Abilify Tablet

Aripiprazole.

It also contain the following inactive ingredients: Cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Colorants include ferric oxide (yellow or red).
Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C₂₃H₂₇Cl₂N₃O₂ and its molecular weight is 448.39.

Pharmacology: Pharmacodynamics: Aripiprazole exhibits high affinity for dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors (K_i values of 0.34, 0.8, 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, α₁-adrenergic and histamine H₁ receptors (K_i values of 44, 15, 39, 57 and 61 nM, respectively), and moderate affinity for the serotonin re-uptake site (K_i=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-HT_1A receptors, and as an antagonist at serotonin 5-HT_2A receptor.
The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia and 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-HT_1A receptors and antagonist activity at 5-HT_2A receptors. Actions at receptors other than D₂, 5-HT_1A and 5-HT_2A 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.
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 two P-450 isozymes, CYP2D6 and CYP3A4.
Absorption: Aripiprazole is well absorbed after administration of the tablet, 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 tablet with a standard high-fat meal did not significantly affect the C_max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T_max by 3 hrs for aripiprazole and 12 hrs for dehydro-aripiprazole.
Distribution: The steady-state volume of distribution of aripiprazole following IV administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are >99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered with aripiprazole 0.5-30 mg/day for 14 days, there was dose-dependent D₂-receptor occupancy indicating brain penetration of aripiprazole in humans.
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). PMs 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 in EMs, results in a 112% increase in aripiprazole plasma exposure, and dosing 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 function, or renal function (see Dosage & Administration). The pharmacokinetics of aripiprazole in special populations are described as follows.
Hepatic Impairment (HI): 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 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), C_max 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 (≥65 years) subjects compared to younger adult subjects (18-64 years). However, there was no detectable age effect 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 Increased Mortality in Elderly Patients with Dementia-Related Psychosis under Warnings and Use in the elderly under Precautions).
Gender: C_max 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.
Drug-Drug Interactions: 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.
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- to 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 (see Precautions).
Aripiprazole had no clinically important interactions with the following drugs: 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 C_max 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 C_max and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.
Lithium: A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not bound to plasma proteins, is 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, dehydro-aripiprazole (C_max and AUC increased by <20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium.
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 known to be dependent on CYP2D6 activity. Aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methyoxymorphan, a pathway known to be 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 endpoint of international normalized ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of a 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.
Clinical Studies: Schizophrenia: The efficacy of Abilify in the treatment of schizophrenia was evaluated in 4 short-term (4- and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Three of the 4 trials were able to distinguish aripiprazole from placebo, but one 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 3 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, 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 4th 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 15, 20 and 30-mg daily doses was established in 2 studies for each dose, whereas the efficacy of the 10-mg dose was established in 1 study. There was no evidence in any study that the higher dose groups offered any advantage over the lowest dose group.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender or race.
A longer-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 or longer. 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.
Bipolar Disorder: 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 one 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 15 or 30 mg/day once daily (with a starting dose of 30 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 on 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 numbers of patients in each of the ethnic groups to adequately assess intergroup differences.
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 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.

Schizophrenia: The efficacy of Abilify in the treatment of schizophrenia was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients (see Pharmacology under Actions). The efficacy of Abilify in maintaining stability in patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of ≥3 months were discontinued from those other medications, and were then administered Abilify 15 mg/day and observed for relapse during a period of up to 26 weeks was demonstrated in a placebo-controlled trial (see Pharmacology under Actions). The physician who elects to use Abilify for extended periods should periodically re-evaluate the long-term usefulness of Abilify for the individual patient (see Dosage & Administration).
Bipolar Disorder: Treatment of acute manic and mixed epithelial episodes associated with bipolar disorder. The efficacy of Abilify was established in 2 placebo-controlled trials (3 weeks) of inpatient with DSM-IV criteria for bipolar I disorder who were expecting an acute manic or mixed episodes with or without psychotic features (see Pharmacology under Actions). The efiicacy of Abilify in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least 6 weeks was demonstrated in a double-blind, placebo-controlled trial. Prior to entering the double-blind, randomization phase of this trial, patients were clinically stabilized for 6 consecutive weeks on Abilify. Following this 6-week maintenance phase, patients were randomized to either placebo or Abilify and monitored for relapse (see Pharmacology under Actions).
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 patient (see Dosage & Administration).
Adjunctive therapy for major depressive disorder.

Schizophrenia: Recommended Starting and Target Dose: 10 or 15 mg once a day 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 a tablet formulation; however, doses >10 or 15 mg/day, the lowest doses in these trials, were not more effective than 10 or 15 mg/day. Dosage increases should be made before 2 weeks, the time needed to achieve steady state.
Special Populations: Dosage adjustments are not routinely indicated on the basis of age, gender, race or renal or hepatic impairment status (see Pharmacokinetics under Actions).
Dosage Adjustments: Patients Taking Aripiprazole Concomitantly with Potential CYP3A4 or CYP2D6 Inhibitors: When concomitant administration of CYP3A4 inhibitor eg, ketoconazole and potential CYP2D6 inhibitors eg, quinidine, fluoxetine or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced to ½ of the usual dose. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
Patients Taking Potential CYP3A4 Inducers: When a potential CYP3A4 inducer eg, carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled (to 20-30 mg). Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10-15 mg.
Maintenance Therapy: 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, demonstrated a benefit of such maintenance treatment (see Pharmacology under Actions). Patients should periodically be reassessed to determine the need for maintenance treatment.
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 Starting Dose: 30 mg once a day. 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.
Special Populations: See Schizophrenia.
Maintenance Therapy: While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, 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 (15 or 30 mg/day) or placebo, and monitored for relapse demonstrated a benefit of such maintenance treatment (see Pharmacology 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 (ie, beyond 6 weeks).

MedDRA terminology has been used to classify the adverse events.
Human Experience: A total of 76 cases of deliberate or accidental overdosage with aripiprazole have been reported worldwide. These include overdoses with aripiprazole alone and in combination with other substances. No fatality was reported from these cases. Of the 44 cases with known outcome, 33 recovered without sequelae and 1 recovered with sequelae (mydriasis and feeling abnormal). The largest known acute ingestion with a known outcome involved 1080 mg of aripiprazole (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 aripiprazole ingestions up to 195 mg with no fatalities.
Symptoms: Common adverse events (reported in at least 5% of all overdose cases) reported with 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 with other substances) include acidosis, aggression, increased aspartate aminotransferase, atrial fibrillation, bradycardia, coma, confusional state, convulsion, increased blood creatine phosphokinase, depressed level of consciousness, hypertension, hypokalaemia, hypotension, lethargy, loss of consciousness, prolonged QRS complex, prolonged QT, aspiration pneumonia, respiratory arrest, status epilepticus and tachycardia.
Treatment: No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and, if QTc 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 C_max 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.

Patients with known hypersensitivity to aripiprazole.

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.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including aripiprazole. Two possible cases of NMS occurred during aripiprazole treatment in the premarketing 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, etc) 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 central nervous system 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. It is unknown whether antipsychotic drug products differ in their potential to cause tardive dyskinesia.
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 reassessed 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 (see Use in Patients with Concomitant Illness: Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease under Precautions).
Hyperglycemia and Diabetes Mellitus: Hypergylcemia, in some extreme cases and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including aripiprazole. There have been few reports of hyperglycemia in patients treated with Abilify. 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 suspected drug.

General: Orthostatic Hypotension: Aripiprazole may be associated with orthostatic hypotension, perhaps due to its α₁-adernergic receptor antagonism. The incidence of orthostatic hypotension-associated events from 5 short-term, placebo-controlled trials in schizophrenia (n=926) on Abilify included: Orthostatic hypotension (placebo 1%, aripiprazole 1.9%), orthostatic lightheadedness (placebo 1%, aripiprazole 0.9%), and syncope (placebo 1%, aripiprazole 0.6%). The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials in bipolar mania (n=597) on Abilify included: Orthostatic hypotension (placebo 0%, aripiprazole 0.7%), orthostatic lightheadedness (placebo 0.5%, aripiprazole 0.5%), and syncope (placebo 0.9%, aripiprazole 0.5%).
The incidence of a significant orthostatic change in blood pressure (defined as a decrease of at least 30 mm Hg in systolic blood pressure when changing from a supine to standing position) for aripiprazole was not statistically different from placebo (in schizophrenia: 14% among aripiprazole-treated patients and 12% among placebo-treated patients and in bipolar mania: 3% among aripiprazole-treated patients and 2% among placebo-treated patients).
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: Seizures occurred in 0.1% (1/926) of aripiprazole-treated patients with schizophrenia in short-term, placebo-controlled trials. In short-term, placebo-controlled clinical trials of patients with bipolar mania, 0.3% (2/597) of aripiprazole-treated patients and 0.2% (1/436) of placebo-treated patients experienced seizures. As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the 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: In short-term, placebo-controlled trials of schizophrenia, somnolence was reported in 11% of patients on Abilify compared to 8% of patients on placebo; somnolence led to discontinuation in 0.1% (1/926) of patients with schizophrenia on Abilify in short-term, placebo-controlled trials. In short-term, placebo-controlled trials of bipolar mania, somnolence was reported in 14% of patients on Abilify compared to 7% of patients on placebo, but did not lead to discontinuation of any patients with bipolar mania. Despite the relatively modest increased incidence of somnolence compared to placebo, Abilify, like other antipsychotics, 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 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.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. 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 Use in Patients with Concomitant Illness as follows).
Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Abilify should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness: Clinical experience with Abilify in patients with certain concomitant systemic illnesses (see Pharmacokinetics: Special Populations: Renal Impairment and Hepatic Impairment under Actions) is limited.
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 pre-marketing clinical studies.
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 ≥5% and aripiprazole incidence at least twice that for placebo were asthenia (placebo 3%, aripiprazole 8%), somnolence (placebo 3%, aripiprazole 9%), 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 in swallowing or excessive somnolence, which could predispose to accidental injury or aspiration (see also Increased Mortality in Elderly Patients with Dementia-Related Psychosis and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis under Warnings).
Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe Abilify: Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol: Patients should be advised to avoid alcohol while taking Abilify.
Heat Exposure and Dehydration: Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
Drug Abuse and Dependence: Controlled Substance: Abilify is not a controlled substance.
Abuse and Dependence: 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: Interference with Cognitive and Motor Performance: 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, Mutagenicity & Impairment of Fertility: Lifetime carcinogenicity studies were conducted in ICR mice and in 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.
The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the 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.
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. Estrous cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased preimplantation 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 perinatally 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.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Abilify.
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 and adolescent patients have not been established.
Use in the elderly: Of the 7951 patients treated with aripiprazole in premarketing clinical trials, 991 (12%) were ≥65 years and 789 (10%) were ≥75 years. The majority (88%) of the 991 patients were diagnosed with dementia of the Alzheimer's type.
Placebo-controlled studies of aripiprazole in schizophrenia or bipolar mania did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. There was no effect of age on the pharmacokinetics of a single 15-mg dose of aripiprazole. Aripiprazole clearance was decreased by 20% in elderly subjects ≥65 years) compared to younger adult subjects (18-64 years), but there was no detectable effect of age in the population pharmacokinetic analysis in schizophrenia patients.
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 Increased Mortality in Elderly Patients with Dementia-Related Psychosis and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis under Warnings and Use in Patients with Concomitant Illness under 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: 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 perinatally 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.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Abilify.
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.

Aripiprazole has been evaluated for safety in 7951 patients who participated in multiple-dose, premarketing trials in schizophrenia, bipolar mania and dementia of the Alzheimer's type, and who had approximately 5235 patient-years of exposure. A total of 2280 aripiprazole-treated patients were treated for at least 180 days and 1558 aripiprazole-treated patients had at least 1 year of exposure.
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, modified COSTART dictionary terminology has been used initially 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 events 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 reported events are included.
The prescriber should be aware that the figures in the 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 prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials of 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 aripiprazole was administered in doses ranging from 2-30 mg/day.
Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials: Overall, there was no difference in the incidence of discontinuation due to adverse events between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse events that led to the discontinuation were similar between the aripiprazole- and placebo-treated patients.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials of Patients with Bipolar Mania: The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which aripiprazole was administered at doses of 15 or 30 mg/day.
Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials: Overall, in patients with bipolar mania, there was no difference in the incidence of discontinuation due to adverse events between aripiprazole-treated (11%) and placebo-treated (9%) patients. The types of adverse events that led to discontinuation were similar between the aripiprazole and placebo-treated patients.
Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials of Patients with Bipolar Mania: Commonly observed adverse events 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. There were no adverse events in the short-term trials of schizophrenia that met these criteria (see Table 1).


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Adverse Events Occurring at an Incidence of ≥2% Among Aripiprazole-Treated Patients and Greater Than Placebo in Short-Term Placebo-Controlled Trials: Table 2 enumerates the pooled incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those events 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 event incidence on the basis of age, gender or race.
Dose-Related Adverse Events: Schizophrenia: Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from 4 trials in patients with schizophrenia comparing various fixed doses (2, 10, 15, 20 and 30 mg/day) of aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse event to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence (placebo, 7.7%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 15.3%).
Extrapyramidal Symptoms (EPS): In the short-term, placebo-controlled trials of schizophrenia, the incidence of reported EPS for aripiprazole-treated patients was 6% versus 6% for placebo. In the short-term, placebo-controlled trials in bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 17% versus 12% for placebo. In the short-term, placebo-controlled trials in bipolar mania, the incidence of akathisia-related events for aripiprazole-treated patients was 15% versus 4% for placebo. 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 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 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.
Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia, 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.
Laboratory Test Abnormalities: A between group comparison for 3- to 6-week placebo-controlled trials 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 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 and total cholesterol measurements.
Weight Gain: In 4- to 6- week trials in 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 3-week trials in 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%).
Table 3 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 body mass index (BMI) at baseline (see Table 3).


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Table 4 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 4).


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Electrocardiogram (ECG) Changes: Between group comparisons for a pooled analysis of placebo-controlled trials in patients with schizophrenia or bipolar mania revealed no significant differences between aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters. Aripiprazole was associated with a median increase in heart rate of 5 bpm compared to a 1 bpm increase among placebo patients.
Additional Findings Observed in Clinical Trials: Adverse Events in a Long-Term, Double-Blind, Placebo-Controlled Trial: The adverse events reported in a 26-week, double-blind trial comparing 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 [9% (13/153) for Abilify vs 1% (2/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (9/13 mild and 4/13 moderate), occurred early in therapy (9/13 ≤49 days) and were of limited duration (9/13 ≤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 for Abilify was 4% (34/859). A similar adverse event profile was observed in a long-term study in bipolar disorder.
Other Adverse Events Observed During the Premarketing Evaluation of Aripiprazole: Following is a list of modified COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to this section reported by patients treated with aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 7951 patients. All reported events are included except those already listed in Table 2 or other parts of this section, those considered in the Warnings or Precautions, those event terms which were so general as to be uninformative, events reported with an incidence of ≤0.05% and which did not have a substantial probability of being acutely life-threatening, events that are otherwise common as background events, and events considered unlikely to be drug-related. It is important to emphasize that, although the events reported occurred during treatment with aripiprazole, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are 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); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Frequent: Flu syndrome, fever, chest pain, rigidity (including neck and extremity), neck pain, pelvic pain. Infrequent: Face edema, suicide attempt, malaise, migraine, chills, photosensitivity, tightness (including abdomen, back, extremity, head, jaw, neck, and tongue), jaw pain, bloating, enlarged abdomen, chest tightness, throat pain. Rare: Moniliasis, head heaviness, throat tightness, Mendelson's syndrome, heat stroke.
Cardiovascular System: Frequent: Tachycardia (including ventricular and supraventricular), hypotension, bradycardia. Infrequent: Palpitation, hemorrhage, heart failure, myocardial infarction, cardiac arrest, atrial fibrillation, AV block, prolonged QT interval, extrasystoles, myocardial ischemia, deep vein thrombosis, angina pectoris, pallor, cardiopulmonary arrest, phlebitis. Rare: Bundle branch block, atrial flutter, vasovagal reaction, cardiomegaly, thrombophlebitis, cardiopulmonary failure.
Digestive System: Frequent: Nausea and vomiting. Infrequent: Increased appetite, dysphagia, gastroenteritis, flatulence, tooth caries, gastritis, gingivitis, gastrointestinal hemorrhage, hemorrhoids, gastroesophageal reflux, periodontal abscess, fecal incontinence, rectal hemorrhage, stomatitis, colitis, tongue edema, cholecystitis, mouth ulcer, oral moniliasis, eructation, fecal impaction, cholelithiasis. Rare: Esophagitis, hematemesis, intestinal obstruction, gum hemorrhage, hepatitis, peptic ulcer, glossitis, melena, duodenal ulcer, cheilitis, hepatomegaly, pancreatitis.
Endocrine System: Infrequent: Hypothyroidism. Rare: Goiter, hyperthyroidism.
Hemic/Lymphatic System: Frequent: Ecchymosis, anemia. Infrequent: Hypochromic anemia, leukocytosis, leukopenia (including neutropenia), lymphadenopathy, eosinophilia, macrocytic anemia. Rare: Thrombocythemia, thrombocytopenia, petechiae.
Metabolic and Nutritional Disorders: Frequent: Weight loss, increased creatine phosphokinase, dehydration. Infrequent: Edema, hyperglycemia, hypercholesteremia, hypokalemia, diabetes mellitus, hypoglycemia, hyperlipemia, increased SGPT, thirst, increased BUN, hyponatremia, increased SGOT, increased creatinine, cyanosis, increased alkaline phosphatase, bilirubinemia, iron deficiency anemia, hyperkalemia, hyperuricemia, obesity. Rare: Increased lactic dehydrogenase, hypernatremia, gout, hypoglycemic reaction.
Musculoskeletal System: Frequent: Muscle cramp. Infrequent: Arthralgia, bone pain, myasthenia, arthritis, arthrosis, muscle weakness, spasm, bursitis, myopathy. Rare: Rhabdomyolysis, tendonitis, tenosynovitis, rheumatoid arthritis.
Nervous System: Frequent: Depression, nervousness, schizophrenic reaction, hallucination, hostility, confusion, paranoid reaction, suicidal thought, manic reaction, abnormal gait, delusions, abnormal dream. Infrequent: Emotional lability, twitch, cogwheel rigidity, impaired concentration, dystonia, vasodilation, paresthesia, impotence, extremity tremor, hypesthesia, vertigo, stupor, bradykinesia, apathy, panic attack, decreased libido, hypersomnia, dyskinesia, manic depressive reaction, ataxia, visual hallucination, cerebrovascular accident, hypokinesia, depersonalization, impaired memory, delirium, dysarthria, tardive dyskinesia, amnesia, hyperactivity, increased libido, myoclonus, restless leg, neuropathy, dysphoria, hyperkinesia, cerebral ischemia, increased reflexes, akinesia, decreased consciousness, hyperesthesia, slowed thinking. Rare: Blunted affect, euphoria, incoordination, oculogyric crisis, obsessive thought, hypotonia, buccoglossal syndrome, decreased reflexes, derealization, intracranial hemorrhage.
Respiratory System: Frequent: Sinusitis, dyspnea, pneumonia, asthma. Infrequent: Epistaxis, hiccup, laryngitis, aspiration pneumonia. Rare: Pulmonary edema, increased sputum, pulmonary embolism, hypoxia, respiratory failure, apnea, dry nasal passages, hemoptysis.
Skin and Appendages: Frequent: Skin ulcer, sweating, dry skin. Infrequent: Pruritus, vesiculobullous rash, acne, eczema, skin discoloration, alopecia, seborrhea, psoriasis. Rare: Maculopapular rash, exfoliative dermatitis, urticaria.
Special Senses: Frequent: Conjunctivitis. Infrequent: Ear pain, dry eye, eye pain, tinnitus, cataract, otitis media, altered taste, blepharitis, eye hemorrhage, deafness. Rare: Diplopia, frequent blinking, ptosis, otitis externa, amblyopia, photophobia.
Urogenital System: Frequent: Urinary incontinence. Infrequent: Urinary frequency, leukorrhea, urinary retention, cystitis, hematuria, dysuria, amenorrhea, abnormal ejaculation, vaginal hemorrhage, kidney failure, vaginal moniliasis, urinary urgency, gynecomastia, kidney calculus, albuminuria, breast pain, urinary burning. Rare: Nocturia, polyuria, menorrhagia, anorgasmy, glycosuria, cervicitis, uterus hemorrhage, female lactation, urolithiasis, priapism.
Other Events Observed During the Post-Marketing Evaluation of Aripiprazole: Voluntary reports of adverse events in patients taking aripiprazole that have been received since market introduction and not listed previously that may have no causal relationship with the drug include very rare occurrences of allergic reaction (eg, anaphylactic reaction, angioedema, laryngospasm, pruritis, or urticaria), temperature regulation disorder (eg, pyrexia, hypothermia), increased γ-GTP, increased blood glucose, blood glucose fluctuation, increased glycosylated hemoglobin, increased weight, grand mal convulsion, jaundice.

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 α₁-adrenergic receptor 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. Aripiprazole 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: 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; weaker 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: 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 be accompanied by similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
Carbamazapine: Co-administration of carbamazapine (200 mg 2 times a day), a potent CYP3A4 inducer, with aripiprazole (30 mg 4 times a day) resulted in an approximate 70% decrease in C_max and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazapine is added to aripiprazole therapy, aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazapine is withdrawn from the combination therapy, aripiprazole should then be reduced.
No clinically significant effect of famotidine, valproate, or lithium was seen on the pharmacokinetics of aripiprazole (see Pharmacokinetics under Actions).
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- to 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 (see Pharmacokinetics under Actions).
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.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

Antipsychotics

N05AX12 - aripiprazole ; Belongs to the class of other antipsychotics.

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