Abilify

Abilify

aripiprazole

Manufacturer:

Thai Otsuka

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Aripiprazole.
Description
Each tablet also contains the following excipients: Cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C blue no. 2 aluminum lake.
Each mL of oral solution also contains the following excipients: Disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water. The oral solution is flavored with natural orange cream and other natural flavors.
Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38.
Action
Antipsychotic agent.
Pharmacology: Mechanism of Action: The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, bipolar disorder, major depressive disorder, and agitation associated with schizophrenia or bipolar disorder, is unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A and 5-HT2A may explain some of the other clinical effects of aripiprazole eg, the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic α1 receptors.
Pharmacodynamics: Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34, 0.8, 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, α1-adrenergic and histamine H1 receptors (Ki values of 44, 15, 39, 57 and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 >1000 nM). Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors and as an antagonist at serotonin 5-HT2A receptor.
Pharmacokinetics: Abilify activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. The mean elimination half-lives are about 75 and 94 hrs for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving 2 P-450 isozymes, CYP2D6 and CYP3A4.
Absorption: Tablet: Aripiprazole is well-absorbed, with peak plasma concentrations occurring within 3-5 hrs; the absolute oral bioavailability of the tablet formulation is 87%. Abilify can be administered with or without food. Administration of a 15-mg Abilify tablet with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hrs for aripiprazole and 12 hrs for dehydro-aripiprazole.
Oral Solution: Aripiprazole is well-absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of aripiprazole 30 mg as the oral solution to aripiprazole 30-mg tablets in healthy subjects, the solution to tablet ratios of geometric mean Cmax and AUC values were 122% and 114%, respectively (see Dosage and Administration). The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5-30 mg.
Metabolism and Elimination: Aripiprazole is metabolized primarily by 3 biotransformation pathways: Dehydrogenation, hydroxylation and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). Poor metabolizers have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Co-administration of Abilify with known inhibitors of CYP2D6 eg, quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure and dose adjustment is needed (see Interactions). The mean elimination half-lives are about 75 and 146 hrs for aripiprazole in EMs and PMs, respectively. Aripiprazole does not inhibit or induce the CYP2D6 pathway.
Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.
Special Populations: In general, no dosage adjustment for Abilify is required on the basis of a patient's age, gender, race, smoking status, hepatic or renal function (see Special Populations under Dosage & Administration). The pharmacokinetics of aripiprazole in special populations is described as follows.
Hepatic Impairment: In a single-dose study (aripiprazole 15 mg) in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B and C), the AUC of aripiprazole, compared to healthy subjects, increased 31% in mild hepatic impairment (HI), increased 8% in moderate HI and decreased 20% in severe HI. None of these differences would require dose adjustment.
Renal Impairment: In patients with severe renal impairment (creatinine clearance <30 mL/min), Cmax of aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-aripiprazole is <1% of the dose. No dosage adjustment is required in subjects with renal impairment.
Elderly: In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly subjects (≥65 years) compared to younger adult subjects (18-64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment is recommended for elderly patients (see Use in the elderly under Precautions).
Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania or major depressive order did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects.
Gender: Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30-40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight (25%) between men and women. No dosage adjustment is recommended based on gender.
Race: Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of aripiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of aripiprazole. No dosage adjustment is recommended based on race.
Smoking: Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics of aripiprazole. Consistent with these in vitro results, population pharmacokinetic evaluation did not reveal any significant pharmacokinetic differences between smokers and nonsmokers. No dosage adjustment is recommended based on smoking status.
Clinical Studies: Schizophrenia: Adults: The efficacy of Abilify in the treatment of schizophrenia was evaluated in 5 short-term (4- and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the 5 trials were able to distinguish aripiprazole from placebo, but 1 study, the smallest did not. Three of these studies also included an active control group consisting of either risperidone (1 trial) or haloperidol (2 trials), but they were not designed to allow for a comparison of Abilify and the active comparators.
In the 4 positive trials for Abilify, 4 primary measures were used for assessing psychiatric signs and symptoms. The positive and negative syndrome scale (PANSS) is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. The PANSS positive subscale is a subset of items in the PANSS that rates 7 positive symptoms of schizophrenia (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution and hostility). The PANSS negative subscale is a subset of items in the PANSS that rates 7 negative symptoms of schizophrenia (blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity/flow of conversation and stereotyped thinking). The clinical global impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
In a 4-week trial (n=414) comparing 2 fixed doses of Abilify (15 or 30 mg/day) and haloperidol (10 mg/day) to placebo, both doses of Abilify were superior to placebo in the PANSS total score, PANSS positive subscale and CGI-severity score. In addition, the 15-mg dose was superior to placebo in the PANSS negative subscale.
In a 4-week trial (n=404) comparing 2 fixed doses of Abilify (20 or 30 mg/day) and risperidone (6 mg/day) to placebo, both doses of Abilify were superior to placebo in the PANSS total score, PANSS positive subscale, PANSS negative subscale and CGI-severity score.
In a 6-week trial (n=420) comparing 3 fixed doses of Abilify (10, 15 or 20 mg/day) to placebo, all 3 doses of Abilify were superior to placebo in the PANSS total score, PANSS positive subscale and the PANSS negative subscale.
In a 6-week trial (n=367) comparing 3 fixed doses of Abilify (2, 5 or 10 mg/day) to placebo, the 10-mg dose of Abilify was superior to the placebo in the PANSS total score, the primary outcome measure of the study. The 2- and 5-mg doses did not demonstrate superiority to placebo on the primary outcome measure.
In a 5th study, a 4-week trial (n=103) comparing Abilify in a range of 5-30 mg/day or haloperidol 5-20 mg/day to placebo, haloperidol was superior to placebo, in the brief psychiatric rating scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in psychosis, and in a responder analysis based on the CGI-severity score, the primary outcomes for that trial. Abilify was only significantly different compared to placebo in a responder analysis based on the CGI-severity score.
Thus, the efficacy of 10-, 15-, 20- and 30-mg daily doses was established in 2 studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender or race.
A long-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of ≥3 months. These patients were discontinued from their antipsychotic medications and randomized to Abilify 15 mg or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients receiving Abilify 15 mg experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo.
Pediatric: The efficacy of Abilify in the treatment of schizophrenia in pediatric patients (13-17 years) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing 2 fixed doses of Abilify (10 or 30 mg/day) to placebo, Abilify was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of Abilify were superior to placebo in the PANSS total score, the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose.
Bipolar Disorder: Adults: The efficacy of Abilify in the treatment of acute manic episodes was established in two 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes (in 1 trial, 21% of placebo and 42% of Abilify-treated patients had data beyond 2 weeks). These trials included patients with or without psychotic features and with or without a rapid-cycling course.
The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance and insight) in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) scale.
In the 2 positive 3-week, placebo-controlled trials (n=268; n=248) which evaluated Abilify 30 mg/day once daily (with a starting dose of 30 mg/day and an allowed reduction to 15 mg/day), Abilify was superior to placebo in the reduction of Y-MRS total score and CGI-BP severity of illness score (mania).
A trial was conducted in patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized in an open-label Abilify and who had maintained a clinical response for at least 6 weeks. The 1st phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label Abilify (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one (161) outpatients were then randomized in a double-blind fashion, to either the same dose of Abilify they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, Abilify was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study. The majority of these relapses were due to manic rather than depressive symptoms. There is insufficient data to know whether Abilify is effective in delaying the time to occurrence of depression in patients with bipolar I disorder.
An examination of the population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient number of patients in each of the ethnic groups to adequately assess intergroup differences.
Pediatric: The efficacy of Abilify in the treatment of bipolar I disorder in pediatric patients (10-17 years) was evaluated in one 4-week placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline. This double-blind, placebo-controlled trial compared 2 fixed doses of Abilify (10 or 30 mg/day) to placebo. The Abilify dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm and in 13 days in the 30 mg/day treatment arm. Both doses of Abilify were superior to placebo in change from baseline to week 4 on the Y-MRS total score.
Adjunctive Treatment of Major Depressive Disorder (MDD): The efficacy of Abilify in the adjunctive treatment of MDD was demonstrated in 2 short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had an inadequate response to prior antidepressant therapy (1-3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram or sertraline). Inadequate response for prospective treatment was defined as <50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMDI7), minimal HAMDl7 score of 14, and a CGI-I rating of no better than minimal improvement. Inadequate response to prior treatment was defined as <50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.
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 (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts). The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on 3 domains of functioning (work/school, social life and family life) with each item scored from 0 (not at all) to 10 (extreme).
In the 2 trials (n=381, n=362), Abilify was superior to placebo in reducing mean MADRS total scores. In one study, Abilify was also superior to placebo in reducing the mean SDS score.
In both trials, patients received Abilify adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, 1 week apart. Allowable doses were 2, 5, 10, 15 and for patients who were not on potent CYF2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final. dose at the end-point for the 2 trials was 10.7 and 11.4 mg/day.
An examination 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 on the MADRS total score was seen in males than in females.
Toxicology: Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40- and 60-mg/kg doses are 13 and 19 times the maximum recommended human dose (MRHD) based on mg/m2 and 7-14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
Indications/Uses
Treatment and maintenance of acute schizophrenia in adults.
Treatment of schizophrenia in adolescents 13-17 years (see Clinical Studies under Actions).
Treatment and maintenance of acute manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults and in pediatric patients 10-17 years. (See Clinical Studies under Actions.)
Adjunctive treatment to antidepressants for major depressive disorder.
Dosage/Direction for Use
Schizophrenia: Usual Dose: Recommended Starting and Target Dose: Adults: 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Abilify has been systematically evaluated and shown to be effective in a dose range of 10-30 mg/day, when administered as the tablet formulation; however, doses >10 or 15 mg/day, were not more effective than 10 or 15 mg/day. Dosage increases should not be made before 2 weeks, the time needed to achieve steady-state. (See Clinical Studies under Actions.)
Adolescents: 10 mg/day. Aripiprazole was studied in pediatric patients 13-17 years with schizophrenia at daily doses of 10 and 30mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Abilify can be administered without regard to meals (see Clinical Studies under Actions).
Maintenance Therapy: Adults: While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, systematic evaluation of patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of ≥3 months, were discontinued from those medications, and were then administered Abilify 15 mg/day and observed for relapse during a period of up to 26 weeks has demonstrated a benefit of such maintenance treatment (see Clinical Studies under Actions). Patients should be periodically re-assessed to determine the need for maintenance treatment.
Pediatric Patients: The efficacy of Abilify for the maintenance treatment of schizophrenia in the pediatric population has not been evaluated.
Switching from Other Antipsychotics: There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to Abilify or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.
Bipolar Disorder: Usual Dose: Adults: In clinical trials, the starting dose was 30 mg once a day, without regard to meals. A dose of 30 mg/day was found to be effective when administered as the tablet formulation. Approximately 15% of patients had their dose decreased to 15 mg based on assessment of tolerability. The safety of doses >30 mg/day has not been evaluated in clinical trials (see Clinical Studies under Actions).
Pediatric Patients: The efficacy of aripiprazole has been established in the treatment of pediatric patients 10-17 years with bipolar I disorder at doses of 10 or 30 mg/day. The recommended target dose of Abilify is 10 mg/day. The starting daily dose of the tablet formulation in these patients was 2 mg/day, which was titrated to 5 mg/day after 2 days and to the target dose of 10 mg/day after 2 additional days. Subsequent dose increases should be administered in 5 mg/day increments. Abilify can be administered without regard to meals. (See Clinical Studies under Actions.)
Maintenance Therapy: Adults: While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, adult patients with bipolar I disorder who had been symptomatically stable on Abilify tablets (15 or 30 mg/day with a starting dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to Abilify tablets (15 or 30 mg/day) or placebo and monitored for relapse, demonstrated a benefit of such maintenance treatment (see Clinical Studies under Actions).
While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of aripiprazole in such longer-term treatment (beyond 6 weeks). Physicians who elect to use Abilify for extended periods ie, >6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual.
Pediatric Patients: The efficacy of Abilify for the maintenance treatment of bipolar I disorder in the pediatric population has not been evaluated.
Adjunctive Treatment of Major Depressive Disorder: Usual Dose: Adults: Starting Dose: 2-5 mg/day. The efficacy of Abilify as an adjunctive therapy for major depressive disorder was established within a dose range of 2-15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week. The long-term efficacy of Abilify for the adjunctive treatment of major depressive disorder has not been established (see Clinical Studies under Actions).
Pediatric Patients: The efficacy of Abilify for the adjunctive treatment of major depressive disorder in the pediatric population has not been evaluated.
Dosage Adjustments: Dosage adjustments in adults are not routinely indicated on the basis of age, gender, race, or renal or hepatic impairment status. (See Use in children under Precautions.)
Dosage adjustment for patients taking aripiprazole concomitantly with strong CYP3A4 inhibitors: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors eg, ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to ½ the usual dose. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased (see Interactions).
Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors eg, quinidine, fluoxetine or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at least to ½ of its normal dose. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased (see Interactions). When adjunctive Abilify is administered to patients with major depressive disorder, Abilify should be administered without dosage adjustment as specified in Dosage & Administration.
Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential CYP3A4 inducer eg, carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10-15 mg (see Interactions).
Dosing for Oral Solution: The oral solution can be substituted for tablets on a mg/mg basis up to the 25 mg dose level. Patients receiving 30 mg should receive 25 mg of the solution (see Pharmacology under Actions).
Overdosage
Symptoms: Human Experience: A total of 76 cases of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These includes overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported for these cases. Of the 44 cases with known outcome, 33 cases recovered without sequelae and 1 case recovered with sequelae (mydriasis and abnormal feeling). The largest known acute ingestion with a known outcome involved oral aripiprazole 1080 mg (36 times the maximum recommended daily dose) in a patient who fully recovered. Included in the 76 cases are 10 cases of deliberate or accidental overdosage in children (≤12 years) involving oral aripiprazole ingestions up to 195 mg with no fatalities.
Common adverse events (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence and tremor. Other clinically important signs and symptoms observed in ≥1 patients with aripiprazole overdoses (alone or in combination with other substances) include acidosis, aggression, increased aspartate aminotransferase, atrial fibrillation, bradycardia, coma, confusional state, convulsion, increased blood creatinine phosphokinase, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, prolonged QRS complex, prolonged QT, aspiration pneumonia, respiratory arrest, status epilepticus and tachycardia.
Management: No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
Charcoal: In the event of an overdose of Abilify, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of activated charcoal 50 g, 1 hr after a single 15-mg oral dose of aripiprazole, decreased the mean AUC and Cmax of aripiprazole by 50%.
Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
Contraindications
Patients with a known hypersensitivity to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis (see Adverse Reactions).
Warnings
Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6-1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared to 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 (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Abilify is not approved for the treatment of patients with dementia-related psychosis.
Clinical Worsening of Depression and Suicide Risk: Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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 trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18-24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults >24 years; there was a reduction with antidepressants compared to placebo in adults ≥65 years.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided as follows:
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Based on Age Range: <18 years: 14 additional cases increased compared to placebo.
18-24 years: 5 additional cases increased compared to placebo.
25-64 years: 1 fewer case decreased compared to placebo.
≥65 years: 6 fewer cases decreased compared to placebo.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described previously, as well as the emergence of suicidality and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Abilify should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.
It should be noted that Abilify is not approved for use in treating depression in the pediatric population.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary CNS pathology.
The management of NMS should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.
Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Abilify should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be re-assessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on Abilify, drug discontinuation should be considered. However, some patients may require treatment with Abilify despite the presence of the syndrome.
Cerebrovascular Adverse Events Including Stroke, in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled clinical studies (2 flexible-dose and 1 fixed-dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (eg, stroke, transient ischemic attack) including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose-response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.
Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease: In 3, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy (placebo 2%, aripiprazole 5%), somnolence (including sedation) (placebo 3%, aripiprazole 8%) and incontinence (primarily urinary incontinence) (placebo 1%, aripiprazole 5%), excessive salivation (placebo 0%, aripiprazole 4%) and lightheadedness (placebo 1%, aripiprazole 4%).
The safety and efficacy of Abilify in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia in patients treated with Abilify (see Adverse Reactions). Although fewer patients have been treated with Abilify, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include Abilify, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because Abilify was not marketed at the time these studies were performed, it is not known if Abilify is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued. However, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Special Precautions
Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral Abilify (n=1894) included orthostatic hypotension (aripiprazole 1.2%, placebo 0.3%), postural dizziness (aripiprazole 0.6%, placebo 0.4%) and syncope (aripiprazole 0.6%, placebo 0.5%); of pediatric patients 10-17 years (n=399) on oral Abilify included orthostatic hypotension (aripiprazole 1%, placebo 0%), postural dizziness (aripiprazole 0.5%, placebo 0%) and syncope (aripiprazole 0.3%, placebo 0%).
The incidence of a significant orthostatic change in blood pressure (defined as a decrease of ≥20 mmHg in systolic blood pressure accompanied by an increase of ≥25 in heart rate when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo: In adult oral aripiprazole-treated patients (aripiprazole 5%, placebo 3%) and in pediatric oral aripiprazole-treated patients 10-17 years (aripiprazole 0%, placebo 0.5%) or in aripiprazole injection-treated patients (aripiprazole 3%, placebo 2%,).
Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications).
Seizure/Convulsion: In short-term, placebo-controlled trials, seizures/convulsions occurred in 0.2% (3/1894) of adult patients treated with oral aripiprazole, in 0.3% (1/399) of pediatric patients (10-17 years) and in 0.2% (1/501) of adult aripiprazole injection-treated patients.
As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold eg, Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years.
Potential for Cognitive and Motor Impairment: Abilify, like other antipsychotics, may have the potential to impair judgment, thinking or motor skills. For example, in short-term, placebo-controlled trials of schizophrenia, somnolence (including sedation) was reported as follows: In adult patients (n=1894) treated with oral Abilify (aripiprazole 11%, placebo 7%) and in pediatric patients 10-17 years (aripiprazole 21%, placebo 5%). Somnolence (including sedation) led to discontinuation in 0.2% (4/1894) of adult patients in 1% (4/399) of pediatric patients (10-17 years) on oral Abilify in short-term, placebo-controlled trials but did not lead to discontinuation of any adult patients on Abilify injection.
Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Abilify does not affect them adversely.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration (see Adverse Reactions).
Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and MDD and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Abilify should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose (see Adverse Reactions).
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including Abilify. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see Adverse Reactions).
In two 6-week placebo-controlled studies of aripiprazole as adjunctive treatment of MDD, the incidences of suicidal ideation and suicide attempts were 0% (0/371) for aripiprazole and 0.5% (2/366) for placebo.
Use in Patients with Concomitant Illness: Clinical experience in patients with certain concomitant systemic illnesses is limited. (See Pharmacology: Special Populations: Renal Impairment and Hepatic Impairment under Actions.)
Abilify has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies (see Warnings and previously mentioned text).
Drug Abuse and Dependence: Abilify is not a controlled substance.
Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse and such patients should be observed closely for signs of Abilify misuse or abuse (eg, development of tolerance, increases in dose, drug-seeking behavior). Effects on the Ability to Drive or Operate Machinery: Because aripiprazole may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole therapy does not affect them adversely.
Carcinogenicity: Lifetime carcinogenicity studies were conducted in ICR mice, Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10 and 30 mg/kg/day to ICR mice and 1, 3 and 10 mg/kg/day to F344 rats [0.2-5 and 0.3-3 times the maximum recommended human dose (MRHD) based on mg/m2, respectively]. In addition, SD rats were dosed orally for 2 years at 10, 20, 40 and 60 mg/kg/day (3-19 times the MRHD based on mg/m2). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3-30 mg/kg/day (0.1-0.9 times human exposure at MRHD based on AUC and 0.5-5 times the MRHD based on mg/m2). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at MRHD based on AUC and 3 times the MRHD based on mg/m2); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 times the MRHD based on mg/m2).
Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4- and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
Mutagenicity: The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, in vitro bacterial DNA repair assay, in vitro forward gene mutation assay in mouse lymphoma cells, in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, in vivo micronucleus assay in mice and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice, however, the response was shown to be due to a mechanism not considered relevant to humans.
Impairment of Fertility: Female rats were treated with oral doses of 2, 6 and 20 mg/kg/day (0.6, 2 and 6 times the MRHD on a mg/m2 basis) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg and decreased fetal weight was seen at 20 mg/kg.
Male rats were treated with oral doses of 20, 40 and 60 mg/kg/day (6, 13 and 19 times the MRHD on a mg/m2 basis) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and 60 mg/kg, but no impairment of fertility was seen.
Use in pregnancy: Pregnancy Category C: In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
Pregnant rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m2 basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg) and delayed skeletal ossification (10 and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg) and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants and live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
Pregnant rabbits were treated with oral doses of 10, 30 and 100 mg/kg/day (2, 3 and 11 times human exposure at MRHD based on AUC and 6, 19 and 65 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg) and minor skeletal variations (100 mg/kg).
In a study in which rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m2 basis) of aripiprazole peri-natally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival, were seen at this dose.
There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Aripiprazole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Labor and Delivery: The effect of aripiprazole on labor and delivery in humans is unknown.
Use in lactation: Aripiprazole was excreted in milk of rats during lactation. It is not known whether aripiprazole or its metabolites are excreted in human milk. It is recommended that women receiving aripiprazole should not breastfeed.
Use in children: Safety and effectiveness in pediatric patients with MDD or agitation associated with schizophrenia or bipolar mania have not been established.
Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients 13-17 years (see Clinical Studies under Actions, Indications, Dosage & Administration, Adverse Reactions).
Safety and effectiveness in pediatric patients with bipolar mania were established in a 4-week, placebo-controlled clinical trial in 197 pediatric patients 10-17 years (see Clinical Studies under Actions, Indications, Dosage & Administration, Adverse Reactions).
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients 10-17 years were similar to·those in adults after correcting for the differences in body weights.
Use in the elderly: In formal single dose pharmacokinetic studies (with aripiprazole given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥65 years) subjects compared to younger adult subjects (18-64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment is recommended for elderly patients (see Precautions).
Of the 12,925 patients treated with oral aripiprazole in clinical trials, 1061 (8%) were ≥65 years and 799 (6%) were ≥75 years. The majority (97%) of the 799 patients were diagnosed with dementia of the Alzheimer's type.
Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania or MDD did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects.
Studies of elderly patients with psychosis associated with Alzheimer's disease have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia (see Precautions). The safety and efficacy of Abilify in the treatment of patients with psychosis associated with Alzheimer's disease has not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised.
Use In Pregnancy & Lactation
Use in pregnancy: In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
Pregnant rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m2 basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg) and delayed skeletal ossification (10 and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg) and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants and live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
Pregnant rabbits were treated with oral doses of 10, 30 and 100 mg/kg/day (2, 3 and 11 times human exposure at MRHD based on AUC and 6, 19 and 65 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg) and minor skeletal variations (100 mg/kg).
In a study in which rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m2 basis) of aripiprazole peri-natally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival, were seen at this dose.
There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Aripiprazole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Labor and Delivery: The effect of aripiprazole on labor and delivery in humans is unknown.
Use in lactation: Aripiprazole was excreted in milk of rats during lactation. It is not known whether aripiprazole or its metabolites are excreted in human milk. It is recommended that women receiving aripiprazole should not breastfeed.
Adverse Reactions
The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia and restlessness.
The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, extrapyramidal disorder, headache and nausea.
Aripiprazole has been evaluated for safety in 12,925 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, MDD and Alzheimer's dementia and who had approximately 7482 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3338 patients were treated with oral aripiprazole for at least 180 days and 1898 patients treated with oral aripiprazole had at least 1 year of exposure.
Aripiprazole has been evaluated for safety in 514 patients (10-17 years) who participated in multiple-dose, clinical trials in schizophrenia or bipolar mania and who had approximately 205 patient-years of exposure to oral aripiprazole. A total of 278 pediatric patients were treated with oral aripiprazole for at least 180 days.
The conditions and duration of treatment with aripiprazole included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies and short- and longer-term exposure.
Adverse events during exposure were obtained by collecting volunteered adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; ie, all events meeting the defined criteria, regardless of investigator causality are included.
Throughout this, adverse reactions are reported. These are adverse events that were considered to be reasonably associated with the use of Abilify (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for Abilify often cannot be reliably established in individual cases.
The figures in tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.
Clinical Studies Experience: Adult Patients with Schizophrenia: The following findings are based on a pool of 5 placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2-30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment: Overall, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole- and placebo-treated patients.
Commonly Observed Adverse Reactions: The only commonly observed adverse reaction associated with the use of aripiprazole in patients with Schizophrenia (incidence of ≥5% and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).
Adult Patients with Bipolar Mania: The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral aripiprazole was administered at doses of 15 or 30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment: Overall, in patients with bipolar mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated (9%) patients. The types of adverse reactions that led to discontinuation were similar between the aripiprazole- and placebo-treated patients.
Commonly Observed Adverse Reactions: Commonly observed adverse reactions associated with the use of aripiprazole in patients with bipolar mania (incidence of ≥5% and aripiprazole incidence at least twice that for placebo) are shown in Table 1. (See Table 1.)

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Less Common Adverse Reactions in Adults: Table 2 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in ≥2% of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. (See Table 2.)

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An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender or race.
Pediatric Patients (13-17 years) with Schizophrenia: The following findings are based on one 6-week placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2-30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between aripiprazole- and placebo-treated pediatric patients (13-17 years) was 5% and 2%, respectively.
Commonly Observed Adverse Reactions: Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of ≥5% and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence and tremor.
Pediatric Patients (10-17 years) with Bipolar Mania: The following findings are based on one 4-week placebo-controlled trial in which oral aripiprazole was administered in doses of 10 or 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between aripiprazole- and placebo-treated pediatric patients (10-17 years) was 7% and 2%, respectively.
Commonly Observed Adverse Reactions: Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with bipolar mania (incidence of ≥5% and aripiprazole incidence at least twice that for placebo) are shown in Table 3. (See Table 3.)

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Less Common Adverse Reactions in Pediatric Patients (10-17 years) with Schizophrenia or Bipolar Mania: Table 4 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 4 weeks in bipolar mania), including only those reactions that occurred in ≥1% of pediatric patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo. (See Table 4.)

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Adult Patients Receiving Abilify as Adjunctive Treatment of Major Depressive Disorder: The following findings are based on a pool of 2 placebo-controlled trials of patients with major depressive disorder in which aripiprazole was administered at doses of 2-20 mg as adjunctive treatment to continued antidepressant therapy.
Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions was 6% for adjunctive aripiprazole-treated patients and 2% for adjunctive placebo-treated patients.
Commonly Observed Adverse Reactions: The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with MDD (incidence of ≥5% and aripiprazole incidence at least twice that for placebo) were: Akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.
Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder (MDD): Table 5 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in ≥2% or more of patients treated with adjunctive aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset. (See Table 5.)

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Dose-Related Adverse Reactions: Schizophrenia: Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from 4 trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20 and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose-response relationship and then, most prominent only with 30 mg, was somnolence (including sedation); (incidences were placebo, 7.1 %; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).
In the study of pediatric patients (13-17 years) with schizophrenia, 3 common adverse reactions appeared to have a possible dose-response relationship: Extrapyramidal disorder (incidences were placebo, 5%; 10 mg, 13%; 30 mg, 21.6%); somnolence (incidences were placebo, 6%; 10 mg, 11%; 30 mg, 21.6%); and tremor (incidences were placebo, 2%; 10 mg, 2%; 30 mg, 11.8%).
Bipolar Mania: In the study of pediatric patients (10-17 years) with bipolar mania, 4 common adverse reactions had a possible dose-response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%, 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1 %).
Extrapyramidal Symptoms (EPS): In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% versus 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% versus 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13-17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% versus 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% versus 6% for placebo. In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 15% versus 8% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 15% versus 4% for placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric patients (10-17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% versus 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% versus 2% for placebo. In the short-term, placebo-controlled trials in MDD; the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% versus 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% versus 4% for adjunctive placebo-treated patients.
Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05). In the pediatric (13-17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale aripiprazole, 0.24; placebo, -0.29). In the adult bipolar mania trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.61; placebo, 0.03 and aripiprazole, 0.25; placebo, -0.06). Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the pediatric (10-17 years) short-term bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.90; placebo, 0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the MDD trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.
Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo.
In the placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 2% versus 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 2% versus 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between aripiprazole and placebo.
Laboratory Test Abnormalities: A between group comparison for 3- to 6-week, placebo-controlled trials in adults or 4- to 6-week, placebo-controlled trials in pediatric patients (10-17 years) revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology or urinalysis in adult or pediatric patients.
In the 6-week trials of aripiprazole as adjunctive therapy for MDD, there were no clinically important differences between the adjunctive aripiprazole-treated and adjunctive placebo-treated patients in the median change from baseline in prolactin, fasting glucose, HDL, LDL, or total cholesterol measurements. The median percent change from baseline in triglycerides was 5% for adjunctive aripiprazole-treated patients versus 0% for adjunctive placebo-treated patients.
In a long-term (26-week), placebo-controlled trial there were no medically important differences between the aripiprazole and placebo patients in the mean change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, or total cholesterol measurements.
Weight Gain: In 4- to 6-week trials in adults with schizophrenia, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.7 kg vs -0.05 kg, respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥7% of body weight [aripiprazole (8%) compared to placebo (3%)]. In a 6-week trial in pediatric patients (13-17 years) with schizophrenia, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.13 kg vs 0.83 kg, respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥7% of body weight [aripiprazole (5%) compared to placebo (1 %)]. In 3-week trials in adults with mania, the mean weight gain for aripiprazole and placebo patients was 0 kg versus -0.2 kg, respectively. The proportion of patients meeting a weight gain criterion of ≥7% of body weight was aripiprazole (3%) compared to placebo (2%).
In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment. The mean weight gain with adjunctive aripiprazole was 1.7 kg versus 0.4 kg with adjunctive placebo. The proportion of patients meeting a weight gain criterion of ≥7% of body weight was 5% with adjunctive aripiprazole compared to 1% with adjunctive placebo.
Table 6 provides the weight change results from a long-term (26-week), placebo-controlled study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥7% of body weight relative to baseline, categorized by BMI at baseline. Although there was no mean weight increase, the aripiprazole group tended to show more patients with a ≥7% weight gain. (See Table 6.)

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Table 7 provides the weight change results from a long-term (52-week) study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥7% of body weight relative to baseline, categorized by BMI at baseline. (See Table 7.)

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ECG Changes: Between group comparisons for a pooled analysis of placebo-controlled trials in patients with schizophrenia, bipolar mania or MDD revealed no significant differences between oral aripiprazole and placebo in the proportion of patients experiencing potentiaily important changes in ECG parameters. Aripiprazole was associated with a median increase in heart rate of 3 beats/min compared to no increase among placebo patients.
In the pooled, placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, there were no significant differences between aripiprazole injection and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, as measured by standard 12-lead ECGs.
Additional Findings Observed in Clinical Trials: Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials: The adverse reactions reported in a 26-week, double-blind trial comparing oral Abilify and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for Abilify vs 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of Abilify. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor was 5% (40/859) for Abilify. A similar profile was observed in a long-term study in bipolar disorder.
Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 12,925 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of Adverse Reactions or those considered in Warnings, Precautions or Overdosage have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.
Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: Those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in <1/1000 patients.
Adults: Oral Administration: Blood and Lymphatic System Disorders: ≥1/1000 and <1/100: Leukopenia, neutropenia; <1/1000: Thrombocytopenia, agranulocytosis, idiopathic thrombocytopenic purpura.
Cardiac Disorders: ≥1/1000 and <1/100: Cardiopulmonary failure, bradycardia, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, bundle branch block; <1/1000: Atrial flutter, ventricular tachycardia, complete atrioventricular block, supraventricular tachycardia.
Eye Disorders: ≥1/1000 and <1/100: Eyelid edema, photophobia, diplopia, photopsia; <1/1000: Excessive blinking.
Gastrointestinal Disorders: ≥1/1000 and <1/100: Dysphagia, gastroesophageal reflux disease, gastrointestinal hemorrhage, swollen tongue, ulcer, esophagitis, angioedema; <1/1000: Pancreatitis.
General Disorders and Administration Site Conditions: ≥1/100: Asthenia; ≥1/1000 and <1/100 patients: Decreased mobility, face edema; <1/1000: Hypothermia.
Hepatobiliary Disorders: ≥1/1000 and <1/100: Cholecystitis, cholelithiasis; <1/1000: Hepatitis, jaundice.
Injury, Poisoning and Procedural Complications: ≥1/100: Fall; ≥1/1000 and <1/100: Self mutilation; <1/1000 patients: Heat stroke.
Investigations: ≥1/100: Increased creatine phosphokinase; ≥1/1000 and <1/100: Increased hepatic enzyme, blood urea, blood bilirubin, blood creatinine, prolonged corrected electrocardiogram QT-interval, increased blood prolactin; <1/1000: increased blood lactate dehydrogenase, glycosylated hemoglobin, GGT.
Metabolism and Nutrition Disorders: ≥1/1000 and <1/100: Anorexia, hyperlipidemia.
Musculoskeletal and Connective Tissue Disorders: ≥1/100: Muscle spasms; ≥1/1000 and <1/100: Muscle rigidity; <1/1000: Rhabdomyolysis.
Nervous System Disorders: ≥1/100: Abnormal coordination; ≥1/1000 and <1/100: Speech disorder, parkinsonism, cogwheel rigidity, memory impairment, cerebrovascular accident, hypokinesia, tardive dyskinesia, hypotonia, hypertonia, akinesia, myoclonus, bradykinesia; <1/1000: Grand Mal convulsion, choreoathetosis.
Psychiatric Disorders: <1/100: Agitation, irritability, suicidal ideation; ≥1/1000 and <1/100: Aggression, loss of libido, increased or decreased libido, hostility, suicide attempt, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000: Psychomotor agitation, premature ejaculation, catatonia, sleep walking.
Renal and Urinary Disorders: ≥1/1000 and <1/100: Urinary retention, polyuria, nocturia.
Reproductive System and Breast Disorders: ≥1/1000 and <1/100: Erectile dysfunction, amenorrhea, irregular menstruation irregular, breast pain; <1/1000: Gynaecomastia, priapism, galactorrhea.
Respiratory, Thoracic and Mediastinal Disorders: ≥1/100: Dyspnea; ≥1/1000 and <1/100: Aspiration pneumonia, respiratory distress; <1/1000: Pulmonary embolism, asphyxia.
Skin and Subcutaneous Tissue Disorders: ≥1/100: Hyperhydrosis; ≥1/1000 and <1/100: Erythema, pruritus, ecchymosis, face edema, photosensitivity reaction, alopecia, urticaria.
Vascular Disorders: ≥1/1000 and <1/100: Hypotension, deep vein thrombosis, phlebitis; <1/1000: Shock, thrombophlebitis.
Pediatric Patients: Oral Administration: Most adverse events observed in the pooled database of 514 pediatric patients 10-17 years were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed as follows: Gastrointestinal Disorders: ≥1/1000 and <1/100: Dry tongue, tongue spasm.
Investigations: ≥1/100: Increased blood insulin.
Nervous System Disorders: ≥1/1000 and <1/100: Sleep talking.
Skin and Subcutaneous Tissue Disorders: ≥1/1000 and <1/100: Hirsutism.
Postmarketing Experience: The following adverse reactions have been identified during postapproval use of Abilify. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: Rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), and blood glucose fluctuation.
Drug Interactions
Given the primary CNS effects of aripiprazole, caution should be used when Abilify is taken in combination with other centrally-acting drugs and alcohol. Due to its α-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
Potential for Other Drugs to Affect Abilify: Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2E1 enzymes. It also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes or other factors eg, smoking, is unlikely.
Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels.
Ketoconazole and Other CYP3A4 Inhibitors: Co-administration of ketoconazole (200 mg/day for 14 days) with a 15-mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to ½ of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
Quinidine and Other CYP2D6 Inhibitors: Co-administration of a 10-mg single dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose should be reduced to ½ of its normal dose when concomitant administration of quinidine with aripiprazole occurs. Other significant inhibitors of CYP2D6 eg, fluoxetine or paroxetine, would be expected to have similar effects and therefore, should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased. When adjunctive Abilify is administered to patients with MDD, it should be administered without dosage adjustment as specified in Dosage & Administration.
Carbamazepine and Other CYP3A4 Inducers: Co-administration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg/day) resulted in approximately 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, aripiprazole dose should then be reduced.
Potential for Abilify to Affect Other Drugs: Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P-450 enzymes. In in vivo studies, 10-30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro.
Alcohol: There was no significant difference between aripiprazole co-administered with ethanol and placebo co-administered with ethanol on performance of gross motor skills or stimulus response in healthy subjects. As with most psychoactive medications, patients should be advised to avoid alcohol while taking Abilify.
Drugs Having No Clinically Important Interactions with Abilify: Famotidine: Co-administration of aripiprazole (given in a single dose of 15 mg) with a 40-mg single dose of the H2-antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the extent of absorption (AUC). No dosage adjustment of aripiprazole is required when administered concomitantly with famotidine.
Valproate: When valproate (500-1500 mg/day) and aripiprazole (30 mg/day) were co-administered, at steady state, the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.
When aripiprazole (30 mg/day) and valproate (1000 mg/day) were co-administered, at steady state, there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with aripiprazole.
Lithium: A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not bound to plasma proteins, not metabolized and almost entirely excreted unchanged in urine. Co-administration of therapeutic doses of lithium (1200-1800 mg/day) for 21 days with aripiprazole (30 mg/day) did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydroaripiprazole (Cmax and AUC increased by <20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium. Co-administration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with aripiprazole.
Dextromethorphan: Aripiprazole at doses of 10-30 mg/day for 14 days had no effect on dextromethorphan's O-dealkylation to its major metabolite, dextrorphan, a pathway dependent on CYP2D6 activity. Aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methyoxymorphinan, a pathway dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with aripiprazole.
Warfarin: Aripiprazole 10 mg/day for 14 days had no effect on the pharmacokinetics of R- and S-warfarin or on the pharmacodynamic end point of International Normalized Ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.
Omeprazole: Aripiprazole 10 mg/day for 15 days had no effect on the pharmacokinetics of a single 20-mg dose of omeprazole, a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with aripiprazole.
Lorazepam: Co-administration of lorazepam injection (2 mg) and aripiprazole injection (15 mg) to healthy subjects (n=40: 35 males and 5 females; 19-45 years) did not result in clinically important changes in the pharmacokinetics of either drug. No dosage adjustment of aripiprazole is required when administered concomitantly with lorazepam. However, the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone (see Precautions).
Escitalopram: Co-administration of oral aripiprazole 10 mg/day for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of escitalopram 10 mg/day, a substrate of CYF2Cl9 and CYF3A4. No dosage adjustment of escitalopram is required when aripiprazole is added to escitalopram.
Venlafaxine: Co-administration of oral aripiprazole 10-20 mg/day for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of venlafaxine and O-desmethylvenlafaxine following 75 mg/day venlafaxine XR, a CYF2D6 substrate. No dosage adjustment of venlafaxine is required when aripiprazole is added to venlafaxine.
Fluoxetine, Paroxetine, and Sertraline: A population pharmacokinetic analysis in patients with MDD showed no substantial change in plasma concentrations of fluoxetine (20 or 40 mglday), paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were co-administered with aripiprazole. Aripiprazole dosing was 2-15 mg/day (when given with fluoxetine or paroxetine) or 2-20 mg/day (when given with sertraline).
Storage
Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Oral Solution: Store at 25°C (77°F); excursions permitted between 15 to 30°C (59-86°F).
Shelf-Life: Opened Bottles: 6 months.
ATC Classification
N05AX12 - aripiprazole ; Belongs to the class of other antipsychotics.
Presentation/Packing
Tab 2 mg x 30's. 5 mg (blue, modified rectangular, debossed on one side with "A-007" and "5" on the other) x 30's. 10 mg (pink, modified rectangular, debossed on one side with "A-008" and "10" on the other) x 30's. 15 mg (yellow, round, debossed on one side with "A-009" and "15" on the other) x 30's. Orally disintegrating tab 10 mg x 30's. 15 mg x 30's.
Oral Soln 1 mg/mL (clear, colorless to light yellow) x 150 mL.
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