Enclosure
`
`[We note your agreement to the labeling below in an electronic
`communication dated November 15, 2002. Additionally, we note
`that, at this time, you intend to market only the 10 mg, 15 mg, 20
`mg, and 30 mg dosage strengths. However, the Agency is
`approving all of the following dosage strengths: 2 mg, 5 mg, 10
`mg, 15 mg, 20 mg, and 30 mg. Additionally, for completeness, we
`are including these dosage strengths into the labeling.]
`
`ABILIFY(cid:212)(cid:212)
`(aripiprazole)
`Tablets
`
`Rx only
`
`DESCRIPTION
`ABILIFY(cid:212)
` (aripiprazole) is a psychotropic drug that is available as tablets 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
`448.38. The chemical structure is:
`
`O
`
`NH
`
`N
`
`N
`
`CH2CH2CH2CH2O
`
`Cl
`
`Cl
`
`ABILIFY tablets are available in 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg
`strengths. Inactive ingredients include lactose monohydrate, cornstarch, microcrystalline
`cellulose, hydroxypropyl cellulose, and magnesium stearate. Colorants include ferric
`oxide (yellow or red) and FD&C Blue No.2 Aluminum Lake.
`
`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
`
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`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, is unknown. However, it has been proposed that the efficacy of
`aripiprazole is mediated through a combination of partial agonist activity at D2 and 5-
`HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other
`than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of
`aripiprazole, eg, the orthostatic hypotension observed with aripiprazole may be explained
`by its antagonist activity at adrenergic 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.
`
`Absorption
`
`Aripiprazole is well absorbed, 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.
`
`Distribution
`
`intravenous
`following
`The steady-state volume of distribution of aripiprazole
`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
`
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`

`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.
`
`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
`
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`In formal single-dose pharmacokinetic studies (with aripiprazole given in a single dose of
`15 mg), aripiprazole clearance was 20% lower in elderly (‡65 years) subjects compared
`to younger adult subjects (18-64 years). There was no detectable age effect, however, in
`the population pharmacokinetic analysis
`in schizophrenia patients. Also,
`the
`pharmacokinetics of aripiprazole after multiple doses in elderly patients appeared similar
`to that observed in young healthy subjects. No dosage adjustment is recommended for
`elderly patients. (see PRECAUTIONS: Geriatric Use).
`
`Gender
`
`Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30-
`40% higher in women than in men, and correspondingly, the apparent oral clearance of
`aripiprazole is lower in women. These differences, however, are largely explained by
`differences in body weight (25%) between men and women. No dosage adjustment is
`recommended based on gender.
`
`Race
`
`Although no specific pharmacokinetic study was conducted to investigate the effects of
`race on the disposition of aripiprazole, population pharmacokinetic evaluation revealed
`no evidence of clinically significant race-related differences in the pharmacokinetics of
`aripiprazole. No dosage adjustment is recommended based on race.
`
`Smoking
`
`Based on studies utilizing human liver enzymes in vitro, aripiprazole is not a substrate for
`CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore,
`not have an effect on the pharmacokinetics of aripiprazole. Consistent with these in vitro
`results, population pharmacokinetic evaluation did not
`reveal any significant
`pharmacokinetic differences between smokers and nonsmokers. No dosage adjustment is
`recommended based on smoking status.
`
`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.
`
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`

`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
`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 co-
`administered at steady state, the Cmax and AUC of aripiprazole were decreased by 25%.
`No dosage adjustment of aripiprazole is required when administered concomitantly with
`valproate.
`
`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 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.
`
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`

`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
`
`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 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
`
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`

`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.
`
`INDICATIONS AND USAGE
`
`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 long-term efficacy of aripiprazole in the treatment of schizophrenia has not been
`established. 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.
`
`CONTRAINDICATIONS
`
`ABILIFY is contraindicated in patients with a known hypersensitivity to the product.
`
`WARNINGS
`
`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
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`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 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.
`
`PRECAUTIONS
`
`General
`
`Orthostatic Hypotension
`
`Aripiprazole may be associated with orthostatic hypotension, perhaps due to its a 1-
`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%, aripiprazole 1.9%), orthostatic
`lightheadedness (placebo 1%, aripiprazole 0.9%), and syncope (placebo 1%, aripiprazole
`0.6%). The incidence of a significant orthostatic change in blood pressure (defined as a
`decrease of at least 30 mmHg in systolic blood pressure when changing from a supine to
`standing position) for aripiprazole was not statistically different from placebo (14%
`among aripiprazole-treated patients and 12% 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 in short-term, placebo-
`controlled trials. 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 or older.
`
`Potential for Cognitive and Motor Impairment
`
`In short-term, placebo-controlled trials, 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 on ABILIFY in short-term, placebo-controlled trials. 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.
`
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`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 PRECAUTIONS: Use in Patients with Concomitant Illness).
`
`Suicide
`
`The possibility of a suicide attempt is inherent in psychotic illnesses, and close
`supervision of high-risk patients should accompany drug therapy. Prescriptions for
`ABILIFY should be written for the smallest quantity of tablets consistent with good
`patient management in order to reduce the risk of overdose.
`
`Use in Patients with Concomitant Illness
`
`Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s
`Disease: In a flexible dose (2 to 15 mg/day), 10-week, placebo-controlled study of
`aripiprazole in elderly patients (mean age: 81.5 years; range: 56-95) with psychosis
`associated with Alzheimer’s dementia, 4 of 105 patients (3.8%) who received ABILIFY
`died compared to no deaths among 102 patients who received placebo during or within
`30 days after termination of the double-blind portion of the study. Three of the patients
`(age 92, 91, and 87 years) died following the discontinuation of ABILIFY in the double-
`blind phase of the study (causes of death were pneumonia, heart failure, and shock). The
`fourth patient (age 78 years) died following hip surgery while in the double-blind portion
`of the study. The treatment-emergent adverse events that were reported at an incidence
`of ‡5% and having a greater incidence than placebo in this study were accidental injury,
`somnolence, and bronchitis. Eight percent of the ABILIFY treated patients reported
`somnolence compared to 1% of placebo patients. In a small pilot, open-label, ascending-
`dose, cohort study (n=30) in elderly patients with dementia, ABILIFY was associated in a
`dose-related fashion with somnolence.
`
`The safety and efficacy of ABILIFY in the treatment of patients with psychosis
`associated with dementia has not been established. If the prescriber elects to treat such
`patients with ABILIFY, vigilance should be exercised, particularly for the emergence of
`difficulty swallowing or excessive somnolence, which could predispose to accidental
`injury or aspiration.
`
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`

`Clinical experience with ABILIFY in patients with certain concomitant systemic illnesses
`(see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment and
`Hepatic Impairment) 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 premarketing clinical studies.
`
`Information for Patients
`
`Physicians are advised to discuss the following issues with patients for whom they
`prescribe ABILIFY:
`
`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.
`
`Pregnancy
`
`Patients should be advised to notify their physician if they become pregnant or intend to
`become pregnant during therapy with ABILIFY.
`
`Nursing
`
`Patients should be advised not to breast-feed an infant if they are taking 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-Drug Interactions
`
`11
`
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`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 a 1-
`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, 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.
`
`Ketoconazole: Coadministration 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 one-half 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: Coadministration 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 one-half of its normal dose
`when concomitant administration of quinidine with aripiprazole occurs. Other significant
`inhibitors of CYP2D6, such as 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.
`
`Carbamazepine: Coadministration of carbamazepine (200 mg BID), a potent CYP3A4
`inducer, with aripiprazole (30 mg QD) resulted in an approximate 70% decrease in Cmax
`and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole.
`When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be
`doubled. Additional dose increases should be based on clinical evaluation. When
`carbamazepine is withdrawn from the combination therapy, aripiprazole dose should then
`be reduced.
`
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`No clinically significant effect of famotidine, valproate, or lithium was seen on the
`pharmacokinetics of aripiprazole (see CLINICAL PHARMACOLOGY: Drug-Drug
`Interactions).
`
`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
`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 Clinical Pharmacology: Drug-Drug Interactions).
`
`Alcohol: There was no significant difference between aripiprazole coadministered with
`ethanol and placebo coadministered 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.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`
`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 to 5 and
`0.3 to 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 to 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 to 30 mg/kg/day (0.1 to 0.9 times human exposure at MRHD based on AUC
`and 0.5 to 5 times the MRHD based on mg/m2).