Aripiprazole (intramuscular): Difference between revisions

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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag={{KS}}
|authorTag={{MN}}
|genericName=Aripiprazole
|genericName=Aripiprazole lauroxil
|aOrAn=an
|aOrAn=an
|drugClass=atypical antipsychotic
|drugClass=atypical [[antipsychotic]]
|indicationType=treatment
|indicationType=treatment
|indication=[[schizophrenia]], [[bipolar I disorder]], [[major depressive disorder]], and [[irritability]] associated with [[autistic disorder]]
|indication=patients with [[schizophrenia]]  
|adverseReactions=akathisia (≥5%)
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions=[[nausea]], [[vomiting]], [[constipation]], [[headache]], [[dizziness]], [[akathisia]], [[anxiety]], [[insomnia]], and [[restlessness]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS</span>
|blackBoxWarningTitle=WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY AND ANTIDEPRESSANT DRUGS
|blackBoxWarningBody=<i><span style="color:#FF0000;">
|blackBoxWarningBody=* Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.
Elderly patients with [[dementia]]-related [[psychosis]] treated with antipsychotic drugs are at an increased risk of death. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.
</span></i>
|fdaLIADAdult=
======Indications======
Aripiprazole lauroxil is indicated for treatment of [[schizophrenia]].


* Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ABILIFY is not approved for use in pediatric patients with depression.
======Dosage======
|fdaLIADAdult======[[Schizophrenia]]=====
:*'''Treatment of [[Schizophrenia]]'''
::*Aripiprazole lauroxil is only to be administered as an [[intramuscular]] injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with Aripiprazole lauroxil. Due to the [[half-life]] of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.


* Dosing Information
::*Depending on individual patient's needs, treatment with Aripiprazole lauroxil can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, which corresponds to 300 mg, 450 mg and 600 mg of aripiprazole, respectively. Treatment may also be initiated with the 882 mg dose every 6 weeks.


:* The recommended starting and target dose for ABILIFY is '''10 mg/day or 15 mg/day''' administered on a once-a-day schedule without regard to meals.
::*Administer Aripiprazole lauroxil either in the deltoid muscle (441 mg dose only) or gluteal muscle (441 mg, 662 mg or 882 mg).


:* Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either ABILIFY 15 mg/day or placebo, and observed for relapse. Patients should be periodically reassessed to determine the continued need for maintenance treatment.
:*'''Table 1: Aripiprazole lauroxil Dosing Frequency and Site of Injection'''
[[File:table1_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


=====Bipolar I Disorder=====
::*Use the following Aripiprazole lauroxil doses for patients who are stabilized on oral aripiprazole, as shown in TABLE 2.


* Dosing Information
:*'''Table 2: Aripiprazole lauroxil Doses Based on Oral Aripiprazole Total Daily Dose'''
[[File:table2_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


:* Acute Treatment of Manic and Mixed Episodes
::*In conjunction with the first Aripiprazole lauroxil injection, administer treatment with oral aripiprazole for 21 consecutive days.
::* ABILIFY is indicated for the acute treatment of manic and mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or valproate. Efficacy as monotherapy was established in four 3-week monotherapy trials in adults and one 4-week monotherapy trial in pediatric patients (10 to 17 years). Efficacy as adjunctive therapy was established in one 6-week adjunctive trial in adults .


:* Maintenance Treatment of Bipolar I Disorder
::*Dose may be adjusted as needed. When making dose and dosing interval adjustments, the [[pharmacokinetics]] and prolonged-release characteristics of Aripiprazole lauroxil should be considered.
::* ABILIFY is indicated for the maintenance treatment of bipolar I disorder, both as monotherapy and as an adjunct to either lithium or valproate. Maintenance efficacy was demonstrated in one monotherapy maintenance trial and in one adjunctive maintenance trial in adults .


=====Adjunctive Treatment of Major Depressive Disorder=====
:*'''Missed Doses'''
::*When a dose is missed, administer the next injection of Aripiprazole lauroxil as soon as possible. If the time elapsed since the last Aripiprazole lauroxil injection exceeds the length of time noted in TABLE 3, use oral aripiprazole supplementation with the next Aripiprazole lauroxil injection as recommended below.


* Dosing Information
:*'''Table 3: Recommendation for Concomitant Oral Aripiprazole Supplementation Following Missed Doses(a)'''
[[File:table3_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>


:* ABILIFY is indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD). Efficacy was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant therapy during the current episode.


=====Irritability Associated with [[Autistic Disorder]]=====
:*'''Early Dosing'''
::*The recommended Aripiprazole lauroxil dosing interval is either monthly for the 441 mg, 662 mg and 882 mg doses or every 6 weeks for 882 mg dose and should be maintained. In the event of early dosing, an Aripiprazole lauroxil injection should not be given earlier than 14 days after the previous injection.


* Dosing Information
:*'''Dose Adjustments for [[CYP450]] Considerations'''
::*Refer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking oral aripiprazole concomitantly with the first dose of Aripiprazole lauroxil.


:* ABILIFY is indicated for the treatment of irritability associated with autistic disorder. Efficacy was established in two 8-week trials in pediatric patients (aged 6 to 17 years) with irritability associated with autistic disorder (including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods) .
::*Once stabilized on Aripiprazole lauroxil, refer to the dosing recommendations below for patients taking [[CYP2D6]] inhibitors, [[CYP3A4]] inhibitors, or [[CYP3A4]] inducers:


=====Agitation Associated with [[Schizophrenia]] or [[Bipolar Mania]] (Intramuscular Injection)=====
:::- No dosage changes recommended for Aripiprazole lauroxil, if [[CYP450]] modulators are added for less than 2 weeks.
:::- Make dose changes to Aripiprazole lauroxil if [[CYP450]] modulators are added for greater than 2 weeks (see TABLE 4).


* Dosing Information
:*'''Table 4: Aripiprazole lauroxil Dose Adjustments with Concomitant CYP450 Modulator Use'''
[[File:table4_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>


:* ABILIFY Injection is indicated for the acute treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed. “Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension.” Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care (eg, threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior), leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation. Efficacy was established in three short-term (24-hour) trials in adults .


=====Dosage Adjustment=====


Dosage adjustments in adults are not routinely indicated on the basis of age, gender, race, or renal or hepatic impairment status.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aripiprazole lauroxil in adult patients.
* Dosage adjustment for patients taking aripiprazole concomitantly with strong [[CYP3A4]] inhibitors: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to one-half of the usual dose. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aripiprazole lauroxil in adult patients.
|fdaLIADPed=Safety and effectiveness of Aripiprazole lauroxil in patients <18 years of age have not been evaluated.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aripiprazole lauroxil in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aripiprazole lauroxil in pediatric patients.
|contraindications=Aripiprazole lauroxil is contraindicated in patients with a known [[hypersensitivity]] reaction to aripiprazole. Hypersensitivity reactions have ranged from [[pruritus]]/[[urticaria]] to [[anaphylaxis]].
|warnings=
======Increased Mortality in Elderly Patients with [[Dementia]]-related [[Psychosis]]======
Elderly patients with dementia-related psychosis treated with [[antipsychotic]] drugs are at an increased risk of death. Analyses of 17 [[placebo]]-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death 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.


* Dosage adjustment for patients taking aripiprazole concomitantly with potential [[CYP2D6]] inhibitors: When concomitant administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at least to one-half of its normal dose. When the [[CYP2D6]] inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased. When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., [[heart failure]], [[sudden death]]) or infectious (e.g., [[pneumonia]]) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.
* Dosing recommendation in patients taking aripiprazole concomitantly with strong [[CYP3A4]] and CYP2D6 inhibitors: When concomitant administration of aripiprazole with strong inhibitors of CYP3A4 (such as [[ketoconazole]] or [[clarithromycin]]) and CYP2D6 (such as [[quinidine]], [[fluoxetine]], or [[paroxetine]]) is indicated, the aripiprazole dose should be reduced to one-quarter (25%) of the usual dose. When the CYP3A4 and/or CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased.


* Dosing recommendation in patients taking aripiprazole concomitantly with strong, moderate, or weak inhibitors of CYP3A4 and CYP2D6: Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (eg, a potent CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.
======Cerebrovascular Adverse Reactions, Including [[Stroke]]======
In [[placebo]]-controlled trials with [[risperidone]], [[aripiprazole]], and [[olanzapine]] in elderly patients with [[dementia]], there was a higher incidence of cerebrovascular adverse reactions ([[cerebrovascular accidents]] and [[transient ischemic attack]]s) including fatalities compared to placebo-treated patients. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.


* Dosing recommendation in patients who are classified as CYP2D6 poor metabolizers (PM): The aripiprazole dose in PM patients should initially be reduced to one-half (50%) of the usual dose and then adjusted to achieve a favorable clinical response. The dose of aripiprazole for PM patients who are administered a strong CYP3A4 inhibitor should be reduced to one-quarter (25%) of the usual dose.
======[[Neuroleptic Malignant Syndrome]]======
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with [[antipsychotic]] drugs, including Aripiprazole lauroxil. 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]].


* Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10 mg to 15 mg.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., [[pneumonia]], systemic infection, etc.) and untreated or inadequately treated [[extrapyramidal sign]]s and symptoms (EPS). Other important considerations in the differential diagnosis include central [[anticholinergic]] toxicity, [[heat stroke]], [[drug fever]], and primary [[central nervous system]] pathology.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aripiprazole in adult patients.
|offLabelAdultNoGuideSupport======Borderline personality disorder=====


* Dosing Information
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.


:* Aripiprazole 10-15 mg/day added to [[sertraline]] 100-200 mg/day<ref name="pmid18848360">{{cite journal| author=Bellino S, Paradiso E, Bogetto F| title=Efficacy and tolerability of aripiprazole augmentation in sertraline-resistant patients with borderline personality disorder. | journal=Psychiatry Res | year= 2008 | volume= 161 | issue= 2 | pages= 206-12 | pmid=18848360 | doi=10.1016/j.psychres.2007.07.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18848360  }} </ref>
If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.
|fdaLIADPed=* Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
|offLabelPedGuideSupport=There is limited information about the guideline-supported off label used in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information about the non-guideline-supported off label used in pediatric patients.
|contraindications=* Known [[hypersensitivity reaction]] to ABILIFY. Reactions have ranged from [[pruritus]]/[[urticaria]] to [[anaphylaxis]].
|warnings======Use in Elderly Patients with Dementia-Related Psychosis=====
======Increased Mortality======
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis
======Cerebrovascular Adverse Events, Including Stroke======
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.
======Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease======
* In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation [placebo 0%, aripiprazole 4%], and lightheadedness [placebo 1%, aripiprazole 4%].


* The safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with ABILIFY, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.
======[[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 predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.


=====Suicidal Thoughts and Behaviors in Adolescents and Young Adults=====
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.


* Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.


* The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 4.  
Given these considerations, Aripiprazole lauroxil 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. 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.


[[File:Abilify T04.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
If signs and symptoms of tardive dyskinesia appear in a patient treated with Aripiprazole lauroxil drug discontinuation should be considered. However, some patients may require treatment with Aripiprazole lauroxil despite the presence of the syndrome.


* No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
======Metabolic Changes======
It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
Atypical [[antipsychotic]] drugs have been associated with metabolic changes that include [[hyperglycemia]]/[[diabetes mellitus]], [[dyslipidemia]], and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
* All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
* The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
* Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
* Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
* Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
* It should be noted that ABILIFY is not approved for use in treating depression in the pediatric population.


=====Neuroleptic Malignant Syndrome (NMS)=====
:*'''[[Hyperglycemia]]/ [[Diabetes Mellitus]]'''
* A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
* The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary 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=====
::*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 reports of hyperglycemia in patients treated with oral aripiprazole. 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 suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
* 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.
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.


=====Metabolic Changes=====
::*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 (e.g., [[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 require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
* Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.


=====Hyperglycemia/Diabetes Mellitus=====
::*In the long-term, open-label [[schizophrenia]] study with Aripiprazole lauroxil, 14% of patients with normal hemoglobin [[A1c]] (<5.7%) at baseline developed elevated levels (≥5.7%) post-baseline.
* 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 reports of hyperglycemia in patients treated with ABILIFY [see ADVERSE REACTIONS (6.2, 6.3)]. 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 suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. 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 anti-diabetic treatment despite discontinuation of the suspect drug.


======Adults======
:*'''[[Dyslipidemia]]'''
* In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 5 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).


[[File:Abilify T05.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
::*Undesirable alterations in [[lipids]] have been observed in patients treated with atypical [[antipsychotics]].


* At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].
::*In the long-term, open-label [[schizophrenia]] study with Aripiprazole lauroxil, shifts in baseline fasting total [[cholesterol]] from normal (<200 mg/dL) to high (≥240 mg/dL) were reported in 1% of patients; shifts in baseline fasting [[LDL]] cholesterol from normal (<100 mg/dL) to high (≥160 mg/dL) were reported in 1% of patients; and shifts in baseline fasting [[triglycerides]] from normal (<150 mg/dL) to high (≥200 mg/dL) were reported in 8% of patients. In the same study, shifts in baseline fasting total [[cholesterol]] from borderline (≥ 200 mg/dL and <240 mg/dL) to high (≥240 mg/dL) were reported in 15% of patients; shifts in baseline fasting [[LDL]] cholesterol from borderline (≥100 mg/dL and <160 mg/dL) to high (≥160 mg/dL) were reported in 8% of patients; and shifts in baseline fasting [[triglycerides]] from borderline (≥150 mg/dL and <200 mg/dL) to high (≥200 mg/dL) were reported in 35% of patients. In addition, the proportion of patients with shifts in fasting HDL [[cholesterol]] from normal (≥40 mg/dL) to low (<40 mg/dL) was reported in 15% of patients.
* The mean change in fasting glucose in adjunctive aripiprazole-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 6 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder.


[[File:Abilify T06.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*'''Weight Gain'''


======Pediatric Patients and Adolescents======
::*Weight gain has been observed with atypical [[antipsychotic]] use. Clinical monitoring of weight is recommended.
* In an analysisof two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in aripiprazole-treated patients (–0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6 mg/dL; N=33). Table 7 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure of 42-43 days) as well as from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days).


[[File:Abilify T07.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
::*The proportion of adult patients with weight gain ≥7% of body weight is presented in TABLE 6.


* At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].
:*'''Table 6: Proportion of Adult Patients with Shifts in Weight in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial'''
[[File:table7_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>


=====Dyslipidemia=====
======Pathological Gambling and Other Compulsive Behaviors======
* Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm for the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
* There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.


======Adults======
======[[Orthostatic Hypotension]]======
* Table 8 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).
Aripiprazole may cause orthostatic hypotension, perhaps due to its [[α1-adrenergic receptor]] antagonism. Associated adverse reactions related to orthostatic hypotension can include [[dizziness]], [[lightheadedness]] and [[tachycardia]]. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from [[hypotension]] include those with [[dehydration]], [[hypovolemia]], treatment with [[antihypertensive]] medication, history of cardiovascular disease (e.g., [[heart failure]], [[myocardial infarction]], [[ischemia]], or [[conduction abnormalities]]), history of [[cerebrovascular disease]], as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose, and monitor orthostatic vital signs.


[[File:Abilify T08.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Orthostatic hypotension was reported for one patient in the Aripiprazole lauroxil 882 mg group (0.5%) and no patients in the Aripiprazole lauroxil 441 mg and [[placebo]] groups in the 12-week [[schizophrenia]] efficacy study. In the long-term open-label schizophrenia study, orthostatic hypotension was reported for 1 (0.2%) patient treated with Aripiprazole lauroxil. Orthostatic hypotension was defined as a decrease in [[systolic blood pressure]] ≥20 mmHg accompanied by an increase in [[heart rate]] ≥25 bpm when comparing standing to [[supine]] values.


* In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.
======[[Leukopenia]], [[Neutropenia]], and [[Agranulocytosis]]======
* Table 9 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days).
In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to [[antipsychotic]] agents. Agranulocytosis has also been reported.


[[File:Abilify T09.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Possible risk factors for leukopenia/neutropenia include pre-existing low [[white blood cell]] count (WBC)/absolute [[neutrophil]] count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a [[complete blood count]] (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Aripiprazole lauroxil at the first sign of a clinical significant decline in WBC in the absence of other causative factors.


======Pediatric Patients and Adolescents======
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Aripiprazole lauroxil in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.
* Table 10 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days).


[[File:Abilify T10.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
======[[Seizures]]======
As with other [[antipsychotic]] drugs, use Aripiprazole lauroxil cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.


* In monotherapy trials of adolescents with schizophrenia and pediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.
======Potential for Cognitive and Motor Impairment======
* Table 11 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder.
Aripiprazole lauroxil, like other [[antipsychotics]], has 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 Aripiprazole lauroxil does not affect them adversely.


[[File:Abilify T11.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
======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 lauroxil for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with [[anticholinergic]] activity, or being subject to [[dehydration]]).


=====Weight Gain=====
======[[Dysphagia]]======
* Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
[[Esophageal dysmotility]] and [[aspiration]] have been associated with [[antipsychotic]] drug use. Aripiprazole lauroxil and other antipsychotic drugs should be used cautiously in patients at risk for [[aspiration pneumonia]].


======Adults======
|clinicalTrials=
* In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.
The following are discussed in more details in other sections of the labeling:
In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive aripiprazole was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.
* Table 12 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.


[[File:Abilify T12.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Increased Mortality in Elderly Patients with [[Dementia]]-related [[Psychosis]]
:*Cerebrovascular Adverse Reactions, Including [[Stroke]]
:*[[Neuroleptic Malignant Syndrome]]
:*[[Tardive Dyskinesia]]
:*Metabolic Changes
:*Pathological Gambling and Other Compulsive Behaviors
:*[[Orthostatic Hypotension]]
:*[[Leukopenia]], [[Neutropenia]], and [[Agranulocytosis]]
:*[[Seizures]]
:*Potential for Cognitive and Motor Impairment
:*Body Temperature Regulation
:*[[Dysphagia]]  


======Pediatric Patients and Adolescents======
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
* In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.
* In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients.
* Table 13 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication.


[[File:Abilify T13.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
======Aripiprazole lauroxil======


* In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with ABILIFY. After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD.
:*Patient Exposure: Aripiprazole lauroxil has been evaluated for safety in 880 adult patients in clinical trials in [[schizophrenia]].
* In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with ABILIFY. The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment.
* When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.


=====Orthostatic Hypotension=====
:*Commonly Observed Adverse Reactions: The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with Aripiprazole lauroxil) was [[akathisia]].
* Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 17 years of age (n=611) on oral ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.3%, 0%), and syncope (0.2%, 0%); and of patients on ABILIFY Injection (n=501) included orthostatic hypotension (0.6%, 0%), postural dizziness (0.2%, 0.5%), and syncope (0.4%, 0%).
* The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), in pediatric oral aripiprazole-treated patients aged 6 to 17 years (0.2%, 1%), or in aripiprazole injection-treated patients (3%, 2%).
* Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).
* If parenteral benzodiazepine therapy is deemed necessary in addition to aripiprazole injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see DRUG INTERACTIONS (7.3)].


=====Leukopenia, Neutropenia, and Agranulocytosis=====
:*Adverse Reactions Occurring at an Incidence of 2% or More in Aripiprazole lauroxil-Treated Patients: Adverse reactions associated with the use of Aripiprazole lauroxil (incidence of 2% or greater, rounded to the nearest percent and Aripiprazole lauroxil incidence greater than [[placebo]]) that occurred are shown in TABLE 7.
* Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. Agranulocytosis has also been reported.
* Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
* Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ABILIFY and have their WBC followed until recovery.


=====Seizures/Convulsions=====
:*'''Table 7: Adverse Reaction in 2% or More of Aripiprazole lauroxil-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial'''
* In short-term, placebo-controlled trials, seizures/convulsions occurred in 0.1% (3/2467) of adult patients treated with oral aripiprazole, in 0.2% (1/611) of pediatric patients (6 to 17 years), and in 0.2% (1/501) of adult aripiprazole injection-treated patients.
[[File:table8_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
* 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=====
:*Injection Site Reactions: Injection site reactions were reported by 4% of patients treated with 441 mg Aripiprazole lauroxil and 5% of patients treated with 882 mg Aripiprazole lauroxil compared to 2% of patients treated with [[placebo]]. Most of these were injection site pain (3%, 4% and 2% in the 441 mg Aripiprazole lauroxil, 882 mg Aripiprazole lauroxil and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of Aripiprazole lauroxil and placebo. Other injection site reactions ([[induration]], swelling and redness) occurred at less than 1%.
* ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2467) treated with oral ABILIFY (11%, 6%), in pediatric patients ages 6 to 17 (n=611) (24%, 6%), and in adult patients (n=501) on ABILIFY Injection (9%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (15/611) of pediatric patients (6 to 17 years) on oral ABILIFY in short-term, placebo-controlled trials, but did not lead to discontinuation of any adult patients on ABILIFY Injection.
* Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY does not affect them adversely.


=====Body Temperature Regulation=====
:*[[Extrapyramidal Symptoms]]: In the 12-week [[schizophrenia]] efficacy study, for Aripiprazole lauroxil-treated patients, the incidence of other EPS-related events, excluding [[akathisia]] and [[restlessness]], was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patient (TABLE 8).
* Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see ADVERSE REACTIONS (6.3)].


=====Suicide=====
:*'''Table 8: Incidence of EPS Compared to Placebo'''
* The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive 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 [see ADVERSE REACTIONS (6.2, 6.3)].
[[File:table9_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
In two 6-week, placebo-controlled studies of aripiprazole as adjunctive treatment of major depressive disorder, the incidences of suicidal ideation and suicide attempts were 0% (0/371) for aripiprazole and 0.5% (2/366) for placebo.
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>


=====Dysphagia=====
:*[[Dystonia]]: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: [[spasm]] of the neck muscles, sometimes progressing to [[tightness]] of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation [[antipsychotic]] drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
* Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE REACTIONS (6.3)].


=====Use in Patients with Concomitant Illness=====
:*Other Adverse Reactions Observed in Clinical Studies: The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
* Clinical experience with ABILIFY in patients with certain concomitant systemic illnesses is limited [see USE IN SPECIFIC POPULATIONS (8.6, 8.7)].
* ABILIFY has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies [see WARNINGS AND PRECAUTIONS (5.1, 5.6)].


|clinicalTrials====Overall Adverse Reactions Profile===
::*Cardiac – [[angina pectoris]], [[tachycardia]], [[palpitations]]
*The following are discussed in more detail in other sections of the labeling:
 
:*Use in Elderly Patients with Dementia-Related Psychosis
::*Gastrointestinal disorders – [[constipation]], [[dry mouth]]
:*Suicidal Thoughts and Behaviors in Adolescents and Young Adults
 
:*Neuroleptic Malignant Syndrome (NMS)
::*General disorders – [[asthenia]]
:*Tardive Dyskinesia
 
:*Metabolic Changes
::*Musculoskeletal – [[muscular weakness]]
:*Orthostatic Hypotension
 
:*Leukopenia, Neutropenia, and Agranulocytosis
::*Nervous system disorders – [[dizziness]]
:*Seizures/Convulsions
 
:*Potential for Cognitive and Motor Impairment
::*Psychiatric disorders – [[anxiety]], [[suicide]]
:*Body Temperature Regulation
:*Suicide
:*Dysphagia
:*Use in Patients with Concomitant Illness 
*The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.
*The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.
*Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure.
*Aripiprazole has been evaluated for safety in 920 patients (6 to 17 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, or autistic disorder and who had approximately 517 patient-years of exposure to oral aripiprazole. A total of 465 pediatric patients were treated with oral aripiprazole for at least 180 days and 117 pediatric patients treated with oral aripiprazole had at least 1 year of exposure.
*The conditions and duration of treatment with aripiprazole (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.
*Adverse events during exposure were obtained by collecting volunteered adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.
*The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; ie, all events meeting the defined criteria, regardless of investigator causality, are included.
*Throughout this section, adverse reactions are reported. These are adverse events that were considered to be reasonably associated with the use of ABILIFY (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for ABILIFY often cannot be reliably established in individual cases.
*The figures in 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 prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.
==== Clinical Studies Experience====
=====Adult Patients with Schizophrenia=====
*The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.
======Adverse Reactions Associated with Discontinuation of Treatment======
*Overall, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients.
======Commonly Observed Adverse Reactions======
*The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).
=====Adult Patients with Bipolar Mania=====
*Monotherapy
:*The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral aripiprazole was administered at doses of 15 mg/day or 30 mg/day.
======Adverse Reactions Associated with Discontinuation of Treatment======
*Overall, in patients with bipolar mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated (10%) patients. The types of adverse reactions that led to discontinuation were similar between the aripiprazole-treated and placebo-treated patients.
======Commonly Observed Adverse Reactions======
*Commonly observed adverse reactions associated with the use of aripiprazole in patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 14.


[[File:Abilify T14.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
======Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole======


======Less Common Adverse Reactions in Adults======
The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Aripiprazole lauroxil.
*Table 15 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more 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.


[[File:Abilify T15.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Blood and Lymphatic System Disorders: [[thrombocytopenia]]


*An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.
:*Cardiac Disorders: [[bradycardia]], [[atrial flutter]], [[cardiorespiratory arrest]], [[atrioventricular block]], [[atrial fibrillation]], [[myocardial ischemia]], [[myocardial infarction]], [[cardiopulmonary failure]]
=====Adult Patients with Adjunctive Therapy with Bipolar Mania=====
*The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which aripiprazole was administered at doses of 15 mg/day or 30 mg/day as adjunctive therapy with lithium or valproate.
======Adverse Reactions Associated with Discontinuation of Treatment======
*In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).
======Commonly Observed Adverse Reactions======
*The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.
=====Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania=====
*Table 16 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses of 15 mg/day or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.


[[File:Abilify T16.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Eye Disorders: [[photophobia]], [[diplopia]]


=====Pediatric Patients (13 to 17 years) with Schizophrenia=====
:*Gastrointestinal Disorders: [[gastroesophageal reflux disease]]
*The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.
======Adverse Reactions Associated with Discontinuation of Treatment======
*The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.
======Commonly Observed Adverse Reactions======
*Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.


[[File:Abilify T17.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*General Disorders and Administration Site Conditions: [[peripheral edema]], [[chest pain]], face [[edema]]


=====Pediatric Patients (10 to 17 years) with Bipolar Mania=====
:*Hepatobiliary Disorders: [[hepatitis]], [[jaundice]]
*The following findings are based on one 4-week, placebo-controlled trial in which oral aripiprazole was administered in doses of 10 mg/day or 30 mg/day.
======Adverse Reactions Associated with Discontinuation of Treatment======
*The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.
======Commonly Observed Adverse Reactions======
*Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 17.


[[File:Abilify T18.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Immune System Disorders: [[hypersensitivity]]


=====Pediatric Patients (6 to 17 years) with Autistic Disorder=====
:*Injury, Poisoning, and Procedural Complications: fall, [[heat stroke]]
*The following findings are based on two 8-week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 mg/day to 15 mg/day.
======Adverse Reactions Associated with Discontinuation of Treatment======
*The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.
======Commonly Observed Adverse Reactions======
*Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 18.


=====Less Common Adverse Reactions in Pediatric Patients (6 to 17 years) with Schizophrenia, Bipolar Mania, or Autistic Disorder=====
:*Investigations: weight decreased, hepatic [[enzyme]] increased, blood glucose increased, blood [[lactate dehydrogenase]] increased, [[gamma glutamyl transferase]] increased, blood [[prolactin]] increased, blood [[urea]] increased, blood [[creatinine]] increased, blood [[bilirubin]] increased, [[electrocardiogram]] [[QT]] prolonged, [[glycosylated hemoglobin]] increased
*Table 19 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, and up to 8 weeks in autistic disorder), including only those reactions that occurred in 1% or more of pediatric patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.


[[File:Abilify T19.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Metabolism and Nutrition Disorders: [[anorexia]], [[hypokalemia]], [[hyponatremia]], [[hypoglycemia]]


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


[[File:Abilify T20.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Nervous System Disorders: memory impairment, [[cogwheel rigidity]], [[hypokinesia]], [[myoclonus]], [[bradykinesia]], [[akinesia]], [[myoclonus]], coordination abnormal, [[speech disorder]], [[choreoathetosis]]


=====Patients with Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)=====
:*Psychiatric Disorders: aggression, loss of [[libido]], [[delirium]], libido increased, [[anorgasmia]], [[tic]], homicidal ideation, [[catatonia]], [[sleep walking]]
*The following findings are based on a pool of three placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar mania in which aripiprazole injection was administered at doses of 5.25 mg to 15 mg.
======Adverse Reactions Associated with Discontinuation of Treatment======
*Overall, in patients with agitation associated with schizophrenia or bipolar mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (0.8%) and placebo-treated (0.5%) patients.
======Commonly Observed Adverse Reactions======
*There was one commonly observed adverse reaction (nausea) associated with the use of aripiprazole injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo).
======Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania======
*Table 21 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with aripiprazole injection (doses ≥5.25 mg/day) and for which the incidence in patients treated with aripiprazole injection was greater than the incidence in patients treated with placebo in the combined dataset.


[[File:Abilify T21.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
:*Renal and Urinary Disorders: [[urinary retention]], [[nocturia]]


====Dose-Related Adverse Reactions====
:*Reproductive System and Breast Disorders: [[erectile dysfunction]], [[gynaecomastia]], menstruation irregular, [[amenorrhea]], [[breast pain]], [[priapism]]
=====Schizophrenia=====
*Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).
*In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).
=====Bipolar Mania=====
*In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).
=====Autistic Disorder=====
*In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).
====Extrapyramidal Symptoms====
======Schizophrenia======
*In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% 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 adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, −0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, −0.29).
*Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo.
=====Bipolar Mania=====
*In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive aripiprazole-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% vs. 2% for placebo.
*In the adult bipolar mania trials with monotherapy aripiprazole, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.50; placebo, −0.01 and aripiprazole, 0.21; placebo, −0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the bipolar mania trials with aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.73; placebo, 0.07 and aripiprazole, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.90; placebo, –0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.
=====Major Depressive Disorder=====
*In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.
*In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.
=====Autistic Disorder=====
*In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo.
*In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.1; placebo, −0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.
=====Agitation Associated with Schizophrenia or Bipolar Mania=====
*In the placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between aripiprazole and placebo.
=====Dystonia=====
*Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
=====Laboratory Test Abnormalities=====
*A between group comparison for 3-week to 6-week, placebo-controlled trials in adults or 4-week to 8-week, placebo-controlled trials in pediatric patients (6 to 17 years) revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis in adult or pediatric patients.
=====ECG Changes=====
*Between group comparisons for a pooled analysis of placebo-controlled trials in patients with schizophrenia, bipolar mania, or major depressive disorder revealed no significant differences between oral 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 2 beats per minute compared to no increase among placebo patients.
*In the pooled, placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, there were no significant differences between aripiprazole injection and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, as measured by standard 12-lead ECGs.
====Additional Findings Observed in Clinical Trials====
=====Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials=====
*The adverse reactions reported in a 26-week, double-blind trial comparing oral ABILIFY and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for ABILIFY vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of ABILIFY. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor was 5% (40/859) for ABILIFY. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder.
=====Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole=====
*Following is a list of MedDRA terms that reflect adverse reactions as defined in ADVERSE REACTIONS (6.1) reported by patients treated with oral aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of ADVERSE REACTIONS (6), or those considered in WARNINGS AND PRECAUTIONS (5) or OVERDOSAGE (10) have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.
*Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.
======Adults - Oral Administration======
*Blood and Lymphatic System Disorders:
≥1/1000 patients and <1/100 patients - leukopenia, neutropenia, thrombocytopenia
*Cardiac Disorders:
≥1/1000 patients and <1/100 patients - bradycardia, palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischemia; <1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia
*Eye Disorders:
≥1/1000 patients and <1/100 patients - photophobia, diplopia, eyelid edema, photopsia
*Gastrointestinal Disorders:
≥1/1000 patients and <1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; <1/1000 patients - pancreatitis
*General Disorders and Administration Site Conditions:
≥1/100 patients - asthenia, peripheral edema, chest pain; ≥1/1000 patients and <1/100 patients - face edema, angioedema; <1/1000 patients - hypothermia
Hepatobiliary Disorders:
<1/1000 patients - hepatitis, jaundice
*Immune System Disorders:
≥1/1000 patients and <1/100 patients - hypersensitivity
Injury, Poisoning, and Procedural Complications:
≥1/100 patients - fall; ≥1/1000 patients and <1/100 patients - self mutilation; <1/1000 patients - heat stroke
*Investigations:
≥1/100 patients - weight decreased, creatine phosphokinase increased; ≥1/1000 patients and <1/100 patients - hepatic enzyme increased, blood glucose increased, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood creatinine increased, blood bilirubin increased; <1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased, gamma-glutamyl transferase increased
*Metabolism and Nutrition Disorders:
≥1/1000 patients and <1/100 patients - hyperlipidemia, anorexia, diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine present), hyperglycemia, hypokalemia, hyponatremia, hypoglycemia, polydipsia; <1/1000 patients - diabetic ketoacidosis
*Musculoskeletal and Connective Tissue Disorders:
≥1/1000 patients and <1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; <1/1000 patients - rhabdomyolysis
*Nervous System Disorders:
≥1/100 patients - coordination abnormal; ≥1/1000 patients and <1/100 patients - speech disorder, parkinsonism, memory impairment, cogwheel rigidity, cerebrovascular accident, hypokinesia, tardive dyskinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia; <1/1000 patients - Grand Mal convulsion, choreoathetosis
*Psychiatric Disorders:
≥1/100 patients - suicidal ideation; ≥1/1000 patients and <1/100 patients - aggression, loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000 patients - catatonia, sleep walking
*Renal and Urinary Disorders:
≥1/1000 patients and <1/100 patients - urinary retention, polyuria, nocturia
Reproductive System and Breast Disorders:
≥1/1000 patients and <1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; <1/1000 patients - gynaecomastia, priapism
*Respiratory, Thoracic, and Mediastinal Disorders:
≥1/100 patients - nasal congestion, dyspnea, pneumonia aspiration
*Skin and Subcutaneous Tissue Disorders:
≥1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥1/1000 patients and <1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria
*Vascular Disorders:
≥1/100 patients - hypertension; ≥1/1000 patients and <1/100 patients - hypotension
======Pediatric Patients - Oral Administration======
Most adverse events observed in the pooled database of 920 pediatric patients, aged 6 to 17 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.
*Gastrointestinal Disorders:
≥1/1000 patients and <1/100 patients - tongue dry, tongue spasm
*Investigations:
≥1/100 patients - blood insulin increased
*Nervous System Disorders:
≥1/1000 patients and <1/100 patients - sleep talking
*Skin and Subcutaneous Tissue Disorders:
≥1/1000 patients and <1/100 patients - hirsutism
======Adults - Intramuscular Injection======
*Most adverse reactions observed in the pooled database of 749 adult patients treated with aripiprazole injection, were also observed in the adult population treated with oral aripiprazole. Additional adverse reactions observed in the aripiprazole injection population are listed below.
:*General Disorders and Administration Site Conditions:
≥1/100 patients - injection site reaction; ≥1/1000 patients and <1/100 patients - venipuncture site bruise.


|postmarketing=*The following adverse reactions have been identified during postapproval use of ABILIFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), and blood glucose fluctuation.
:*Respiratory, Thoracic, and Mediastinal Disorders: [[nasal congestion]], [[dyspnea]]
|drugInteractions=* Given the primary CNS effects of aripiprazole, caution should be used when ABILIFY is taken in combination with other centrally-acting drugs or alcohol.


* Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain [[antihypertensive agents]].
:*Skin and Subcutaneous Tissue Disorders: [[rash]], [[hyperhidrosis]], [[pruritus]], [[photosensitivity]] reaction, [[alopecia]], [[urticaria]]


====Potential for Other Drugs to Affect ABILIFY====
:*Vascular Disorders: [[hypotension]], [[hypertension]]


* 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.
|postmarketing=The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: occurrences of allergic reaction ([[anaphylactic]] reaction, [[angioedema]], [[laryngospasm]], [[pruritus]]/[[urticaria]], or [[oropharyngeal]] [[spasm]]), pathological gambling, [[hiccups]] and blood glucose fluctuation.
|drugInteractions=


* 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 level.
======Drugs Having Clinically Important Interactions with Aripiprazole lauroxil======
:*'''Table 9: Clinically Important Drug Interactions with Aripiprazole lauroxil'''
[[File:table10_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>


=====Ketoconazole and Other CYP3A4 Inhibitors=====
======Drugs Having No Clinically Important Interactions with Aripiprazole lauroxil======
Based on [[pharmacokinetic]] studies with oral aripiprazole, no dosage adjustment of Aripiprazole lauroxil is required when administered concomitantly with [[famotidine]], [[valproate]], [[lithium]].


* 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 [[ketoconazole]] is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of its normal dose.
In addition, no dosage adjustment is necessary for substrates of [[CYP2D6]] (e.g., [[dextromethorphan]], [[fluoxetine]], [[paroxetine]], or [[venlafaxine]]), [[CYP2C9]] (e.g., [[warfarin]]), [[CYP2C19]] (e.g., [[omeprazole]], [[warfarin]], [[escitalopram]]), or CYP3A4 (e.g., [[dextromethorphan]]) when co-administered with Aripiprazole lauroxil. Additionally, no dosage adjustment is necessary for [[valproate]], [[lithium]], [[lamotrigine]], or [[sertraline]] when co-administered with Aripiprazole lauroxil.
* Other strong inhibitors of [[CYP3A4]] ([[itraconazole]]) would be expected to have similar effects and need similar dose reductions; moderate inhibitors ([[erythromycin]], [[grapefruit juice]]) have not been studied. When the [[CYP3A4]] inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased.


=====Quinidine and Other CYP2D6 Inhibitors=====
|FDAPregCat=
* 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 quinidine is given concomitantly with aripiprazole.
|useInPregnancyFDA=N
* Other significant inhibitors of CYP2D6, such as [[fluoxetine]] or [[paroxetine]], would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment.


=====Carbamazepine and Other CYP3A4 Inducers=====
:*'''Pregnancy Exposure Registry'''


* Coadministration of [[carbamazepine]] (200 mg twice daily), a potent [[CYP3A4]] inducer, with aripiprazole (30 mg/day) 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, the aripiprazole dose should be reduced
::*There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aripiprazole lauroxil during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ .


====Potential for ABILIFY to Affect Other Drugs====
:*'''Risk Summary'''


* Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by [[cytochrome P450]] enzymes. In in vivo studies, 10 mg/day 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.
::*Neonates exposed to [[antipsychotic]] drugs during the third trimester of pregnancy are at risk for [[extrapyramidal]] and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or [[miscarriage]]. No [[teratogenicity]] was observed in animal reproductive studies with [[intramuscular]] administration of aripiprazole lauroxil to rats and rabbits during [[organogenesis]] at doses up to 6 and 18 times, respectively, the maximum recommended human dose (MRHD) of 882 mg based on [[body surface area]] (mg/m2). However, aripiprazole caused developmental [[toxicity]] and possible [[teratogenic]] effects in rats and rabbits. The background risk of major birth defects and [[miscarriage]] for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and [[miscarriage]] in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.
* No effect of aripiprazole was seen on the pharmacokinetics of [[lithium]] or [[valproate]].


====Drugs Having No Clinically Important Interactions with ABILIFY====
:*'''Clinical Considerations'''


=====Famotidine=====
::*Fetal/Neonatal Adverse Reactions
* 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=====
:::*Extrapyramidal and/or withdrawal symptoms, including [[agitation]], [[hypertonia]], [[hypotonia]], [[tremor]], [[somnolence]], [[respiratory distress]] and [[feeding disorder]] have been reported in neonates who were exposed to [[antipsychotic]] drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for [[extrapyramidal]] and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.
* When [[valproate]] (500 mg/day-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.
* When aripiprazole (30 mg/day) and [[valproate]] (1000 mg/day) were coadministered, at steady-state there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with aripiprazole.


=====Lithium=====
:*'''Data'''
* 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 mg/day-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]].
* Coadministration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of [[lithium]]. No dosage adjustment of [[lithium]] is required when administered concomitantly with aripiprazole.


=====Lamotrigine=====
::*Animal Data for Aripiprazole Lauroxil
* Coadministration of 10 mg/day to 30 mg/day oral doses of aripiprazole for 14 days to patients with [[bipolar I disorder]] had no effect on the steady-state pharmacokinetics of 100 mg/day to 400 mg/day [[lamotrigine]], a [[UDP-glucuronosyltransferase]] 1A4 substrate. No dosage adjustment of lamotrigine is required when aripiprazole is added to [[lamotrigine]].


=====Dextromethorphan=====
:::*Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of [[organogenesis]] at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.7 to 6 times the maximum recommended human dose (MRHD) of 882 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 18 times the MRHD on mg/m2 basis. However, aripiprazole caused developmental toxicity and possible [[teratogenic]] effects in rats and rabbits.
* Aripiprazole at doses of 10 mg/day to 30 mg/day for 14 days had no effect on [[dextromethorphan]]'s O-dealkylation to its major metabolite, dextrorphan, a pathway dependent on CYP2D6 activity. Aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methoxymorphinan, a pathway dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with aripiprazole.


=====Warfarin=====
::*Animal Data for Aripiprazole
* Aripiprazole 10 mg/day for 14 days had no effect on the pharmacokinetics of R-warfarin and S-warfarin or on the pharmacodynamic end point of [[International Normalized Ratio]], indicating the lack of a clinically relevant effect of aripiprazole on [[CYP2C9]] and [[CYP2C19]] metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.


=====Omeprazole=====
:::*Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis of aripiprazole during the period of [[organogenesis]]. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal [[ossification]] was observed at 3 and 10 times the oral MRHD on mg/m2 basis.
* Aripiprazole 10 mg/day for 15 days had no effect on the pharmacokinetics of a single 20 mg dose of [[omeprazole]], a [[CYP2C19]] substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with aripiprazole.


=====Lorazepam=====
:::*At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of [[hepatodiaphragmatic nodules]] and [[diaphragmatic hernia]] were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, [[corpora lutea]], implants, [[live fetuses]], and increased [[post-implantation loss]], likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
* Coadministration of [[lorazepam]] injection (2 mg) and aripiprazole injection (15 mg) to healthy subjects (n=40: 35 males and 5 females; ages 19-45 years old) did not result in clinically important changes in the pharmacokinetics of either drug. No dosage adjustment of aripiprazole is required when administered concomitantly with [[lorazepam]]. However, the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with [[lorazepam]] alone.


=====Escitalopram=====
:::*In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on [[AUC]] and 6 to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of [[organogenesis]] decreased maternal food consumption and increased [[abortions]] were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC.
* Coadministration of 10 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of 10 mg/day [[escitalopram]], a substrate of CYP2C19 and CYP3A4. No dosage adjustment of escitalopram is required when aripiprazole is added to [[escitalopram]].


=====Venlafaxine=====
:::*In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on 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 the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.
* Coadministration of 10 mg/day to 20 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of [[venlafaxine]] and O-desmethylvenlafaxine following 75 mg/day [[venlafaxine]] XR, a CYP2D6 substrate. No dosage adjustment of [[venlafaxine]] is required when aripiprazole is added to [[venlafaxine]].


=====Fluoxetine, Paroxetine, and Sertraline=====
|useInNursing=Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Aripiprazole lauroxil and any potential adverse effects on the breastfed infant from Aripiprazole lauroxil or from the underlying maternal condition.
* A population pharmacokinetic analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of [[fluoxetine]] (20 mg/day or 40 mg/day), [[paroxetine]] CR (37.5 mg/day or 50 mg/day), or [[sertraline]] (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of [[fluoxetine]] and [[norfluoxetine]] increased by about 18% and 36%, respectively, and concentrations of [[paroxetine]] decreased by about 27%. The steady-state plasma concentrations of [[sertraline]] and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole. Aripiprazole dosing was 2 mg/day to 15 mg/day (when given with [[fluoxetine]] or [[paroxetine]]) or 2 mg/day to 20 mg/day (when given with [[sertraline]]).
|useInPed=Safety and effectiveness of Aripiprazole lauroxil in patients <18 years of age have not been evaluated.
|useInGeri=Safety and effectiveness of Aripiprazole lauroxil in patients >65 years of age have not been evaluated.
|useInRenalImpair=No dosage adjustment for Aripiprazole lauroxil is required based on a patient's [[renal function]] (mild to severe renal impairment, [[glomerular filtration rate]] between 15 and 90 mL/minute).
|useInHepaticImpair=No dosage adjustment for Aripiprazole lauroxil is required based on a patient's [[hepatic function]] (mild to severe hepatic impairment, [[Child-Pugh]] score between 5 and 15).




|useInPregnancyFDA=
|othersTitle=CYP2D6 Poor Metabolizers
|useInOthers=Dosage adjustment is recommended in known [[CYP2D6]] poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).


*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.


=====Teratogenic Effects=====
|othersTitle=Other Specific Populations
*Pregnancy Category C: In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
|useInOthers=No dosage adjustment for Aripiprazole lauroxil is required on the basis of a patient's sex, race, or smoking status.
:*Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the maximum recommended human dose [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 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg 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 mg/kg and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, 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.
:*In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity.
:*Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at MRHD based on AUC and 6 times, 19 times, 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 mg/kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg).
:*In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m2.
:*In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, 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.
:*In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.
=====Non-teratogenic Effects=====
*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. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates


|useInPregnancyAUS=(Description)
|useInLaborDelivery=*The effect of aripiprazole on labor and delivery in humans is unknown.
|useInNursing=*Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
|useInPed=*Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
*Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years . Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
*Safety and effectiveness in pediatric patients with bipolar mania were established in a 4-week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years . Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
*The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
*Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years . A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on ABILIFY for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue ABILIFY treatment or switch to placebo. In this trial, the efficacy of ABILIFY for the maintenance treatment of irritability associated with autistic disorder was not established.
*The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight
|useInGeri=*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 also BOXED WARNING and WARNINGS AND PRECAUTIONS].
*Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. The majority (81%) of the 1073 patients were diagnosed with Dementia of the Alzheimer's type.
*Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
*Of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. Placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
*Studies of elderly patients with psychosis associated with Alzheimer's disease have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia [see also BOXED WARNING and WARNINGS AND 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.
|useInGender=*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 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.
|useInRace=*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.
|useInRenalImpair=*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.
|useInHepaticImpair=*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.
|othersTitle=Others
|useInOthers=*'''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.
|administration=
|administration=
* Oral
:*'''Instructions for Use'''
* Intramuscular
::*The kit contains a syringe containing Aripiprazole lauroxil sterile aqueous suspension and 2 or 3 safety needles depending on dose (a 2-inch 20 gauge needle with yellow needle hub, a 1 ½-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gauge needle with green needle hub (441 mg kit only)) for [[intramuscular]] injection. All materials should be stored at room temperature.
 
 
[[File:ari1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>
 
::'''1.''' '''TAP''' and '''SHAKE''' the syringe.
 
[[File:ari2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
:::'''1a.''' '''Tap''' the syringe at least 10 times to dislodge any material which may have settled.
 
:::'''1b.''' '''Shake''' the syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds.
 
::'''2.''' '''SELECT''' the injection needle.
 
:::'''2a.''' '''Select''' injection site.
 
:::'''2b.''' '''Select''' needle length based on injection site. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.


|monitoring=
:*'''Table 5: Injection Site and Associated Needle Length'''
[[File:table5_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


=====Neuroleptic Malignant Syndrome=====
::'''3.''' '''ATTACH''' the injection needle.


* Manage with immediate discontinuation and close monitoring
:::'''Attach''' the appropriate needle securely with a clockwise twisting motion. Do NOT overtighten. Overtightening could lead to needle hub cracking.


=====Hyperglycemia/Diabetes Mellitus=====
[[File:ari3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


* Monitor glucose regularly in patients with and at risk for diabetes
::'''4.''' [[PRIME]] the syringe to remove air.


=====Weight Gain=====
:::'''4a.''' '''Bring''' the syringe into upright position and tap the syringe to bring air to the top.


* Weight gain has been observed with atypical antipsychotic use. Monitor weight.
[[File:ari4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


=====Leukopenia, Neutropenia, and Agranulocytosis=====
:::'''4b.''' '''Remove''' air by depressing the plunger rod. A few drops of suspension will be released.


Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics including ABILIFY. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
[[File:ari5.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


|IVCompat=There is limited information regarding IV Compatibility of Aripiprazole in the drug label.
::'''5.''' '''ADMINISTER''' the entire content intramuscularly. Do not inject by any other route. Inject in a rapid and continuous manner (less than 10 seconds).
|overdose===== OVERDOSAGE====
*MedDRA terminology has been used to classify the adverse reactions.
=====Human Experience=====
*In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities.  


*Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.
[[File:ari6.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
=====Management of Overdosage=====


*No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
::'''6.''' '''DISPOSE''' of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container.
 
[[File:ari7.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
|overdose=
:*'''Human Experience'''
::*The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.
 
::*Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include [[vomiting]], [[somnolence]], and [[tremor]]. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include [[acidosis]], [[aggression]], [[aspartate aminotransferase]] increased, [[atrial fibrillation]], [[bradycardia]], [[coma]], [[confusional state]], [[convulsion]], blood [[creatine phosphokinase]] increased, depressed level of consciousness, [[hypertension]], [[hypokalemia]], [[hypotension]], [[lethargy]], loss of consciousness, [[QRS]] complex prolonged, [[QT]] prolonged, [[pneumonia aspiration]], [[respiratory arrest]], [[status epilepticus]], and [[tachycardia]].
 
:*'''Management of Overdosage'''
::*In case of overdosage, call the Poison control center immediately at 1-800-222-1222.


*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 50 g of activated charcoal, one hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and Cmax of aripiprazole by 50%.


*Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.


|drugBox={{Drugbox2
|drugBox={{Drugbox2
| Verifiedfields =
| Watchedfields =
| verifiedrevid =
| IUPAC_name = [7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
| image = ari15.png
| width =


| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443398218
| IUPAC_name = 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1''H'')-one
| image = Aripiprazole2D1.png
| width = 300
| image2 = Aripiprazole3DanBall.gif
| width2 = 250
<!--Clinical data-->
<!--Clinical data-->
| tradename = Abilify
| tradename = Aristada
| Drugs.com = {{drugs.com|monograph|aripiprazole}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| MedlinePlus = a603012
| pregnancy_US = <!-- A / B            / C / D / X -->
| licence_EU = Abilify
| pregnancy_category =
| licence_US = Aripiprazole
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| pregnancy_AU = B3
| legal_CA =  
| pregnancy_US = C
| legal_UK =
| legal_AU = S4
| legal_US =  
| legal_CA = Rx-only
| legal_status =  
| legal_US = Rx-only
| routes_of_administration = [[Intramuscular injection|Intramuscular]]
| legal_UK = POM
| routes_of_administration = Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a [[Injection (medicine)|depot]])


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = 87%<ref name = DM>{{cite web|title=ABILIFY (aripiprazole) tablet ABILIFY (aripiprazole) solution ABILIFY DISCMELT (aripiprazole) tablet, orally disintegrating ABILIFY (aripiprazole) injection, solution [Otsuka America Pharmaceutical, Inc.]|date=April 2013|accessdate=22 October 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c040bd1d-45b7-49f2-93ea-aed7220b30ac|publisher=Otsuka America Pharmaceutical, Inc.|work=DailyMed}}</ref><ref name = EMC>{{cite web|title=Abilify Tablets, Orodispersible Tablets, Oral Solution - Summary of Product Characteristics (SPC)|date=20 September 2013|accessdate=22 October 2013|publisher=Otsuka Pharmaceuticals (UK) Ltd|work=electronic Medicines Compendium|url=http://www.medicines.org.uk/emc/medicine/18494/SPC/Abilify+Tablets%2c+Orodispersible+Tablets%2c+Oral+Solution/}}</ref><ref name = EMA>{{cite web|title=ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS|work=European Medicines Agency|publisher=Otsuka Pharmaceutical Europe Ltd.|accessdate=22 October 2013|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000471/WC500020170.pdf}}</ref>
| bioavailability =  
| protein_bound = >99%<ref name = DM/><ref name = EMC/><ref name = EMA/>
| protein_bound =  
| metabolism = [[Hepatic]] (liver; mostly via [[CYP3A4]] and [[CYP2D6]]<ref name = DM/><ref name = EMC/><ref name = EMA/>)
| metabolism =  
| elimination_half-life = 75 hours (active metabolite is 94 hours)<ref name = DM/><ref name = EMC/><ref name = EMA/>
| elimination_half-life =  
| excretion = [[Renal]] (27%; <1% unchanged), [[Faeces|Faecal]] (60%; 18% unchanged)<ref name = DM/><ref name = EMC/><ref name = EMA/>
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref =  
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1259305-29-7
| CAS_number = 129722-12-9
| CAS_supplemental =
| ATC_prefix = N05
| ATC_prefix =  
| ATC_suffix = AX12
| ATC_suffix =  
| PubChem = 60795
| PubChem = 49831411
| IUPHAR_ligand = 34
| DrugBank_Ref =  
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank =  
| DrugBank = DB01238
| ChemSpiderID_Ref =  
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 28651973
| ChemSpiderID = 54790
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 82VFR53I78
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01164
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 31236
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1112


<!--Chemical data-->
<!--Chemical data-->
| C=23 | H=27 | Cl=2 | N=3 | O=2
| C=36 | H=51 | Cl=2 | N=3 | O=4
| molecular_weight = 448.385
| molecular_weight = 660.71384 g/mol
| smiles = Clc4cccc(N3CCN(CCCCOc2ccc1c(NC(=O)CC1)c2)CC3)c4Cl
| smiles = CCCCCCCCCCCC(=O)OCN1C(=O)CCC2=C1C=C(C=C2)OCCCCN3CCN(CC3)C4=C(C(=CC=C4)Cl)Cl
| InChI = 1/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29)
| StdInChI = 1S/C36H51Cl2N3O4/c1-2-3-4-5-6-7-8-9-10-16-35(43)45-28-41-33-27-30(19-17-29(33)18-20-34(41)42)44-26-12-11-21-39-22-24-40(25-23-39)32-15-13-14-31(37)36(32)38/h13-15,17,19,27H,2-12,16,18,20-26,28H2,1H3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DDINXHAORAAYAD-UHFFFAOYSA-N
| StdInChI = 1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29)
| synonyms = ALKS-9070, ALKS-9072, RDC-3317
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CEUORZQYGODEFX-UHFFFAOYSA-N
}}
}}
|mechAction=*The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, and agitation associated with schizophrenia or bipolar disorder, is unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of aripiprazole (eg, the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).
|structure=*Aripiprazole is a psychotropic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution, and ABILIFY® (aripiprazole) Injection, a solution for intramuscular injection. 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:


[[File:Abilify structure.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


*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 and 15 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 Oral Solution is a clear, colorless to light-yellow solution available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose, and purified water. The oral solution is flavored with natural orange cream and other natural flavors.
*ABILIFY Injection is available in single-dose vials as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) clear, colorless, sterile, aqueous solution for intramuscular use only. Inactive ingredients for this solution include 150 mg/mL of sulfobutylether β-cyclodextrin (SBECD), tartaric acid, sodium hydroxide, and water for injection
|PD=*Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, 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 nM, 15 nM, 39 nM, 57 nM, 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.
|PK=*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
|nonClinToxic=====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 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day to ICR mice and 1 mg/kg/day, 3 mg/kg/day, and 10 mg/kg/day to F344 rats (0.2 times to 5 times and 0.3 times 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 mg/kg/day, 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day (3 times 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 mg/kg/day to 30 mg/kg/day (0.1 times to 0.9 times human exposure at MRHD based on AUC and 0.5 times to 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-week 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.
=====Mutagenesis=====
*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 due to a mechanism not considered relevant to humans.
=====Impairment of Fertility=====
*Female rats were treated with oral doses of 2 mg/kg/day, 6 mg/kg/day, and 20 mg/kg/day (0.6 times, 2 times, and 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 mg/kg and 20 mg/kg and decreased fetal weight was seen at 20 mg/kg.
*Male rats were treated with oral doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day (6 times, 13 times, 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 mg/kg and 60 mg/kg, but no impairment of fertility was seen.
====Animal Toxicology and/or Pharmacology====
*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 mg/kg and 60 mg/kg. The 40 mg/kg and 60 mg/kg doses are 13 times and 19 times the maximum recommended human dose (MRHD) based on mg/m2 and 7 times to 14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
|clinicalStudies=====Schizophrenia====
=====Adults=====
*The efficacy of ABILIFY in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five 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 four 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 mg/day or 30 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 mg/day or 30 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.
|mechAction=Aripiprazole lauroxil is a [[prodrug]] of aripiprazole. Following [[intramuscular]] injection, Aripiprazole lauroxil is likely converted by [[enzyme]]-mediated [[hydrolysis]] to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The [[mechanism of action]] of aripiprazole in the body is unknown. However, efficacy could be mediated through a combination of partial agonist activity [[D2]] and [[5-HT1A]] receptors and antagonist activity at [[5-HT2A]] receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the [[orthostatic hypotension]] observed with aripiprazole may be explained by its antagonist activity at adrenergic [[alpha1 receptor]]s).
 
 
|structure=
Aripiprazole lauroxil is an atypical [[antipsychotic]].
 
The chemical name of Aripiprazole lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C36H51Cl2N3O4 and its molecular weight is 660.7 g/mol. The chemical structure is:
 
[[File:ari8.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
Aripiprazole lauroxil is available as a white to off-white sterile aqueous extended-release suspension for [[intramuscular]] injection in the following strengths of aripiprazole lauroxil (and deliverable volumes from a single-use pre-filled syringe): 441 mg (1.6 mL), 662 mg (2.4 mL) and 882 mg (3.2 mL). The inactive ingredients include sorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous, sodium phosphate monobasic and water for injection.
 
|PD=Aripiprazole exhibits high affinity for [[dopamine]] D2 and D3, [[serotonin]] [[5-HT1A]] and [[5-HT2A]] receptors (Ki values 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin [[5-HT2C]] and [[5-HT7]], [[alpha1-adrenergic]] and [[histamine]] H1 receptors (Ki values 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the [[serotonin]] reuptake site (Ki =98 nM). Aripiprazole has no appreciable affinity for [[cholinergic muscarinic receptor]]s (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.
|PK=
Aripiprazole lauroxil is a [[prodrug]] of aripiprazole and its activity in the body is primarily due to aripiprazole, and to a lesser extent dehydro-aripiprazole (major [[metabolite]] of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.
 
:*'''[[Absorption]] and [[Distribution]]'''
 
::*After single [[intramuscular]] injection the appearance of aripiprazole in the systemic circulation starts from 5 to 6 days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of Aripiprazole lauroxil and reach steady-state following the fourth monthly injection. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole.
 
::*With the addition of oral aripiprazole supplementation for 21 days at the time of the first Aripiprazole lauroxil dose, aripiprazole concentrations reach therapeutic levels within 4 days.
 
::*Based on population [[pharmacokinetic]] analysis, the apparent [[volume of distribution]] of aripiprazole following [[intramuscular]] injection of Aripiprazole lauroxil was 268 L, indicating extensive [[extravascular]] distribution following absorption. 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 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.
 
::*Aripiprazole exposure was similar for [[deltoid]] and [[gluteal]] intramuscular injections of 441 mg Aripiprazole lauroxil, thus are interchangeable.
 
::*Administration of 882 mg every 6 weeks results in plasma aripiprazole concentrations that are within the established therapeutic range for 441 to 882 mg monthly.
 
:*'''[[Metabolism]] and Elimination'''
 
::*The [[biotransformation]] of Aripiprazole lauroxil likely involves [[enzyme]]-mediated [[hydrolysis]] to form N-hydroxymethyl-aripiprazole, which subsequently undergoes water mediated hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving [[CYP3A4]] and [[CYP2D6]]. Dosage adjustments are recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations.
 
::*The mean aripiprazole terminal elimination [[half-life]] ranged from 29.2 days to 34.9 days after every 4-week injection of Aripiprazole lauroxil 441, 662 and 882 mg. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following Aripiprazole lauroxil administration.
 
:*'''Drug Interaction Studies'''
 
::*No specific drug interaction studies have been performed with Aripiprazole lauroxil. The drug interaction data provided below is obtained from studies with oral aripiprazole.
 
::*Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in FIGURE 1 and FIGURE 2, respectively. Based on simulation, a 4.5-fold increase in mean [[Cmax]] and [[AUC]] values at steady-state is expected when extensive metabolizers of [[CYP2D6]] are administered with both strong [[CYP2D6]] and [[CYP3A4]] inhibitors. After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.
 
:*'''Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics'''
[[File:figure1_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
:*'''Figure 2: The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics'''
[[File:figure2_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
The effects of aripiprazole on the exposures of other drugs are summarized in FIGURE 3.
 
:*'''Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs'''
[[File:figure3_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
:*'''Specific Population Studies'''
 
::*A population [[pharmacokinetic]] analysis showed no effect of sex, race or smoking on Aripiprazole lauroxil pharmacokinetics.
 
::*Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in FIGURE 4 and FIGURE 5, respectively.
 
 
:*'''Figure 4: Effects of Intrinsic Factors on Aripiprazole Pharmacokinetics'''
[[File:figure4_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
:*'''Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics'''
[[File:figure5_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
 
 
|nonClinToxic=======[[Carcinogenesis]], [[Mutagenesis]], Impairment of [[Fertility]]======
:*'''Carcinogenesis'''
 
::*Lifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil.
 
::*Lifetime carcinogenicity studies with oral aripiprazole have been 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 times and 0.3 to 3 times the oral maximum recommended human dose [MRHD] of 30 mg/day 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 oral 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 which are 0.1 to 0.9 times human exposure at the oral MRHD based on [[AUC]] and 0.5 to 5 times the oral MRHD on mg/m2 basis. In female rats, the incidence of mammary gland [[fibroadenomas]] was increased at a dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and 3 times the oral MRHD on mg/m2 basis; and the incidences of [[adrenocortical carcinoma]]s and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m2 basis.
 
::*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. The relevance for human risk of the findings of prolactin-mediated [[endocrine]] [[tumors]] in rodents is unknown.
 
:*'''Mutagenesis'''
 
::*Aripiprazole lauroxil was not mutagenic in the [[in vitro]] bacterial reverse mutation assay or [[clastogenic]] in the [[in vitro]] [[chromosome]] aberration assay in human [[peripheral blood]] [[lymphocytes]].
 
::*Aripiprazole and its [[metabolite]] (2,3-DCPP) were [[clastogenic]] in the [[in vitro]] [[chromosome]] aberration assay in Chinese hamster lung (CHL) cells both in the presence and absence of 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 oral [[in vivo]] micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.
 
:*'''Impairment of Fertility'''
 
::*Animal Data for Aripiprazole Lauroxil
 
:::*In a rat fertility study, aripiprazole lauroxil was administered intramuscularly. Males were treated with doses of 18, 49, or 144 mg /animal, which are approximately 0.5 to 4 times the maximum recommended human dose [MRHD] of 882 mg on mg/m2 basis, on Days 1, 21, and 42 prior to and through mating; females were treated at these doses, which are approximately 0.7 to 6 times the MRHD on mg/m2 basis, once 14 days prior to mating.
 
:::*In females, persistent diestrus was observed at all doses and the mean number of cycles was significantly decreased at the highest dose together with an increase in the copulatory interval (delay in mating). Additional changes at the high dose included slight increases in [[corpora lutea]] and pre-implantation loss, decline in mating, fertility, and fecundity indices in females and lower mating and fertility indices in males.
 
::*Animal Data for Aripiprazole
 
:::*Female rats were treated with oral aripiprazole doses of 2, 6, and 20 mg/kg/day, which are 0.6 to 6 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis, 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 observed. Increased pre-implantation loss was found at 2 and 6 times the oral MRHD on mg/m2 basis and decreased fetal weight was noted at the highest dose which is 6 times the oral MRHD on mg/m2 basis.
 
:::*Male rats were treated with oral aripiprazole doses of 20, 40, and 60 mg/kg/day, which are 6 to 19 times the oral MRHD on mg/m2 basis, from 9 weeks prior to and through mating. Disturbances in [[spermatogenesis]] at the highest dose and [[prostate]] atrophy at the mid and high doses were noted which are 13 and 19 times the oral MRHD on mg/m2 basis, but no impairment of fertility was observed.
 
======Animal Toxicology and/or Pharmacology======
 
Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to 6 months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to 2 times and 0.5 to 4 times the maximum recommended human dose [MRHD] of 882 mg on mg/m2 basis in males and females, respectively) and in dogs treated up to 9 months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to 8 times and 0.7 to 10 times the MRHD in males and females, respectively on mg/m2 basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The [[granulomas]] did not completely resolve 2 months following the last injection in the 6 month rat study and 4 months following the last injection in the 9 month dog study (the low dose groups were not examined for reversibility in these studies).
 
Orally administered aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m2 basis, and in a 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m2 basis and 7 to 14 times human exposure at the oral MRHD based on [[AUC]]. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of [[retinal degeneration]]. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
 
|clinicalStudies=
The efficacy of Aripiprazole lauroxil in the treatment of patients with [[schizophrenia]] was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of Aripiprazole lauroxil was established in a 12-week, randomized, double-blind, [[placebo]] controlled, fixed-dose study in adult patients with [[schizophrenia]] meeting DSM IV TR criteria [Study 1, n = 622; 207 (Aripiprazole lauroxil 441 mg), 208 (Aripiprazole lauroxil 882 mg), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first 3 weeks. The [[intramuscular]] (IM) injections were administered on Days 1, 29 and 57.
 
Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I):
 
:*The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of [[schizophrenia]] (7 items), and general [[psychopathology]] (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210.
:*The CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition.
 
Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and a score of ≥4 for at least 2 of the selected Positive Scale items. Patients were also required to have a CGI-S score of ≥4.
 
The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each Aripiprazole lauroxil dose group (TABLE 10).
 
:*'''Table 10: Primary Efficacy Results'''
[[File:table11_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>
 
The visit-wise mean change from baseline on PANSS total score change for each treatment group is shown in FIGURE 6.
 
:*'''Figure 6: Change from Baseline in PANSS Total Score'''
[[File:figure6_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
<SMALL>ARISTADA: Aripiprazole lauroxil's Brand name</SMALL>
 
 
 
|howSupplied=
Aripiprazole lauroxil is a white to off-white aqueous extended-release suspension provided in a single-use pre-filled syringe for intramuscular injection in the deltoid or gluteal muscle at the 441 mg dose strength and in the gluteal muscle at dose strengths of 662 mg and 882 mg.
 
Aripiprazole lauroxil extended-release injectable suspension is available in strengths of 441 mg in 1.6 mL, 662 mg in 2.4 mL, and 882 mg in 3.2 mL. The kit contains a 5-mL pre-filled syringe containing Aripiprazole lauroxil sterile aqueous suspension and safety needles.
 
:*The 441 mg strength kit (NDC 65757-401-03; light blue label) contains three safety needles; a 1-inch (25 mm) 21 gauge, a 1½-inch (38 mm) 20 gauge, and a 2-inch (50 mm) 20 gauge needle.
:*The 662 mg strength kit (NDC 65757-402-03; green label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.
:*The 882 mg strength kit (NDC 65757-403-03; burgundy label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.
 
Aripiprazole lauroxil is available as described in TABLE 11.
 
:*'''Table 11: Presentations of Aripiprazole lauroxil'''
[[File:table6_ari.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
 
|storage=Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F).
|packLabel=
 
 
[[File:ari9.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:ari10.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:ari11.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:ari12.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:ari13.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:ari14.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
 
 
|fdaPatientInfo=
Advise patients to read FDA-approved patient labeling (MEDICATION GUIDE).
 
:*'''Pathological Gambling and Other Compulsive Behaviors'''
 
::*Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped.
 
:*'''[[Neuroleptic Malignant Syndrome]]'''
 
::*Counsel patients about a potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of [[antipsychotic]] drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS.
 
:*'''[[Tardive Dyskinesia]]'''
 
::*Advise patients that abnormal involuntary movements have been associated with administration of [[antipsychotic]] drugs. Counsel patients to notify their healthcare provider if they notice any movements which they cannot control in their face, tongue, or other body part.
 
:*'''Metabolic Changes ([[Hyperglycemia]] and [[Diabetes Mellitus]], [[Dyslipidemia]], and Weight Gain)'''


:*In a 6-week trial (n=420) comparing three fixed doses of ABILIFY (10 mg/day, 15 mg/day, 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.  
::*Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight.


:*In a 6-week trial (n=367) comparing three fixed doses of ABILIFY (2 mg/day, 5 mg/day, or 10 mg/day) to placebo, the 10 mg dose of ABILIFY was superior to placebo in the PANSS total score, the primary outcome measure of the study. The 2 mg and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.
:*'''[[Orthostatic Hypotension]]'''


:*In a fifth study, a 4-week trial (n=103) comparing ABILIFY in a range of 5 mg/day to 30 mg/day to placebo, ABILIFY was only significantly different compared to placebo in a responder analysis based on the CGI-severity score, a primary outcome for that trial.
::*Educate patients about the risk of orthostatic hypotension (symptoms include feeling [[dizzy]] or [[lightheaded]] upon standing), particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose.
*Thus, the efficacy of 10 mg, 15 mg, 20 mg, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies.
*An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.
*A 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/day 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/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo.
====Pediatric Patients====
*The efficacy of ABILIFY (aripiprazole) in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of ABILIFY (10 mg/day or 30 mg/day) to placebo, ABILIFY was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in the PANSS total score, the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
====Bipolar Disorder====
=====Acute Treatment of Manic and Mixed Episodes=====
======Adults======
'''Monotherapy'''
*The efficacy of ABILIFY as monotherapy in the acute treatment of manic episodes was established in four 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients 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 four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated ABILIFY in a range of 15 mg to 30 mg, once daily (with a starting dose of 15 mg/day in two studies and 30 mg/day in two studies), ABILIFY was superior to placebo in the reduction of Y-MRS total score and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.
'''Adjunctive Therapy'''
*The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2-week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features.
*Patients were initiated on open-label lithium (0.6 mEq/L to 1.0 mEq/L) or valproate (50 μg/mL to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either aripiprazole (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week, placebo-controlled phase, adjunctive ABILIFY starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.0 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-week endpoint.
=====Pediatric Patients=====
*The efficacy of ABILIFY in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of ABILIFY (10 mg/day or 30 mg/day) to placebo. The ABILIFY dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in change from baseline to week 4 on the Y-MRS total score.
=====Maintenance Treatment of Bipolar I Disorder=====
'''Monotherapy Maintenance Therapy'''
*A maintenance trial was conducted in adult 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 mg/day 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. A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the ABILIFY group and 36 were from the placebo group. The number of observed manic episodes in the ABILIFY group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the ABILIFY group (9) was similar to that in the placebo group (11).
*An examination of 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 inter-group differences.
=====Adjunctive Maintenance Therapy=====
*An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 mEq/L to 1.0 mEq/L) or valproate (50 μg/mL to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤35% improvement on the Y-MRS total score) to lithium or valproate received aripiprazole with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as day 4, as adjunctive therapy with open-label lithium or valproate. Prior to randomization, patients on the combination of single-blind aripiprazole and lithium or valproate were required to maintain stability (Y-MRS and MADRS total scores ≤12) for 12 consecutive weeks. Three hundred thirty-seven patients were then randomized in a double-blind fashion, to either the same dose of ABILIFY they were on at the end of the stabilization period or placebo plus lithium or valproate and were then monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks. ABILIFY was superior to placebo on the primary endpoint, time from randomization to relapse to any mood event. A mood event was defined as hospitalization for a manic, mixed, or depressive episode, study discontinuation due to lack of efficacy accompanied by Y-MRS score >16 and/or a MADRS >16, or an SAE of worsening disease accompanied by Y-MRS score >16 and/or a MADRS >16. A total of 68 mood events were observed during the double-blind treatment phase. Twenty-five were from the ABILIFY group and 43 were from the placebo group. The number of observed manic episodes in the ABILIFY group (7) were fewer than that in the placebo group (19), while the number of depressive episodes in the ABILIFY group (14) was similar to that in the placebo group (18). The Kaplan-Meier curves of the time from randomization to relapse to any mood event during the 52-week, double-blind treatment phase for ABILIFY and placebo groups are shown in Figure 1


*An examination of 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 inter-group differences.
:*'''[[Leukopenia]]/ [[Neutropenia]]'''
====Adjunctive Treatment of Major Depressive Disorder====
=====Adults=====
*The efficacy of ABILIFY in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). *Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.
*The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life, and family life) with each item scored from 0 (not at all) to 10 (extreme).
*In the two trials (n=381, n=362), ABILIFY was superior to placebo in reducing mean MADRS total scores. In one study, ABILIFY was also superior to placebo in reducing the mean SDS score.
*In both trials, patients received ABILIFY adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 mg/day and 11.4 mg/day.
*An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.
====Irritability Associated with Autistic Disorder====
=====Pediatric Patients=====
*The efficacy of ABILIFY (aripiprazole) in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age.
*Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of irritability in autistic disorder, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.
*The results of these trials are as follows:
:*In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or ABILIFY 2 mg/day to 15 mg/day. ABILIFY, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of ABILIFY at the end of 8-week treatment was 8.6 mg/day.
:*In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of ABILIFY (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. ABILIFY dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 mg and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm. All three doses of ABILIFY significantly improved scores on the ABC-I subscale compared with placebo.
:*In a clinical trial with ABILIFY conducted in children and adolescents (6 to 17 years of age), the efficacy of ABILIFY for the maintenance treatment of irritability associated with autistic disorder was not established.
====Agitation Associated with Schizophrenia or Bipolar Mania====
*The efficacy of intramuscular aripiprazole for injection for the treatment of agitation was established in three short-term (24-hour), placebo-controlled trials in agitated inpatients from two diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar mania study). Patients could receive up to three injections during the 24-hour treatment periods; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed. Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥15 on the five items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (ie, poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least two individual item scores ≥4 using a 1-7 scoring system (1 = absent, 4 = moderate, 7 = extreme). In the studies, the mean baseline PANSS Excited Component score was 19, with scores ranging from 15 to 34 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. A key secondary measure was the Clinical Global Impression of Improvement (CGI-I) Scale. The results of the trials follow:
:*In a placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=350), four fixed aripiprazole injection doses of 1 mg, 5.25 mg, 9.75 mg, and 15 mg were evaluated. At 2 hours post-injection, the 5.25 mg, 9.75 mg, and 15 mg doses were statistically superior to placebo in the PANSS Excited Component and on the CGI-I Scale.
:*In a second placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=445), one fixed aripiprazole injection dose of 9.75 mg was evaluated. At 2 hours post-injection, aripiprazole for injection was statistically superior to placebo in the PANSS Excited Component and on the CGI-I Scale.


:*In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (manic or mixed) (n=291), two fixed aripiprazole injection doses of 9.75 mg and 15 mg were evaluated. At 2 hours post-injection, both doses were statistically superior to placebo in the PANSS Excited Component.
::*Advise patients with a pre-existing low [[WBC]] count or a history of drug-induced leucopenia/neutropenia that they should have their [[CBC]] monitored while receiving Aripiprazole lauroxil.
*Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.


|howSupplied=*ABILIFY® (aripiprazole) Tablets have markings on one side and are available in the strengths and packages listed in Table 22.
:*'''Interference with Cognitive and Motor Performance'''


*ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets are round tablets with markings on either side. ABILIFY DISCMELT is available in the strengths and packages listed in Table 23
::*Because Aripiprazole lauroxil may have the potential to impair judgment, thinking or motor skills, instruct patients to be cautious about operating hazardous machinery, including automobiles, until they are reasonably certain that Aripiprazole lauroxil therapy does not affect them adversely.


*ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is supplied in child-resistant bottles along with a calibrated oral dosing cup. ABILIFY Oral Solution is available as follows:
:*'''Heat Exposure and [[Dehydration]]'''
 
:*150 mL bottle NDC 59148-013-15
::*Advise patients regarding appropriate care in avoiding overheating and dehydration.
ABILIFY® (aripiprazole) Injection for intramuscular use is available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials as follows:
 
:*'''Concomitant Medication'''
:*9.75 mg/1.3 mL single-dose vial NDC 59148-016-65
 
|fdaPatientInfo=====Information for Patients====
::*Advise patients 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.
=====Physicians are advised to discuss the following issues with patients for whom they prescribe ABILIFY:=====
 
======Increased Mortality in Elderly Patients with Dementia-Related Psychosis======
:*'''Pregnancy'''
*Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with antipsychotic drugs are at increased risk of death. ABILIFY is not approved for elderly patients with dementia-related psychosis.
 
======Suicidal Thoughts and Behaviors in Adolescents and Young Adults======
::*Advise patients that Aripiprazole lauroxil may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aripiprazole lauroxil during pregnancy.
*Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
 
*Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ABILIFY and should counsel them in its appropriate use. A patient Medication Guide including information about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for ABILIFY. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. *Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. It should be noted that ABILIFY is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder.
[[File:ari16.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
======Use of Orally Disintegrating Tablet======
 
*Do not open the blister until ready to administer. For single tablet removal, open the package and peel back the foil on the blister to expose the tablet. Do not push the tablet through the foil because this could damage the tablet. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire ABILIFY DISCMELT Orally Disintegrating Tablet on the tongue. Tablet disintegration occurs rapidly in saliva. It is recommended that ABILIFY DISCMELT be taken without liquid. However, if needed, it can be taken with liquid. Do not attempt to split the tablet.
 
======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.
|brandNames=ARISTADA®
======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.
======ConcomitantMedication======
*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.
======Sugar Content======
*Patients should be advised that each mL of ABILIFY Oral Solution contains 400 mg of sucrose and 200 mg of fructose.
|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.
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[[Category:Drug]]
[[Category:Atypical antipsychotics]]
[[Category:Mood stabilizers]]

Latest revision as of 19:54, 16 February 2017

Aripiprazole (intramuscular)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]

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Black Box Warning

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete Boxed Warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.

Overview

Aripiprazole (intramuscular) is an atypical antipsychotic that is FDA approved for the treatment of patients with schizophrenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include akathisia (≥5%).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Aripiprazole lauroxil is indicated for treatment of schizophrenia.

Dosage
  • Aripiprazole lauroxil is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with Aripiprazole lauroxil. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
  • Depending on individual patient's needs, treatment with Aripiprazole lauroxil can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, which corresponds to 300 mg, 450 mg and 600 mg of aripiprazole, respectively. Treatment may also be initiated with the 882 mg dose every 6 weeks.
  • Administer Aripiprazole lauroxil either in the deltoid muscle (441 mg dose only) or gluteal muscle (441 mg, 662 mg or 882 mg).
  • Table 1: Aripiprazole lauroxil Dosing Frequency and Site of Injection
This image is provided by the National Library of Medicine.
  • Use the following Aripiprazole lauroxil doses for patients who are stabilized on oral aripiprazole, as shown in TABLE 2.
  • Table 2: Aripiprazole lauroxil Doses Based on Oral Aripiprazole Total Daily Dose
This image is provided by the National Library of Medicine.
  • In conjunction with the first Aripiprazole lauroxil injection, administer treatment with oral aripiprazole for 21 consecutive days.
  • Dose may be adjusted as needed. When making dose and dosing interval adjustments, the pharmacokinetics and prolonged-release characteristics of Aripiprazole lauroxil should be considered.
  • Missed Doses
  • When a dose is missed, administer the next injection of Aripiprazole lauroxil as soon as possible. If the time elapsed since the last Aripiprazole lauroxil injection exceeds the length of time noted in TABLE 3, use oral aripiprazole supplementation with the next Aripiprazole lauroxil injection as recommended below.
  • Table 3: Recommendation for Concomitant Oral Aripiprazole Supplementation Following Missed Doses(a)
This image is provided by the National Library of Medicine.

ARISTADA: Aripiprazole lauroxil's Brand name


  • Early Dosing
  • The recommended Aripiprazole lauroxil dosing interval is either monthly for the 441 mg, 662 mg and 882 mg doses or every 6 weeks for 882 mg dose and should be maintained. In the event of early dosing, an Aripiprazole lauroxil injection should not be given earlier than 14 days after the previous injection.
  • Dose Adjustments for CYP450 Considerations
  • Refer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking oral aripiprazole concomitantly with the first dose of Aripiprazole lauroxil.
  • Once stabilized on Aripiprazole lauroxil, refer to the dosing recommendations below for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 inducers:
- No dosage changes recommended for Aripiprazole lauroxil, if CYP450 modulators are added for less than 2 weeks.
- Make dose changes to Aripiprazole lauroxil if CYP450 modulators are added for greater than 2 weeks (see TABLE 4).
  • Table 4: Aripiprazole lauroxil Dose Adjustments with Concomitant CYP450 Modulator Use
This image is provided by the National Library of Medicine.

ARISTADA: Aripiprazole lauroxil's Brand name

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Aripiprazole lauroxil in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Aripiprazole lauroxil in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness of Aripiprazole lauroxil in patients <18 years of age have not been evaluated.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Aripiprazole lauroxil in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Aripiprazole lauroxil in pediatric patients.

Contraindications

Aripiprazole lauroxil is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis.

Warnings

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete Boxed Warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.

Increased Mortality in Elderly Patients with Dementia-related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death 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 (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular Adverse Reactions, Including Stroke

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. Aripiprazole lauroxil is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with antipsychotic drugs, including Aripiprazole lauroxil. 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 identify cases in which the clinical presentation includes both serious medical illness (e.g., 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 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 appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely 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 predict which patients will 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 appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, Aripiprazole lauroxil 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. 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 treated with Aripiprazole lauroxil drug discontinuation should be considered. However, some patients may require treatment with Aripiprazole lauroxil despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

  • 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 reports of hyperglycemia in patients treated with oral aripiprazole. 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 suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
  • 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 (e.g., 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 require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
  • In the long-term, open-label schizophrenia study with Aripiprazole lauroxil, 14% of patients with normal hemoglobin A1c (<5.7%) at baseline developed elevated levels (≥5.7%) post-baseline.
  • Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
  • In the long-term, open-label schizophrenia study with Aripiprazole lauroxil, shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL) were reported in 1% of patients; shifts in baseline fasting LDL cholesterol from normal (<100 mg/dL) to high (≥160 mg/dL) were reported in 1% of patients; and shifts in baseline fasting triglycerides from normal (<150 mg/dL) to high (≥200 mg/dL) were reported in 8% of patients. In the same study, shifts in baseline fasting total cholesterol from borderline (≥ 200 mg/dL and <240 mg/dL) to high (≥240 mg/dL) were reported in 15% of patients; shifts in baseline fasting LDL cholesterol from borderline (≥100 mg/dL and <160 mg/dL) to high (≥160 mg/dL) were reported in 8% of patients; and shifts in baseline fasting triglycerides from borderline (≥150 mg/dL and <200 mg/dL) to high (≥200 mg/dL) were reported in 35% of patients. In addition, the proportion of patients with shifts in fasting HDL cholesterol from normal (≥40 mg/dL) to low (<40 mg/dL) was reported in 15% of patients.
  • Weight Gain
  • Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
  • The proportion of adult patients with weight gain ≥7% of body weight is presented in TABLE 6.
  • Table 6: Proportion of Adult Patients with Shifts in Weight in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial
This image is provided by the National Library of Medicine.

ARISTADA: Aripiprazole lauroxil's Brand name

Pathological Gambling and Other Compulsive Behaviors

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm for the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

Orthostatic Hypotension

Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose, and monitor orthostatic vital signs.

Orthostatic hypotension was reported for one patient in the Aripiprazole lauroxil 882 mg group (0.5%) and no patients in the Aripiprazole lauroxil 441 mg and placebo groups in the 12-week schizophrenia efficacy study. In the long-term open-label schizophrenia study, orthostatic hypotension was reported for 1 (0.2%) patient treated with Aripiprazole lauroxil. Orthostatic hypotension was defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values.

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Aripiprazole lauroxil at the first sign of a clinical significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Aripiprazole lauroxil in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

Seizures

As with other antipsychotic drugs, use Aripiprazole lauroxil cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Potential for Cognitive and Motor Impairment

Aripiprazole lauroxil, like other antipsychotics, has 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 Aripiprazole lauroxil 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 lauroxil for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., 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. Aripiprazole lauroxil and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Adverse Reactions

Clinical Trials Experience

The following are discussed in more details in other sections of the labeling:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Aripiprazole lauroxil
  • Patient Exposure: Aripiprazole lauroxil has been evaluated for safety in 880 adult patients in clinical trials in schizophrenia.
  • Commonly Observed Adverse Reactions: The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with Aripiprazole lauroxil) was akathisia.
  • Adverse Reactions Occurring at an Incidence of 2% or More in Aripiprazole lauroxil-Treated Patients: Adverse reactions associated with the use of Aripiprazole lauroxil (incidence of 2% or greater, rounded to the nearest percent and Aripiprazole lauroxil incidence greater than placebo) that occurred are shown in TABLE 7.
  • Table 7: Adverse Reaction in 2% or More of Aripiprazole lauroxil-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial
This image is provided by the National Library of Medicine.
  • Injection Site Reactions: Injection site reactions were reported by 4% of patients treated with 441 mg Aripiprazole lauroxil and 5% of patients treated with 882 mg Aripiprazole lauroxil compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg Aripiprazole lauroxil, 882 mg Aripiprazole lauroxil and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of Aripiprazole lauroxil and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%.
  • Extrapyramidal Symptoms: In the 12-week schizophrenia efficacy study, for Aripiprazole lauroxil-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patient (TABLE 8).
  • Table 8: Incidence of EPS Compared to Placebo
This image is provided by the National Library of Medicine.

ARISTADA: Aripiprazole lauroxil's Brand name

  • Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
  • Other Adverse Reactions Observed in Clinical Studies: The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole

The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Aripiprazole lauroxil.

  • Injury, Poisoning, and Procedural Complications: fall, heat stroke

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.

Drug Interactions

Drugs Having Clinically Important Interactions with Aripiprazole lauroxil
  • Table 9: Clinically Important Drug Interactions with Aripiprazole lauroxil
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ARISTADA: Aripiprazole lauroxil's Brand name

Drugs Having No Clinically Important Interactions with Aripiprazole lauroxil

Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of Aripiprazole lauroxil is required when administered concomitantly with famotidine, valproate, lithium.

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with Aripiprazole lauroxil. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with Aripiprazole lauroxil.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): N

  • Pregnancy Exposure Registry
  • Risk Summary
  • Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage. No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 6 and 18 times, respectively, the maximum recommended human dose (MRHD) of 882 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.
  • Clinical Considerations
  • Fetal/Neonatal Adverse Reactions
  • Data
  • Animal Data for Aripiprazole Lauroxil
  • Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.7 to 6 times the maximum recommended human dose (MRHD) of 882 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 18 times the MRHD on mg/m2 basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits.
  • Animal Data for Aripiprazole
  • Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m2 basis.
  • At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
  • In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC.
  • In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on 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 the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aripiprazole (intramuscular) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Aripiprazole (intramuscular) during labor and delivery.

Nursing Mothers

Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Aripiprazole lauroxil and any potential adverse effects on the breastfed infant from Aripiprazole lauroxil or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of Aripiprazole lauroxil in patients <18 years of age have not been evaluated.

Geriatic Use

Safety and effectiveness of Aripiprazole lauroxil in patients >65 years of age have not been evaluated.

Gender

There is no FDA guidance on the use of Aripiprazole (intramuscular) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Aripiprazole (intramuscular) with respect to specific racial populations.

Renal Impairment

No dosage adjustment for Aripiprazole lauroxil is required based on a patient's renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute).

Hepatic Impairment

No dosage adjustment for Aripiprazole lauroxil is required based on a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15).

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Aripiprazole (intramuscular) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Aripiprazole (intramuscular) in patients who are immunocompromised.

Other Specific Populations

No dosage adjustment for Aripiprazole lauroxil is required on the basis of a patient's sex, race, or smoking status.

Administration and Monitoring

Administration

  • Instructions for Use
  • The kit contains a syringe containing Aripiprazole lauroxil sterile aqueous suspension and 2 or 3 safety needles depending on dose (a 2-inch 20 gauge needle with yellow needle hub, a 1 ½-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gauge needle with green needle hub (441 mg kit only)) for intramuscular injection. All materials should be stored at room temperature.


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ARISTADA: Aripiprazole lauroxil's Brand name

1. TAP and SHAKE the syringe.
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1a. Tap the syringe at least 10 times to dislodge any material which may have settled.
1b. Shake the syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds.
2. SELECT the injection needle.
2a. Select injection site.
2b. Select needle length based on injection site. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.
  • Table 5: Injection Site and Associated Needle Length
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3. ATTACH the injection needle.
Attach the appropriate needle securely with a clockwise twisting motion. Do NOT overtighten. Overtightening could lead to needle hub cracking.
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4. PRIME the syringe to remove air.
4a. Bring the syringe into upright position and tap the syringe to bring air to the top.
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4b. Remove air by depressing the plunger rod. A few drops of suspension will be released.
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5. ADMINISTER the entire content intramuscularly. Do not inject by any other route. Inject in a rapid and continuous manner (less than 10 seconds).
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6. DISPOSE of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container.
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Monitoring

There is limited information regarding Aripiprazole (intramuscular) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Aripiprazole (intramuscular) and IV administrations.

Overdosage

  • Human Experience
  • The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.
  • Management of Overdosage
  • In case of overdosage, call the Poison control center immediately at 1-800-222-1222.

Pharmacology

Template:Px
Aripiprazole (intramuscular)
Systematic (IUPAC) name
[7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate
Identifiers
CAS number 1259305-29-7
ATC code ?
PubChem 49831411
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 660.71384 g/mol
SMILES eMolecules & PubChem
Synonyms ALKS-9070, ALKS-9072, RDC-3317
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes Intramuscular

Mechanism of Action

Aripiprazole lauroxil is a prodrug of aripiprazole. Following intramuscular injection, Aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in the body is unknown. However, efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

Structure

Aripiprazole lauroxil is an atypical antipsychotic.

The chemical name of Aripiprazole lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C36H51Cl2N3O4 and its molecular weight is 660.7 g/mol. The chemical structure is:

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Aripiprazole lauroxil is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following strengths of aripiprazole lauroxil (and deliverable volumes from a single-use pre-filled syringe): 441 mg (1.6 mL), 662 mg (2.4 mL) and 882 mg (3.2 mL). The inactive ingredients include sorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous, sodium phosphate monobasic and water for injection.

Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki =98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.

Pharmacokinetics

Aripiprazole lauroxil is a prodrug of aripiprazole and its activity in the body is primarily due to aripiprazole, and to a lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.

  • After single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from 5 to 6 days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of Aripiprazole lauroxil and reach steady-state following the fourth monthly injection. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole.
  • With the addition of oral aripiprazole supplementation for 21 days at the time of the first Aripiprazole lauroxil dose, aripiprazole concentrations reach therapeutic levels within 4 days.
  • Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of Aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. 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 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.
  • Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg Aripiprazole lauroxil, thus are interchangeable.
  • Administration of 882 mg every 6 weeks results in plasma aripiprazole concentrations that are within the established therapeutic range for 441 to 882 mg monthly.
  • The biotransformation of Aripiprazole lauroxil likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes water mediated hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6. Dosage adjustments are recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations.
  • The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of Aripiprazole lauroxil 441, 662 and 882 mg. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following Aripiprazole lauroxil administration.
  • Drug Interaction Studies
  • No specific drug interaction studies have been performed with Aripiprazole lauroxil. The drug interaction data provided below is obtained from studies with oral aripiprazole.
  • Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in FIGURE 1 and FIGURE 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.
  • Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics
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  • Figure 2: The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics
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The effects of aripiprazole on the exposures of other drugs are summarized in FIGURE 3.

  • Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs
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  • Specific Population Studies
  • A population pharmacokinetic analysis showed no effect of sex, race or smoking on Aripiprazole lauroxil pharmacokinetics.
  • Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in FIGURE 4 and FIGURE 5, respectively.


  • Figure 4: Effects of Intrinsic Factors on Aripiprazole Pharmacokinetics
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  • Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics
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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Carcinogenesis
  • Lifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil.
  • Lifetime carcinogenicity studies with oral aripiprazole have been 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 times and 0.3 to 3 times the oral maximum recommended human dose [MRHD] of 30 mg/day 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 oral 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 which are 0.1 to 0.9 times human exposure at the oral MRHD based on AUC and 0.5 to 5 times the oral MRHD on mg/m2 basis. In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and 3 times the oral MRHD on mg/m2 basis; and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m2 basis.
  • 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. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
  • Mutagenesis
  • Aripiprazole and its metabolite (2,3-DCPP) were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung (CHL) cells both in the presence and absence of 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 oral in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.
  • Impairment of Fertility
  • Animal Data for Aripiprazole Lauroxil
  • In a rat fertility study, aripiprazole lauroxil was administered intramuscularly. Males were treated with doses of 18, 49, or 144 mg /animal, which are approximately 0.5 to 4 times the maximum recommended human dose [MRHD] of 882 mg on mg/m2 basis, on Days 1, 21, and 42 prior to and through mating; females were treated at these doses, which are approximately 0.7 to 6 times the MRHD on mg/m2 basis, once 14 days prior to mating.
  • In females, persistent diestrus was observed at all doses and the mean number of cycles was significantly decreased at the highest dose together with an increase in the copulatory interval (delay in mating). Additional changes at the high dose included slight increases in corpora lutea and pre-implantation loss, decline in mating, fertility, and fecundity indices in females and lower mating and fertility indices in males.
  • Animal Data for Aripiprazole
  • Female rats were treated with oral aripiprazole doses of 2, 6, and 20 mg/kg/day, which are 0.6 to 6 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis, 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 observed. Increased pre-implantation loss was found at 2 and 6 times the oral MRHD on mg/m2 basis and decreased fetal weight was noted at the highest dose which is 6 times the oral MRHD on mg/m2 basis.
  • Male rats were treated with oral aripiprazole doses of 20, 40, and 60 mg/kg/day, which are 6 to 19 times the oral MRHD on mg/m2 basis, from 9 weeks prior to and through mating. Disturbances in spermatogenesis at the highest dose and prostate atrophy at the mid and high doses were noted which are 13 and 19 times the oral MRHD on mg/m2 basis, but no impairment of fertility was observed.
Animal Toxicology and/or Pharmacology

Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to 6 months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to 2 times and 0.5 to 4 times the maximum recommended human dose [MRHD] of 882 mg on mg/m2 basis in males and females, respectively) and in dogs treated up to 9 months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to 8 times and 0.7 to 10 times the MRHD in males and females, respectively on mg/m2 basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The granulomas did not completely resolve 2 months following the last injection in the 6 month rat study and 4 months following the last injection in the 9 month dog study (the low dose groups were not examined for reversibility in these studies).

Orally administered aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m2 basis, and in a 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m2 basis and 7 to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

Clinical Studies

The efficacy of Aripiprazole lauroxil in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of Aripiprazole lauroxil was established in a 12-week, randomized, double-blind, placebo controlled, fixed-dose study in adult patients with schizophrenia meeting DSM IV TR criteria [Study 1, n = 622; 207 (Aripiprazole lauroxil 441 mg), 208 (Aripiprazole lauroxil 882 mg), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first 3 weeks. The intramuscular (IM) injections were administered on Days 1, 29 and 57.

Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I):

  • The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210.
  • The CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition.

Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and a score of ≥4 for at least 2 of the selected Positive Scale items. Patients were also required to have a CGI-S score of ≥4.

The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each Aripiprazole lauroxil dose group (TABLE 10).

  • Table 10: Primary Efficacy Results
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ARISTADA: Aripiprazole lauroxil's Brand name

The visit-wise mean change from baseline on PANSS total score change for each treatment group is shown in FIGURE 6.

  • Figure 6: Change from Baseline in PANSS Total Score
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ARISTADA: Aripiprazole lauroxil's Brand name

How Supplied

Aripiprazole lauroxil is a white to off-white aqueous extended-release suspension provided in a single-use pre-filled syringe for intramuscular injection in the deltoid or gluteal muscle at the 441 mg dose strength and in the gluteal muscle at dose strengths of 662 mg and 882 mg.

Aripiprazole lauroxil extended-release injectable suspension is available in strengths of 441 mg in 1.6 mL, 662 mg in 2.4 mL, and 882 mg in 3.2 mL. The kit contains a 5-mL pre-filled syringe containing Aripiprazole lauroxil sterile aqueous suspension and safety needles.

  • The 441 mg strength kit (NDC 65757-401-03; light blue label) contains three safety needles; a 1-inch (25 mm) 21 gauge, a 1½-inch (38 mm) 20 gauge, and a 2-inch (50 mm) 20 gauge needle.
  • The 662 mg strength kit (NDC 65757-402-03; green label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.
  • The 882 mg strength kit (NDC 65757-403-03; burgundy label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.

Aripiprazole lauroxil is available as described in TABLE 11.

  • Table 11: Presentations of Aripiprazole lauroxil
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Storage

Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F).

Images

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Package and Label Display Panel

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Patient Counseling Information

Advise patients to read FDA-approved patient labeling (MEDICATION GUIDE).

  • Pathological Gambling and Other Compulsive Behaviors
  • Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped.
  • Counsel patients about a potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS.
  • Advise patients that abnormal involuntary movements have been associated with administration of antipsychotic drugs. Counsel patients to notify their healthcare provider if they notice any movements which they cannot control in their face, tongue, or other body part.
  • Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight.
  • Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing), particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose.
  • Advise patients with a pre-existing low WBC count or a history of drug-induced leucopenia/neutropenia that they should have their CBC monitored while receiving Aripiprazole lauroxil.
  • Interference with Cognitive and Motor Performance
  • Because Aripiprazole lauroxil may have the potential to impair judgment, thinking or motor skills, instruct patients to be cautious about operating hazardous machinery, including automobiles, until they are reasonably certain that Aripiprazole lauroxil therapy does not affect them adversely.
  • Advise patients regarding appropriate care in avoiding overheating and dehydration.
  • Concomitant Medication
  • Advise patients 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.
  • Pregnancy
  • Advise patients that Aripiprazole lauroxil may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aripiprazole lauroxil during pregnancy.
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Precautions with Alcohol

Alcohol-Aripiprazole (intramuscular) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

ARISTADA®

Look-Alike Drug Names

There is limited information regarding Aripiprazole (intramuscular) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.