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Increased Mortality 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.
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: The safety and efficacy of ARIPIPRAZOLE in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with ARIPIPRAZOLE, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.
Cerebrovascular Adverse Event, Including Stroke: ARIPIPRAZOLE increases incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), ARIPIPRAZOLE is not approved for the treatment of patients with dementia-related psychosis.
Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults: 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 disorder, and these disorder 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.
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 previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for ARIPIPRAZOLE 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 that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder, such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that ARIPIPRAZOLE is not approved for use in treating depression in the pediatric population.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as 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 (e.g., 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: Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, ARIPIPRAZOLE 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 ARIPIPRAZOLE, drug discontinuation should be considered. However, some patients may require treatment with ARIPIPRAZOLE despite the presence of the syndrome.
Metabolic Changes: 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: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been occurred in patients treated with atypical antipsychotics. 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. 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 (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 required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pathological Gambling and Other Compulsive Behaviors: The 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 to the patient and other 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 α-1 adrenergic receptor antagonism. Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction and 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).
Falls: Antipsychotics, including ARIPIPRAZOLE, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis: Class Effect: Events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including ARIPIPRAZOLE. 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 ARIPIPRAZOLE should be considered at the first sign of a clinically 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 treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue ARIPIPRAZOLE and have their WBC followed until recovery.
Seizures/Convulsions: Seizures/convulsions occurred of adult patients treated with oral ARIPIPRAZOLE, in pediatric patients (6 to 17 years).
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: ARIPIPRAZOLE like other antipsychotic, may have the potential to impair judgment, thinking or motor skills. For example somnolence (including sedation) was reported in adult patients treated with oral ARIPIPRAZOLE, and in pediatric patients ages 6 to 17. Somnolence (including sedation) led to discontinuation in adult patients and pediatric patients on oral ARIPIPRAZOLE. Despite the relatively modest increased incidence of these events, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ARIPIPRAZOLE does not affect them adversely.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ARIPIPRAZOLE for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).
Suicide: 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 ARIPIPRAZOLE should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ARIPIPRAZOLE. 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 drug should be used cautiously in patients at risk for aspiration pneumonia.
Use In Patients with Concomitant illness: ARIPIPRAZOLE has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.
Drug Abuse and Dependence: Controlled Substance: ARIPIPRAZOLE is not controlled substance.
Abuse and Dependence: Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ARIPIPRAZOLE misuse or abuse (eg. development of tolerance, increases in dose, drug-seeking behavior).
Use in Specific Populations: In general, no dosage adjustment for ARIPIPRAZOLE is required on the basis of a patient's age, gender, race, smoking status, hepatic function, or renal function (see DOSAGE & ADMINISTRATION).
Gender: No dosage adjustment e recommended based on gender.
Race: No dosage adjustment is recommended based on race.
Smoking: No dosage adjustment is recommended based on smoking status.
Renal Impairment: No dosage adjustment is required in subjects with renal impairment.
Hepatic Impairment: No dosage adjustment is required in subjects with hepatic impairment.
Use in Children: Safety and effectiveness in pediatric patients with major depressive disorder have not been 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.
Use in the Elderly: No dosage adjustment is recommended for elderly patients. ARIPIPRAZOLE is not approved for the treatment of patients with psychosis associated with Alzheimer's disease.
