Abilify Tablet Special Precautions

General: Orthostatic Hypotension: Aripiprazole may be associated with orthostatic hypotension, perhaps due to its α₁-adernergic receptor antagonism. The incidence of orthostatic hypotension-associated events from 5 short-term, placebo-controlled trials in schizophrenia (n=926) on Abilify included: Orthostatic hypotension (placebo 1%, aripiprazole 1.9%), orthostatic lightheadedness (placebo 1%, aripiprazole 0.9%), and syncope (placebo 1%, aripiprazole 0.6%). The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials in bipolar mania (n=597) on Abilify included: Orthostatic hypotension (placebo 0%, aripiprazole 0.7%), orthostatic lightheadedness (placebo 0.5%, aripiprazole 0.5%), and syncope (placebo 0.9%, aripiprazole 0.5%).
The incidence of a significant orthostatic change in blood pressure (defined as a decrease of at least 30 mm Hg in systolic blood pressure when changing from a supine to standing position) for aripiprazole was not statistically different from placebo (in schizophrenia: 14% among aripiprazole-treated patients and 12% among placebo-treated patients and in bipolar mania: 3% among aripiprazole-treated patients and 2% among placebo-treated patients).
Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).
Seizure: Seizures occurred in 0.1% (1/926) of aripiprazole-treated patients with schizophrenia in short-term, placebo-controlled trials. In short-term, placebo-controlled clinical trials of patients with bipolar mania, 0.3% (2/597) of aripiprazole-treated patients and 0.2% (1/436) of placebo-treated patients experienced seizures. As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold eg, Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of >65 years.
Potential for Cognitive and Motor Impairment: In short-term, placebo-controlled trials of schizophrenia, somnolence was reported in 11% of patients on Abilify compared to 8% of patients on placebo; somnolence led to discontinuation in 0.1% (1/926) of patients with schizophrenia on Abilify in short-term, placebo-controlled trials. In short-term, placebo-controlled trials of bipolar mania, somnolence was reported in 14% of patients on Abilify compared to 7% of patients on placebo, but did not lead to discontinuation of any patients with bipolar mania. Despite the relatively modest increased incidence of somnolence compared to placebo, Abilify, like other antipsychotics, may have the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Abilify does not affect them adversely.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia (see Use in Patients with Concomitant Illness as follows).
Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Abilify should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness: Clinical experience with Abilify in patients with certain concomitant systemic illnesses (see Pharmacokinetics: Special Populations: Renal Impairment and Hepatic Impairment under Actions) is limited.
Abilify has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies.
Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease: In 3, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥5% and aripiprazole incidence at least twice that for placebo were asthenia (placebo 3%, aripiprazole 8%), somnolence (placebo 3%, aripiprazole 9%), urinary incontinence (placebo 1%, aripiprazole 5%), excessive salivation (placebo 0%, aripiprazole 4%), and lightheadedness (placebo 1%, aripiprazole 4%).
The safety and efficacy of Abilify in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised, particularly for the emergence of difficulty in swallowing or excessive somnolence, which could predispose to accidental injury or aspiration (see also Increased Mortality in Elderly Patients with Dementia-Related Psychosis and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis under Warnings).
Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe Abilify: Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol: Patients should be advised to avoid alcohol while taking Abilify.
Heat Exposure and Dehydration: Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
Drug Abuse and Dependence: Controlled Substance: Abilify is not a controlled substance.
Abuse and Dependence: Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse and such patients should be observed closely for signs of Abilify misuse or abuse (eg, development of tolerance, increases in dose, drug-seeking behavior).
Effects on the Ability to Drive or Operate Machinery: Interference with Cognitive and Motor Performance: Because aripiprazole may have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole therapy does not affect them adversely.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Lifetime carcinogenicity studies were conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10 and 30 mg/kg/day to ICR mice and 1, 3 and 10 mg/kg/day to F344 rats [0.2-5 and 0.3-3 times the maximum recommended human dose (MRHD) based on mg/m², respectively]. In addition, SD rats were dosed orally for 2 years at 10, 20, 40 and 60 mg/kg/day (3-19 times the MRHD based on mg/m²). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3-30 mg/kg/day (0.1-0.9 times human exposure at MRHD based on AUC and 0.5-5 times the MRHD based on mg/m²). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at MRHD based on AUC and 3 times the MRHD based on mg/m²); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 times the MRHD based on mg/m²).
Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4- and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice, however, the response was shown to be due to a mechanism not considered relevant to humans.
Female rats were treated with oral doses of 2, 6 and 20 mg/kg/day (0.6, 2 and 6 times the MRHD on a mg/m² basis) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrous cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased preimplantation loss was seen at 6 and 20 mg/kg and decreased fetal weight was seen at 20 mg/kg.
Male rats were treated with oral doses of 20, 40 and 60 mg/kg/day (6, 13 and 19 times the MRHD on a mg/m² basis) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and 60 mg/kg, but no impairment of fertility was seen.
Use in pregnancy: Pregnancy Category C: In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
Pregnant rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m² basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg) and delayed skeletal ossification (10 and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg) and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants and live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg, however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
Pregnant rabbits were treated with oral doses of 10, 30 and 100 mg/kg/day (2, 3 and 11 times human exposure at MRHD based on AUC and 6, 19 and 65 times the MRHD based on mg/m²) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 and 100 mg/kg) and minor skeletal variations (100 mg/kg).
In a study in which rats were treated with oral doses of 3, 10 and 30 mg/kg/day (1, 3 and 10 times the MRHD on a mg/m² basis) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths, and decreases in pup weight (persisting into adulthood) and survival, were seen at this dose.
There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Aripiprazole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with Abilify.
Labor and Delivery: The effect of aripiprazole on labor and delivery in humans is unknown.
Use in lactation: Aripiprazole was excreted in milk of rats during lactation. It is not known whether aripiprazole or its metabolites are excreted in human milk. It is recommended that women receiving aripiprazole should not breastfeed.
Use in children: Safety and effectiveness in pediatric and adolescent patients have not been established.
Use in the elderly: Of the 7951 patients treated with aripiprazole in premarketing clinical trials, 991 (12%) were ≥65 years and 789 (10%) were ≥75 years. The majority (88%) of the 991 patients were diagnosed with dementia of the Alzheimer's type.
Placebo-controlled studies of aripiprazole in schizophrenia or bipolar mania did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. There was no effect of age on the pharmacokinetics of a single 15-mg dose of aripiprazole. Aripiprazole clearance was decreased by 20% in elderly subjects ≥65 years) compared to younger adult subjects (18-64 years), but there was no detectable effect of age in the population pharmacokinetic analysis in schizophrenia patients.
Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia (see Increased Mortality in Elderly Patients with Dementia-Related Psychosis and Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis under Warnings and Use in Patients with Concomitant Illness under Precautions). The safety and efficacy of Abilify in the treatment of patients with psychosis associated with Alzheimer’s disease has not been established. If the prescriber elects to treat such patients with Abilify, vigilance should be exercised.