aripiprazole 20 mg tablet generic abilify

Uses

Aripiprazole is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Aripiprazole also is used orally for the treatment of manic and mixed episodes associated with bipolar I disorder, as an adjunct to antidepressants for the acute treatment of major depressive disorder, for the acute treatment of irritability associated with autistic disorder, and for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome). Short-acting (immediate-release) aripiprazole injection (Abilify) is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia. Extended-release IM preparations of aripiprazole (Abilify Maintena) and aripiprazole lauroxil (Aristada) are used for the treatment of schizophrenia.

Psychotic Disorders

Aripiprazole is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia). 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. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. 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.

Schizophrenia

Aripiprazole is used orally for the acute and maintenance treatment of schizophrenia. In addition, extended-release formulations of aripiprazole (Abilify Maintena) and aripiprazole lauroxil (Aristada) are used IM for the treatment of schizophrenia. 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. 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. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. 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). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

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. Four of the 5 studies were able to distinguish aripiprazole from placebo, but the smallest study did not. 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. 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. 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. 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. An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.

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. Relapse was based on results of the CGI-Improvement and PANSS psychiatric rating scales. Patients receiving aripiprazole experienced a significantly longer time to relapse over the subsequent 26 weeks compared with those receiving placebo. 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.

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. Patients were randomized to receive a fixed dosage of aripiprazole 10 mg daily or 30 mg daily or to receive placebo. 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. However, the 30-mg daily dosage failed to demonstrate superiority over the 10-mg daily dosage. The drug was generally well tolerated.

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. Patients in this study were randomized to receive IM injections of extended-release aripiprazole (400 mg) or placebo every 4 weeks. 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. 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. The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 10). Patients treated with extended-release IM aripiprazole injection demonstrated substantially greater improvement in mean PANSS total scores compared with those receiving placebo.

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. 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. 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. 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.

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. 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. Patients were randomized to receive extended-release aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo by IM injection every 4 weeks. 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. The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 12). 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. 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. The secondary efficacy end point was the Clinical Global Impression-Improvement (CGI-I) score on day 85. Both groups of patients receiving extended-release aripiprazole lauroxil therapy demonstrated substantially better CGI-I scores compared with the placebo group. 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.

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.

If aripiprazole is used for extended periods as maintenance therapy for schizophrenia, the need for continued therapy should be reassessed periodically. (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. 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. 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. 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.

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. 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).

Efficacy of 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. These studies included patients with or without psychotic features and 2 of the studies also included patients with or without a rapid cycling course. 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). The main secondary rating instrument used in these trials was the Clinical Global Impression-Bipolar (CGI-BP) scale. 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). 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.

Aripiprazole is used 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. 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. Patients in this study received aripiprazole 10 mg daily, aripiprazole 30 mg daily, or placebo. 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. 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.

Efficacy of 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). 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. 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. 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.

The use of 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. 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.

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. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.

Aripiprazole has been used as monotherapy and adjunctive therapy in the maintenance treatment of bipolar I disorder. However, efficacy results from controlled, long-term studies conducted to date have not been compelling, particularly with regard to delaying time to relapse to depressive episodes compared with placebo, and maintenance treatment of bipolar disorder is no longer included as a labeled indication in the prescribing information for oral aripiprazole in the US.

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. 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. There were no differences between aripiprazole and placebo in time to relapse to depressive or mixed episodes or in the number of depressive episodes. 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; 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). Time to relapse to depressive episode was not substantially different between treatment groups during the 74-week extension phase.

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. 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. 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. 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, particularly for relapse to manic episode; no difference between the treatment groups was observed for time to relapse to depressive episode.

Major Depressive Disorder

Aripiprazole is used orally as an adjunct to antidepressants for the acute treatment of major depressive disorder. 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. The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. 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). 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. 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. 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.

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

Irritability Associated with Autistic Disorder

Aripiprazole is used orally for the acute treatment of irritability associated with autistic disorder. 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. Over 75% of the enrolled patients were under 13 years of age. The primary instruments used for assessing clinical efficacy were the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to end point in the irritability subscale of the ABC (ABC-I). 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. In this trial, aripiprazole improved scores on both the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dosage of aripiprazole at the end of the 8-week treatment period was approximately 9 mg daily. 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. Aripiprazole therapy was started at 2 mg daily and was increased to 5 mg daily after 1 week. 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. Patients receiving all 3 aripiprazole dosages in this study demonstrated improved ABC-I subscale and CGI-I scores compared with placebo.

Tourette's Syndrome

Aripiprazole is used orally for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome). 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). The YGTSS is a fully validated scale that measures current tic severity. The primary outcome measure in both trials was the change from baseline to end point in the TTS on the YGTSS (YGTSS TTS). Over 65% of the enrolled patients were under 13 years of age.

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. 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. 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.

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. The aripiprazole-treated patients in this study demonstrated substantially improved scores on the YGTSS TTS compared with patients receiving placebo. The mean daily dosage of aripiprazole at the end of the 10-week treatment period was approximately 6.5 mg daily.

Agitation Associated with Schizophrenia or Bipolar Mania

Aripiprazole is 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).

The efficacy of IM aripiprazole for the management of acute agitation was established in 3 short-term (i.e., single-day), placebo-controlled trials in hospitalized, agitated patients with either schizophrenia or bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the 3 trials used a single active comparator treatment of either haloperidol injection (for the schizophrenia studies) or lorazepam (for the bipolar mania study). Patients enrolled in the studies needed to be judged by the investigators as clinically agitated and appropriate candidates for IM therapy. In addition, the patients needed to exhibit a level of agitation that met or exceeded a threshold score of 15 on the 5 items constituting the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least 2 individual item scores of 4 (''moderate'') or greater using a 1-7 scoring system, where scores of 1 or 7 indicate absent or extreme agitation, respectively. The primary measure used for assessing efficacy in managing agitation in these trials was the change from baseline in the PANSS Excited Component at 2 hours postinjection. A key secondary measure was the Clinical Global Impression-Improvement (CGI-I) scale. Patients could receive up to 3 injections of IM aripiprazole; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed.

In the first placebo-controlled trial, IM aripiprazole was given in fixed single doses of 1, 5.25, 9.75, or 15 mg in agitated hospitalized patients presenting predominantly with schizophrenia. All IM aripiprazole doses, with the exception of the 1-mg dose, were found to be superior to placebo in reducing the PANSS Excited Component score and on the CGI-I scale at 2 hours following injection in this study. In the second placebo-controlled trial in agitated hospitalized patients predominantly with schizophrenia, one fixed IM dose of aripiprazole 9.75 mg was evaluated and found to be superior to placebo on the PANSS Excited Component and on the CGI-I scale at 2 hours following injection. In the third placebo-controlled trial in agitated hospitalized patients with bipolar I disorder (manic or mixed), 2 fixed aripiprazole injection doses of 9.75 mg and 15 mg were evaluated; both doses were found to be superior to placebo in reducing the PANSS Excited Component score at 2 hours postinjection. An analysis of these 3 controlled studies for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.

Dosage and Administration

Administration

Aripiprazole is administered orally or by IM injection. Aripiprazole lauroxil is administered only by IM injection.

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.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Oral Administration

Aripiprazole conventional tablets, orally disintegrating tablets, and oral solution are administered orally once daily without regard to meals.

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

IM Administration

Clinicians should be aware that there are 3 different IM formulations of aripiprazole with different indications, dosages, and dosing frequencies.The short-acting, immediate-release IM formulation of aripiprazole (e.g., Abilify®; 9.75 mg per vial) is used for agitation associated with schizophrenia and bipolar maniaand should not be confused with or substituted for the extended-release IM formulation of aripiprazole (Abilify Maintena®; available in 300- and 400-mg vials and prefilled syringes) or aripiprazole lauroxil (Aristada®; available in 441-, 662-, and 882-mg prefilled syringes) used for the treatment of schizophrenia.

Immediate- and extended-release aripiprazole injection and extended-release aripiprazole lauroxil injection are administered only by IM injection by a healthcare professional. Extended-release aripiprazole and aripiprazole lauroxil injections are administered monthly; extended-release aripiprazole lauroxil injection 882 mg also may be administered every 6 weeks.

The manufacturers state that tolerability with oral aripiprazole therapy should be established prior to initiating IM therapy with the extended-release formulations of aripiprazole (Abilify Maintena) or aripiprazole lauroxil (Aristada).

Short-acting Aripiprazole Injection

Aripiprazole injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The required volume of injection should be withdrawn from the vial into a syringe and then injected slowly IM, deep into the muscle mass. Aripiprazole injection should not be administered IV or subcutaneously. Unused portions of the solution should be discarded.

Extended-release Aripiprazole Injection

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

Aripiprazole extended-release IM injection must be reconstituted with sterile water for injection prior to administration. 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). 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). 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. Kits containing single-use vials should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C. 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.

Following reconstitution, the prefilled syringe or vial should be shaken vigorously for 20 or 30 seconds, respectively, to ensure a uniform suspension. 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. If using vials, the appropriate dose of aripiprazole should be drawn from the vial into the syringe supplied by the manufacturer and injected immediately. 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. 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.

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. Injection sites should be rotated between the 2 deltoid or gluteal muscles. Following IM administration, the injection site should not be massaged.

Extended-release Aripiprazole Lauroxil Injection

Extended-release aripiprazole lauroxil injectable suspension (Aristada) is administered by IM injection monthly into the deltoid (441-mg dose only) or gluteal muscle (441-, 662-, or 882-mg doses). The 882-mg dose also may be administered every 6 weeks by IM injection into the gluteal muscle. The manufacturer states that if a dose is given earlier than the scheduled time, at least 14 days should elapse between doses. Each injection should be administered only by IM injection by a healthcare professional.

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

The entire contents of the syringe should be administered rapidly and continuously (i.e., within 10 seconds) by deep IM injection into either the deltoid (441-mg dose only) or gluteal muscle using the appropriate length needle supplied by the manufacturer. 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.

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. 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. The dosage of oral aripiprazole supplementation should be the same as when the patient started receiving aripiprazole lauroxil injection.(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. 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.

Since conventional tablets and orally disintegrating tablets of aripiprazole are bioequivalent, dosing for the orally disintegrating tablets is the same as for the conventional tablets. However, IM administration of a dose of the commercially available immediate-release injection results in maximum plasma aripiprazole concentrations and areas under the plasma concentration-time curve (AUCs) (2 hours post-administration) that are about 19 and 90% higher, respectively, than those resulting from an identical oral dose.

Dosage of aripiprazole lauroxil is expressed in terms of aripiprazole lauroxil.

Extended-release aripiprazole lauroxil (Aristada) dosages of 441, 662, or 882 mg IM once monthly correspond to extended-release aripiprazole (Abilify Maintena) dosages of 300, 450, or 600 mg IM once monthly, respectively.

Schizophrenia

Oral Dosage

For the acute management of schizophrenia in adults, the recommended initial and target dosage of aripiprazole is 10 or 15 mg orally once daily. Although dosages ranging from 10-30 mg daily administered as conventional tablets were effective in clinical trials, the manufacturer states that dosages exceeding 10-15 mg daily did not result in greater efficacy. 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.

For the acute management of schizophrenia in adolescents 13-17 years of age, the recommended target dosage of aripiprazole is 10 mg orally once daily. 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 10 mg once daily after 2 additional days. The manufacturer recommends that any subsequent dosage increases be made in 5-mg, once-daily increments. 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.

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. 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.

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.

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. 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. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

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

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. 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. In all patients, the period of overlapping antipsychotic administration should be minimized.

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). Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

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). In patients experiencing adverse effects, a reduction in dosage to 300 mg every month may be considered.

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.

If a dose of extended-release aripiprazole injection is missed, the next dose should be administered as soon as possible. Supplementation with oral aripiprazole may be required depending on the time elapsed. 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. 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.

IM Dosage of Aripiprazole Lauroxil

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). Because of the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

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 or 882 mg every 6 weeks by IM injection. Oral aripiprazole should be administered with the first IM injection of aripiprazole lauroxil and continued for 21 days.

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

For patients established on oral aripiprazole 15 mg daily, the recommended IM dosage of extended-release aripiprazole lauroxil is 662 mg every month.

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.

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.

If a dose of aripiprazole lauroxil injection is missed, the next dose should be administered as soon as possible. Supplementation with oral aripiprazole may be required depending on the dosage and the time elapsed.

Bipolar Disorder

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

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. The recommended dosage when aripiprazole is given as adjunctive therapy with lithium or valproate is the same as that for monotherapy. Subsequent increases in the daily dosage of aripiprazole, if necessary, should be made in 5-mg increments.

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. Subsequent dosage adjustments of up to 5 mg daily should occur gradually at intervals of at least 1 week; the recommended dosage is 5-10 mg once daily, and the maximum recommended dosage is 15 mg daily. Efficacy of the drug was established within a dosage range of 2-15 mg daily in clinical studies.

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

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. 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. Dosage increases should be gradual, at intervals of at least 1 week.

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

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.

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. In patients who do not achieve optimal control of tics, the dosage may be increased to 10 mg once daily. Dosage adjustments should be made gradually at intervals of at least 1 week.

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. In patients who do not achieve optimal control of tics, the dosage may be increased up to 20 mg once daily. Dosage adjustments should be made gradually in increments of 5 mg daily at intervals of at least 1 week.

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

Agitation Associated with Schizophrenia or Bipolar Mania

For the prompt control of agitation associated with schizophrenia or bipolar mania in adults, the recommended dose of aripiprazole is 9.75 mg given IM as a single dose. In clinical trials, effectiveness of IM aripiprazole in controlling agitation in schizophrenia and bipolar mania was demonstrated with doses of 5.25-15 mg IM; however, no additional benefit was demonstrated for the 15-mg dose compared with the 9.75-mg dose. A lower initial IM dose of 5.25 mg may be considered when clinically warranted.

If agitation persists following the initial dose of aripiprazole, subsequent doses up to a cumulative dose of 30 mg daily may be given. However, the manufacturer states that the efficacy of repeated doses of IM aripiprazole in agitated patients has not been systematically evaluated in controlled trials. In addition, the safety of total daily IM doses exceeding 30 mg or IM injections given more frequently than every 2 hours has not been adequately evaluated in clinical trials.

If continued aripiprazole therapy is clinically necessary, oral aripiprazole therapy in a dosage of 10-30 mg daily should replace IM therapy as soon as possible.

Special Populations

No dosage adjustment is necessary in patients with renal or hepatic impairment or in geriatric patients. In addition, no dosage adjustment is recommended based on gender, race, or smoking status.

Poor CYP2D6 Metabolizers

Patients who are known poor metabolizers of cytochrome P-450 isoenzyme 2D6 (CYP2D6) should receive one-half (50%) of the usual oral aripiprazole dosage. Such patients who are also taking a potent CYP3A4 inhibitor should receive 25% of the usual oral aripiprazole dosage.(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.

The manufacturer of aripiprazole extended-release injection (Abilify Maintena) recommends a dosage of 300 mg every month in patients who are poor CYP2D6 metabolizers. 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.

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. 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. If the potent CYP3A4 inhibitor is used for less than 2 weeks, this dosage adjustment is not necessary. No further dosage adjustment is necessary in patients who are poor CYP2D6 metabolizers receiving a concomitant potent CYP2D6 inhibitor.

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. Dosage adjustment is not necessary when oral aripiprazole is used as adjunctive treatment of major depressive disorder.

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. 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. A dosage of 882 mg every 6 weeks should be reduced to 441 mg every 4 weeks. 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.

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. Dosage adjustment is not necessary when oral aripiprazole is used as adjunctive treatment of major depressive disorder.

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. 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 taking the 662- or 882-mg dosage of extended-release aripiprazole lauroxil injection. If such therapy is used for less than 14 days, dosage adjustment of extended-release aripiprazole or aripiprazole lauroxil injection is not necessary.

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). The oral aripiprazole dosage may then be adjusted based on clinical response.(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.

In patients receiving potent CYP3A4 inducers (e.g., carbamazepine, rifampin), dosage of oral aripiprazole should be doubled over 1-2 weeks of concomitant therapy. When the CYP3A4 inducer is discontinued, the dosage should be reduced back to the original dosage over 1-2 weeks.(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). 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 or 882 mg every month. If a potent CYP3A4 inducer is used for less than 2 weeks, dosage adjustment is not necessary.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Cautions

Contraindications

Known hypersensitivity to aripiprazole; hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis.(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. 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. 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. 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. 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.

The manufacturers state that aripiprazole is not approved for the treatment of patients with dementia-related psychosis. 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. (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. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. 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. 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. 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.

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. 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.

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. 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. 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.

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. 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).

Aripiprazole is not approved for use in treating depression in the pediatric population.(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.(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). A statistically significant dose-response relationship for adverse cerebrovascular events was observed in patients receiving oral aripiprazole in the fixed-dose study. The manufacturers state that aripiprazole is not approved for the treatment of patients with dementia-related psychosis. (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.)

Impulse Control/Compulsive Behaviors

Serious impulse-control and compulsive behaviors, particularly pathological gambling, have been reported rarely in adult and pediatric patients treated with aripiprazole. 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. Other impulse-control and compulsive behaviors reported less frequently than gambling include compulsive or binge eating, compulsive spending or shopping, and compulsive sexual behaviors. The majority of patients in these cases had no history of compulsive behaviors and experienced the uncontrollable urges only after beginning treatment with aripiprazole. 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.

FDA recommends that clinicians advise patients and caregivers of the risk of uncontrollable urges with aripiprazole therapy and specifically ask patients whether they have developed any new or increased urges while receiving the drug. 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.(See Advice to Patients.)

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.(See Advice to Patients.)

Tardive Dyskinesia

Because use of antipsychotic agents, including aripiprazole, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), aripiprazole should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. 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. 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.

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. 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.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain. While all of these drugs produce some metabolic changes, each drug has its own specific risk profile. (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. Hyperglycemia has been reported in patients treated with aripiprazole. 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. 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.

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. 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.(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.

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. 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.

Weight Gain

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

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. 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.

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.

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. The risk of orthostatic hypotension generally appears to be greatest during initiation of therapy and dosage titration. 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. 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.

If parenteral benzodiazepine therapy is necessary in patients receiving aripiprazole, patients should be monitored for excessive sedation and orthostatic hypotension.(See Drug Interactions: Lorazepam and Other Benzodiazepines.)

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis also has been reported.

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia. 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. Aripiprazole should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.

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. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm), aripiprazole should be discontinued and the leukocyte count monitored until recovery occurs. 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.

Seizures

As with other antipsychotic agents, aripiprazole may cause seizures. Seizures have occurred in 0.1% of adult and pediatric patients (6-18 years of age) treated with oral aripiprazole, and in 0.2% of adults treated with parenteral short-acting aripiprazole. 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.

Cognitive and Motor Impairment

Like other antipsychotic agents, aripiprazole potentially may impair judgment, thinking, or motor skills. In short-term clinical trials, somnolence (including sedation) was reported in 11 and 9% of adults treated with oral or short-acting parenteral aripiprazole, respectively, compared with 6% of those receiving placebo. 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.(See Advice to Patients.)

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. 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).

Suicide

Attendant risk with psychotic illnesses, bipolar disorder, and major depressive disorder; high-risk patients should be closely supervised. Aripiprazole should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.(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. Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Aripiprazole should be used with caution in patients at risk for aspiration pneumonia.(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. Aripiprazole conventional tablets and oral solution do not contain aspartame.

Specific Populations

Pregnancy

Category C.

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. 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.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/atypicalantipsychotic/.

Lactation

Aripiprazole is distributed into milk in humans. 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. Because of the potential for serious adverse reactions to aripiprazole in nursing infants, the manufacturer of aripiprazole tablets, oral solution, and the short-acting IM injection 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. 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.

Pediatric Use

Safety and efficacy of oral aripiprazole have not been established in pediatric patients with major depressive disorder. Safety and efficacy of immediate-release IM aripiprazole have not been established for agitation associated with schizophrenia or bipolar mania in pediatric patients. 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.

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. 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.(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.

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. However, efficacy can be extrapolated from adult data in addition to pharmacokinetic comparisons of aripiprazole between adult and pediatric populations.

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. 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.

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. Efficacy of the drug as maintenance therapy in pediatric patients with Tourette's syndrome has not been systematically evaluated.(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.

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. 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. Similar gains in weight were observed in short-term studies in pediatric patients with irritability associated with autistic disorder and Tourette's syndrome.

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). 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. No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of aripiprazole in a child or adolescent for any clinical use.(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. 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.

In clinical studies, approximately 13% of over 700 patients treated with short-acting IM aripiprazole were 65 years of age or older and approximately 10% were 75 years of age or older. Experience from placebo-controlled trials with short-acting aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania who are 65 years of age and older is insufficient to determine whether they respond differently than younger adults.

The manufacturer of oral aripiprazole and the short-acting and extended-release IM formulations of the drug states that dosage adjustment is not necessary in geriatric patients on the basis of age alone. 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.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. 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. Aripiprazole is not approved for the treatment of dementia-related psychosis. (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.) For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, .

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.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

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. Approximately 8% of Caucasians and 3-8% of Blacks/African Americans cannot metabolize CYP2D6 substrates and are classified as poor CYP2D6 metabolizers.(See Poor CYP2D6 Metabolizers 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, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

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

In clinical trials, nausea was the only adverse effect that occurred in more than 5% of patients with agitation associated with schizophrenia or bipolar mania receiving immediate-release IM aripiprazole and at an incidence at least twice that for placebo.

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, akathisia, injection site pain, and sedation.

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. 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.

Drug Interactions

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.(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.

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. 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.

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. 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. When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the aripiprazole dosage should be increased.(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. 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.

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. 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. When the potent CYP2D6 inhibitor is withdrawn from combined therapy, the aripiprazole dosage should be increased.(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. Concomitant use of aripiprazole with other potent CYP3A4 inducers (e.g., rifampin) may result in substantially decreased systemic exposure to aripiprazole.

Oral aripiprazole dosage should be doubled over 1-2 weeks of concurrent use with potent CYP3A4 inducers. Concurrent use of CYP3A4 inducers and extended-release aripiprazole injection (Abilify Maintena) should be avoided since aripiprazole concentrations may fall below therapeutic concentrations. 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- or 882-mg doses of the drug. When the potent CYP3A4 inducer is withdrawn from combined therapy, the aripiprazole dosage should be reduced to the original dosage over 1-2 weeks.(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.

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.(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. During concomitant use, blood pressure should be monitored and antihypertensive dosage(s) adjusted accordingly.

Lorazepam and Other Benzodiazepines

Clinically important pharmacokinetic changes have not been reported during concurrent administration of lorazepam and aripiprazole. The manufacturers state that routine dosage adjustment of aripiprazole or lorazepam is not necessary when the drugs are concurrently administered. However, increased sedative and orthostatic hypotensive effects have been reported in patients receiving these drugs in combination. 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.(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. The manufacturer of the extended-release IM formulation of aripiprazole (Abilify Maintena) states that alcohol should be avoided during therapy. 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.

Dextromethorphan

Clinically important pharmacokinetic interaction is unlikely. Dosage adjustment of dextromethorphan (a CYP2D6 and CYP3A4 substrate) is not necessary when administered concomitantly with aripiprazole.

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. Dosage adjustment of escitalopram is not necessary when administered concurrently with aripiprazole.

Famotidine

Concomitant use of aripiprazole and famotidine may result in decreased peak plasma concentrations and systemic exposure of aripiprazole; however, a clinically important pharmacokinetic interaction between the drugs appears unlikely. No dosage adjustment of aripiprazole is necessary when administered concurrently with famotidine.

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. Therefore, dosage adjustment of fluoxetine, paroxetine, and sertraline is not necessary in patients concomitantly receiving aripiprazole therapy.

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. When fluoxetine or paroxetine is withdrawn from combined therapy with aripiprazole, the aripiprazole dosage should be increased back to the original dosage. When adjunctive aripiprazole is concurrently administered to patients with major depressive disorder receiving fluoxetine or paroxetine, aripiprazole should be given without dosage adjustment. (See Dosage and Administration: Special Populations.)

Lamotrigine

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

Lithium

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

Omeprazole

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

Valproate

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

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. Dosage adjustment of venlafaxine is not necessary during concurrent use of aripiprazole.

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. Warfarin dosage adjustment is not necessary when administered concurrently with aripiprazole.