Rx only
`
`
`ABILIFY® (aripiprazole) Tablets
`ABILIFY® DISCMELT™ (aripiprazole) Orally
`Disintegrating Tablets
`ABILIFY® (aripiprazole) Oral Solution
`WARNING
`
`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 seventeen
`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 to 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 (aripiprazole) is not approved for
`the treatment of patients with dementia-related psychosis.
`
`DESCRIPTION
`
`Aripiprazole is a psychotropic drug that is available as ABILIFY® (aripiprazole) tablets,
`ABILIFY® DISCMELT™ (aripiprazole) orally disintegrating tablets, and in solution for
`oral administration. 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. The chemical structure is:
`
`O
`
`NH
`
`N
`
`N
`
`CH2CH2CH2CH2O
`
`1 of 41
`
`Cl
`
`Cl
`
`

`

`
`
`ABILIFY tablets are available in 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg
`strengths. Inactive ingredients include 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.
`
`ABILIFY DISCMELT orally disintegrating tablets are available in 10-mg, 15-mg,
`20-mg, and 30-mg strengths. Inactive ingredients include acesulfame potassium,
`aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla
`(natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon
`dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and
`FD&C Blue No. 2 Aluminum Lake.
`
`ABILIFY is also available as a 1 mg/mL oral solution. The inactive ingredients
`this solution
`include disodium edetate, fructose, glycerin, dl-lactic acid,
`for
`methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose, and
`purified water. The oral solution is flavored with natural orange cream and other natural
`flavors.
`
`CLINICAL PHARMACOLOGY
`
`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, alpha1-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.
`
`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-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at
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`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 alpha1 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 hours and
`94 hours
`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 are dose-proportional. Elimination of
`aripiprazole is mainly through hepatic metabolism involving two P450 isozymes,
`CYP2D6 and CYP3A4.
`
`Pharmacokinetic studies showed that ABILIFY DISCMELT orally disintegrating
`tablets are bioequivalent to ABILIFY tablets.
`
`Absorption
`
`Tablet
`
`Aripiprazole is well absorbed after administration of the tablet, with peak plasma
`concentrations occurring within 3 to 5 hours; 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 hours for aripiprazole and 12 hours 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 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets
`in healthy subjects, the solution to tablet ratios of geometric mean Cmax and AUC values
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`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 to 30 mg.
`
`Distribution
`
`intravenous
`The steady-state volume of distribution of aripiprazole following
`administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution.
`At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99%
`bound to serum proteins, primarily to albumin. In healthy human volunteers administered
`0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor
`occupancy indicating brain penetration of aripiprazole in humans.
`
`Metabolism and Elimination
`
`three biotransformation pathways:
`is metabolized primarily by
`Aripiprazole
`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. Coadministration of ABILIFY with known inhibitors of CYP2D6, like
`quinidine in EMs, results in a 112% increase in aripiprazole plasma exposure, and dosing
`adjustment is needed (see PRECAUTIONS: Drug-Drug Interactions). The mean
`elimination half-lives are about 75 hours and 146 hours 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.
`
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`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 AND
`ADMINISTRATION: Dosage in Special Populations). The pharmacokinetics of
`aripiprazole in special populations are described below.
`
`Hepatic Impairment
`
`In a single-dose study (15 mg of aripiprazole) 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), 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 less than 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 to 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 Boxed WARNING, WARNINGS: Increased Mortality in Elderly
`Patients with Dementia-Related Psychosis, and PRECAUTIONS: Geriatric Use).
`
`Gender
`
`Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30 to
`40% higher in women than in men, and correspondingly, the apparent oral clearance of
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`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. Aripiprazole also does not undergo direct
`glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or
`inducers of these enzymes, or other factors, like 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 P450 enzymes. In in vivo studies, 10- to 30-mg/day
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`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: Drug-Drug Interactions).
`
`Aripiprazole had no clinically important interactions with the following drugs:
`
`Famotidine: Coadministration 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 coadministered 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.
`
`Lithium: A pharmacokinetic interaction of aripiprazole with lithium is unlikely
`because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely
`excreted unchanged in urine. Coadministration 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 (Cmax and AUC increased by less than 20%). No dosage
`adjustment of aripiprazole is required when administered concomitantly with lithium.
`
`Dextromethorphan: Aripiprazole at doses of 10 to 30 mg per 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 per 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
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`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 per 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 four 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 four 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 (one
`trial) or haloperidol (two trials), but they were not designed to allow for a comparison of
`ABILIFY and the active comparators.
`
`In the three positive trials for ABILIFY, four 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 seven 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 seven 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 two fixed doses of ABILIFY (15 or 30
`mg/day) and haloperidol (10 mg/day) to placebo, both doses of ABILIFY were superior
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`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 two 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 three fixed doses of ABILIFY (10, 15, or
`20 mg/day) to placebo, all three doses of ABILIFY were superior to placebo in the
`PANSS total score, PANSS positive subscale, and the PANSS negative subscale.
`
`In a fourth study, a 4-week trial (n=103) comparing ABILIFY in a range of 5 to
`30 mg/day or haloperidol 5 to 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-mg, 20-mg, and 30-mg daily doses was established in
`two studies for each dose, whereas the efficacy of the 10-mg dose was established in one
`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.
`
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`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 two 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 two 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 first 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
`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 population subgroups did not reveal any clear evidence of
`differential responsiveness on the basis of age and gender; however, there were
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`insufficient numbers of patients in each of the ethnic groups to adequately assess inter-
`group differences.
`
`INDICATIONS AND USAGE
`
`Schizophrenia
`
`ABILIFY is indicated for the treatment of 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 CLINICAL PHARMACOLOGY: Clinical Studies).
`
`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 or longer, 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
`(see CLINICAL
`weeks was demonstrated
`in
`a placebo-controlled
`trial
`PHARMACOLOGY: Clinical Studies). The physician who elects to use ABILIFY for
`extended periods should periodically re-evaluate the long-term usefulness of the drug for
`the individual patient (see DOSAGE AND ADMINISTRATION).
`
`Bipolar Disorder
`
`ABILIFY is indicated for the treatment of acute manic and mixed episodes associated
`with Bipolar Disorder.
`
`The efficacy of ABILIFY was established in two placebo-controlled trials (3
`week) of inpatients with DSM-IV criteria for Bipolar I Disorder who were experiencing
`an acute manic or mixed episode with or without psychotic features (see CLINICAL
`PHARMACOLOGY: Clinical Studies).
`
`The efficacy 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 and maintained their stability 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 CLINICAL PHARMACOLOGY: Clinical
`Studies). Physicians who elect to use ABILIFY for extended periods, that is, longer than
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`6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the
`individual patient (see DOSAGE AND ADMINISTRATION).
`
`CONTRAINDICATIONS
`
`ABILIFY is contraindicated in patients with a known hypersensitivity to the product.
`
`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. ABILIFY
`(aripiprazole) is not approved for the treatment of patients with dementia-related
`psychosis (see Boxed WARNING).
`
`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: 1) immediate discontinuation of
`antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive
`symptomatic treatment and medical monitoring; and 3) treatment of any concomitant
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`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
`(1) is known to respond to antipsychotic drugs, and (2) 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.
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`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 (two flexible dose and one 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 also Boxed WARNING, WARNINGS:
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis, and
`PRECAUTIONS: Use in Patients with Concomitant Illness: Safety Experience in
`Elderly Patients with Psychosis Associated with Alzheimer’s Disease.)
`
`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. 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.
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`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 anti-diabetic treatment despite discontinuation of the suspect drug.
`
`PRECAUTIONS
`
`General
`
`Orthostatic Hypotension
`
`Aripiprazole may be associated with orthostatic hypotension, perhaps due to its α1-
`adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated
`events from five short-term, placebo-controlled trials in schizophrenia (n=926) on
`ABILIFY included: orthostatic hypotension (placebo 1%, ari