonin type 1 (5-HT_1A) and type 2 (5-HT_2A) receptors.^{[1][2][3][4][5][6][7]} However, aripiprazole appears to differ from other atypical antipsychotic agents because the drug demonstrates partial agonist activity at D₂ and 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors.^{[1][2][3][4][5][6][7][89]} Antagonism at other receptors (e.g., α₁-adrenergic receptors, histamine H₁ receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence) observed with aripiprazole.^[1][89]

Aripiprazole is well absorbed following oral administration; peak plasma concentrations following oral administration of conventional tablets occur within 3-5 hours.^[1] Administration with a high-fat meal does not affect peak plasma concentration or systemic exposure of aripiprazole or dehydro-aripiprazole.^[1] Absolute oral bioavailability of conventional tablets is 87%.^[1] Following administration of the oral solution, plasma aripiprazole concentrations are higher than those after administration of equivalent dosages of the conventional tablets.^[1] Steady-state plasma concentrations of both aripiprazole and dehydro-aripiprazole are achieved within 14 days with oral administration.^[1] Aripiprazole is extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by the cytochrome P-450 (CYP) 2D6 and 3A4 isoenzymes.^[1] The major active metabolite of aripiprazole, dehydro-aripiprazole, exhibits affinity for D₂ receptors similar to that of the parent compound and represents approximately 40% of aripiprazole area under the concentration-time curve (AUC) in plasma.^[1] Poor CYP2D6 metabolizers have substantially increased aripiprazole and dehydro-aripiprazole exposures compared with extensive metabolizers (see Dosage and Administration: Special Populations).^[1] Approximately 18% of an orally administered dose of aripiprazole is excreted unchanged in feces and less than 1% is excreted unchanged in urine.^[1]

Following IM administration of immediate-release aripiprazole injection (no longer commercially available in the US), peak plasma concentrations were achieved within 1-3 hours and were an average of 19% higher than those achieved following oral administration of conventional tablets.^[1] Systemic exposure is similar following IM and oral administration of aripiprazole; however, in the first 2 hours after administration, AUC was 90% higher following IM administration of the injection compared with oral administration of the conventional tablets.^[1]

Following IM administration of extended-release aripiprazole (Abilify Maintena^®), the low solubility of aripiprazole particles results in prolonged aripiprazole absorption.^[1] Following multiple IM doses, peak plasma aripiprazole concentrations occur after a median of 4 or 5-7 days when administered into the deltoid or gluteal muscle, respectively.^[118] Single IM injections into the deltoid result in 31% higher peak plasma concentrations compared with the gluteal site; however, aripiprazole systemic exposures and peak plasma concentrations at steady state were similar for both injection sites.^[118] Dose-proportional increases in aripiprazole and dehydro-aripiprazole systemic exposures were observed following extended-release aripiprazole IM doses of 300 or 400 mg given every 4 weeks.^[118] Steady-state plasma concentrations of aripiprazole are achieved by the fourth dose of extended-release aripiprazole for both sites of administration.^[118] Following gluteal administration of multiple 300- or 400-mg doses of extended-release aripiprazole every 4 weeks, the mean terminal half-life of aripiprazole is 29.9 or 46.5 days, respectively.^[118]

Aripiprazole lauroxil is a prodrug of aripiprazole.^[119] Following IM injection, aripiprazole lauroxil is probably converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole.^[119] Following IM administration of extended-release aripiprazole lauroxil (Aristada^®), aripiprazole begins to appear in the systemic circulation in 5-6 days and is continually released for an additional 36 days.^[119] Plasma concentrations of aripiprazole increase with consecutive doses and reach steady-state concentrations following the fourth monthly injection.^[119] When administered with oral aripiprazole for 21 days following the first injection, therapeutic plasma concentrations of aripiprazole are achieved within 4 days.^[119] IM injection of extended-release aripiprazole lauroxil (441 mg) into the deltoid and gluteal areas results in similar systemic exposure; therefore, these injection sites are considered interchangeable.^[119] In addition, IM administration of aripiprazole lauroxil 882 mg every 6 weeks or 1064 mg every 2 months results in plasma aripiprazole concentrations that are within the established therapeutic range for dosages of 441 and 882 mg once monthly.^[119] The mean terminal half-life of aripiprazole ranges from about 54-57 days following monthly, every 6 week, or every 2 month injections of extended-release aripiprazole lauroxil.^[119]

Aripiprazole Tablets with Sensor

Aripiprazole is available as part of a digital ingestion tracking system comprised of the following components: aripiprazole tablets embedded with an ingestible event marker sensor (IEM; Abilify MyCite^®); a wearable sensor (MyCite^® patch), which detects the signal from the IEM sensor after ingestion and transmits data to a compatible mobile device (i.e., a smart phone); a software application (app) for compatible mobile devices (e.g., smart phones; MyCite^® App), which displays information for the patient; and a web-based portal for healthcare professionals and caregivers.^[139]

Following oral administration of aripiprazole tablets with sensor, magnesium and cuprous chloride within the sensor react with gastric fluid to activate and power the sensor.^[139] Once activated, the ingestible sensor communicates with the wearable sensor within a 9-foot proximity using Bluetooth^® technology.^[139] The wearable sensor records the date and time of ingestions and transmits the data to the mobile software application.^[139][142] The mobile software application records and displays ingestion data for patients to review;^[139] subjective data such as activity level, mood, and quality of rest also may be reported to the software application.^[142] Healthcare professionals, caregivers, and/or family members may access ingestion data shared by the patient through a web-based portal or dashboard.^[139][142] The manufacturer states that this access is granted by the patient and may be withdrawn by the patient at any time.^[142]

Most ingestions of aripiprazole tablets with sensor are detected within 30 minutes of oral administration; however, it may take up to 2 hours for the mobile device and web portal to detect ingestion of the sensor and, in some cases, the ingestion may not be detected at all.^[139] In a study to assess accuracy and latency of post-ingestion detection of the ingestible sensor in 29 healthy individuals, a wearable sensor was placed and paired with a mobile device provided and monitored by investigators.^[143] Placebo tablets with embedded ingestible sensors were then administered under observation every 2 hours for 4 doses without regard to food.^[143] The overall ingestion detection rate was 96.6%; approximately 90% of ingestions were detected by the mobile software application within 30 minutes of ingestion.^[143] Mean time from ingestion to detection by the wearable sensor was 1.1-1.3 minutes and from detection by the wearable sensor to detection on the cloud-based server was 6.2-10.3 minutes.^[143]

Importance of providing copy of written patient information (medication guide) each time aripiprazole is dispensed.^{[1][76][77][78][118][119][139][147]} Importance of advising patients to read the patient information before taking aripiprazole and each time the prescription is refilled.^{[1][76][118][119][139][147]}

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{[1][28][73][98][113][118][119][139][147]} Patients and caregivers also should be informed that aripiprazole is not approved for treating geriatric patients with dementia-related psychosis.^{[1][73][98][118][119][139][147]}

Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, manic or hypomanic symptoms, irritability, agitation, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.^{[1][76][77][78][139]} (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Because somnolence and impairment of judgment, thinking, or motor skills may be associated with aripiprazole, avoid driving, operating machinery, or performing hazardous tasks while taking aripiprazole until the drug's effects on the individual are known.^{[1][118][119][139][147]}

Importance of avoiding alcohol during extended-release IM aripiprazole (Abilify Maintena^®) therapy.^[118]

Importance of informing patients and caregivers about the risk of neuroleptic malignant syndrome (NMS); importance of immediately contacting clinician or seeking emergency medical attention if signs and symptoms of this rare but potentially life-threatening syndrome develop (e.g., high fever, muscle stiffness, sweating, fast or irregular heart beat, change in blood pressure, confusion, kidney damage).^{[1][118][119][139][147]}

Importance of clinicians informing patients in whom chronic aripiprazole use is contemplated of risk of tardive dyskinesia.^{[1][98][118][119][139][147]} Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.^{[98][118][119][139][147]}

Risk of leukopenia, neutropenia, and agranulocytosis.^{[1][118][119][139][147]} Importance of advising patients with a preexisting low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their complete blood cell (CBC) count monitored during aripiprazole therapy.^{[1][118][119][139][147]}

Importance of informing patients about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain), how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight, for such changes during therapy.^{[1][118][119][139][147]}

Risk of pathological gambling and other compulsive behaviors.^{[1][118][119][123][139][147]} Importance of advising patients and caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating, and/or other compulsive urges and the inability to control these urges during aripiprazole therapy.^{[1][118][119][123][139][147]} In some cases, but not all, the urges reportedly stopped when the dosage was reduced or the drug was discontinued.^{[1][118][119][123][139][147]} Importance of advising patients or their caregivers to contact a clinician promptly if they experience any such urges that seem out of the ordinary; importance of also advising patients not to abruptly stop taking aripiprazole without first consulting their clinician.^[123]

Importance of informing patients about the risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.^{[1][118][119][139][147]}

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular or cerebrovascular disease, diabetes mellitus, seizures).^{[1][118][119][139][147]}

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{[1][108][119][139][147]} Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy, including that third trimester use of aripiprazole may cause extrapyramidal and/or withdrawal symptoms in a neonate, and about the pregnancy exposure registry (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).^{[1][108][119][139][147]} Importance of advising patients not to stop taking aripiprazole if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.^[108] Importance of advising patients that aripiprazole can pass into breast milk and to consult with their clinician about the best way to feed their infant during aripiprazole therapy.^{[1][119][139][147]}

Importance of avoiding overheating or dehydration.^{[1][118][119][139][147]}

For patients taking aripiprazole orally disintegrating tablets, importance of not removing a tablet from the blister package until just before administering a dose; importance of peeling blister open with dry hands and placing tablet on tongue to dissolve and be swallowed with saliva.^[1]

Importance of informing patients with phenylketonuria that aripiprazole orally disintegrating 10- and 15-mg tablets (Abilify Discmelt^®) contain 1.12 and 1.68 mg of phenylalanine, respectively.^[1]

Importance of informing patients of other important precautionary information.^{[1][118][119][139][147]} (See Cautions.)

Aripiprazole Tablets with Sensor

Importance of instructing patients to download the MyCite^® App prior to initial use of aripiprazole tablets with sensor and ensure that the software is compatible with their mobile device (i.e., smart phone).^[139] Patients should refer to the information provided by the manufacturer and within the MyCite^® App for instructions regarding applying and changing the wearable sensor (i.e., MyCite^® patch) and pairing the wearable sensor to their mobile device.^[139] Importance of advising patients that initial use of the MyCite^® system should be facilitated by a healthcare professional.^[139]

Importance of advising patients that most ingestions of the tablets with sensor will be detected within 30 minutes; however, it may sometimes take over 2 hours for the mobile device and web portal to detect the ingestion of the tablet with sensor, and, in some cases, ingestion may not be detected at all.^[139] Importance of advising patients not to repeat a dose if the tablet with sensor is not detected after ingestion.^[139]

Importance of advising patients that if their mobile device is lost, impaired, or otherwise rendered unusable, patients should change the wearable sensor immediately and connect to a new mobile device using their current account information.^[139] Inform patients that some data collected by the system may be lost; however, data that have been previously synchronized to the patient's account will be available.^[139]

Importance of informing patients that in order for the wearable sensor to communicate with the mobile device, the device must be powered on and Bluetooth^®-enabled.^[139] Importance of advising patients that the wearable sensor will communicate with a paired device when it is within a 9-foot proximity.^[139] Advise patients to keep the wearable sensor in place while showering, swimming, or exercising since it is intended to tolerate exposure to water and perspiration.^[139] However, the wearable sensor should be removed before magnetic resonance imaging (MRI) and replaced with a new wearable sensor as soon as possible following the MRI.^[139] Importance of advising patients to remove the wearable sensor if skin irritation occurs.^[139] (See Tablets with Sensor under Administration: Oral Administration, in Dosage and Administration.)

Importance of instructing patients to swallow aripiprazole tablets with sensor whole.^[139] Do not divide, crush, or chew the tablets.^[139]

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

\* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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