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WARNING
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. ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS].
Aripiprazole is an atypical antipsychotic which is present in ABILIFY ASIMTUFII as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2•H2O and its molecular weight is 466.40. The chemical structure is:
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ABILIFY ASIMTUFII (aripiprazole) is available as a white to off-white, sterile, aqueous extended-release suspension for intramuscular injection in 720 mg or 960 mg dose strength, pre-filled syringes. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients are carboxymethylcellulose sodium (5 mg/mL), polyethylene glycol 400 (1 mg/mL), povidone (4 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate monobasic monohydrate (0.74 mg/mL), sodium hydroxide (to adjust pH) and water for injection (q.s.).
ABILIFY ASIMTUFII is indicated:
For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY ASIMTUFII. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.
ABILIFY ASIMTUFII must be administered as an intramuscular gluteal injection by a healthcare professional. Do not administer by any other route.
For detailed preparation and administration instructions, see Preparation And Administration Instructions.
The recommended dosage of ABILIFY ASIMTUFII is 960 mg, administered once every 2 months (56 days after previous injection).
When ABILIFY ASIMTUFII injection is initiated in patients receiving oral aripiprazole, administer the first dose of ABILIFY ASIMTUFII along with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days.
For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer the first ABILIFY ASIMTUFII injection along with the oral antipsychotic for 14 consecutive days.
For patients receiving Abilify Maintena (once monthly dosing), administer ABILIFY ASIMTUFII 960 mg (once every 2 month dosing) in place of the next scheduled injection of the Abilify Maintena. The first ABILIFY ASIMTUFII injection may be administered in place of the second, or later injection of Abilify Maintena.
If there are adverse reactions with the ABILIFY ASIMTUFII 960 mg dosage, the dosage may be reduced to 720 mg once every 2 months.
Patients may be given the ABILIFY ASIMTUFII injection up to 2 weeks before or 2 weeks after the 2-month scheduled timepoint.
If more than 8 weeks and less than 14 weeks have elapsed since the last injection, administer the next dose of ABILIFY ASIMTUFII as soon as possible. The once every 2 month schedule should be resumed.
If more than 14 weeks have elapsed since the last injection, restart concomitant oral aripiprazole for 14 days with the next administered injection of ABILIFY ASIMTUFII.
Dosage adjustments for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for more than 14 days are described in Table 1.
If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage of ABILIFY ASIMTUFII may need to be increased to the previous dose.
Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.
Table 1: Dosage Recommendations for ABILIFY ASIMTUFII in Patients Who are Known CYP2D6 Poor Metabolizers, Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, or CYP3A4 Inducers for Greater than 14 days
| Factors | Dosage Recommendation |
| CYP2D6 Poor Metabolizers | |
| Known CYP2D6 Poor Metabolizers | 720 mg once every 2 months |
| Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors | Avoid use |
| Patients Taking 960 mg of ABILIFY ASIMTUFII | |
| Concomitant use of ABILIFY ASIMTUFII with Strong CYP2D6 inhibitors | 720 mg once every 2 months |
| Concomitant use of ABILIFY ASIMTUFII with Strong CYP3A4 inhibitors | 720 mg once every 2 months |
| Concomitant use of ABILIFY ASIMTUFII with Strong CYP2D6 and Strong CYP3A4 inhibitors | Avoid use |
| Concomitant use of ABILIFY ASIMTUFII with CYP3A4 inducers | Avoid use |
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Figure 1
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Figure 2
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Needle selection is determined by patient body type.
For gluteal intramuscular administration only.
Figure 3
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Figure 4
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Figure 5
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Do not administer by any other route.
Do not massage the injection site.
Figure 6
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Figure 7
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Figure 8
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Extended-release injectable suspension: sterile, white to off-white, aqueous suspension in a single-dose, pre-filled syringe.
Table 2: ABILIFY ASIMTUFII Presentations
| Dose Strength | Volume | Label Color | Syringe Tip Wrap |
| 720 mg | 2.4 mL | Light Blue | Aqua |
| 960 mg | 3.2 mL | Pink | Light Blue |
ABILIFY ASIMTUFII (aripiprazole) is available as white to off-white, sterile aqueous extended-release injectable suspension in single-dose, pre-filled syringes in 720 mg/2.4 mL or 960 mg/3.2 mL strengths.
The single-use kit contains 1 pre-filled syringe and 2 safety needles (a 1.5 inch 22 gauge needle and a 2 inch 21 gauge needle).
Store at 25°C (77°F), excursions permitted between 15° and 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Manufactured by: Otsuka Pharmaceutical Co., Ltd., 2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo, 101-8535 Japan. Revised: Apr 2023
The following adverse reactions are discussed in more detail 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.
The safety of ABILIFY ASIMTUFII for the treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults is based on adequate and well-controlled studies of Abilify Maintena. The safety data from those studies is presented below.
Oral aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.
Abilify Maintena (once monthly dosing) has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to Abilify Maintena. A total of 1,229 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 935 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections).
Abilify Maintena has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to Abilify Maintena. A total of 419 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 287 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections).
In a 32-week open-label study of ABILIFY ASIMTUFII in adult patients with schizophrenia or bipolar I disorder, 266 patients were randomized to receive either ABILIFY ASIMTUFII 960 mg (132 patients) or Abilify Maintena 400 mg (134 patients). A total of the 132 patients received at least one injection of ABILIFY ASIMTUFII, a total of 114 patients received at least two consecutive injections (4 months treatment) of ABILIFY ASIMTUFII, and a total of 104 patients received at least four consecutive injections (8 months treatment) of ABILIFY ASIMTUFII. Of the total 266 patients receiving ABILIFY ASIMTUFII 960 mg or Abilify Maintena 400 mg, 185 had schizophrenia and 81 had bipolar I disorder. Injection site reactionsfor ABILIFY ASIMTUFII (once every 2 month dosing) presented in this section is based on this open-label study (see section titled “Injection Site Reactions with Abilify ASIMTUFII”).
The conditions and duration of treatment with Abilify Maintena included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of Abilify Maintena in adult patients with schizophrenia.
Based on the placebo-controlled trial of Abilify Maintena in schizophrenia, the most commonly observed adverse reactions associated with the use of Abilify Maintena in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%).
The following findings are based on the double-blind, placebo-controlled trial that compared Abilify Maintena 400 mg or 300 mg to placebo in patients with schizophrenia. Table 6 lists the adverse reactions reported in 2% or more of Abilify Maintena-treated patients and at a greater proportion than in the placebo group.
Table 6: Adverse Reactions in ≥2% of Adult Patients with Schizophrenia Treated with Abilify Maintena in a 12-Week Double-Blind, Placebo-Controlled Study*
| Preferred Term | Abilify Maintena (n=167) |
Placebo (n=172) |
| Gastrointestinal Disorders | ||
| Constipation | 10 | 7 |
| Dry Mouth | 4 | 2 |
| Diarrhea | 3 | 2 |
| Vomiting | 3 | 1 |
| Abdominal Discomfort | 2 | 1 |
| General Disorders and Administration Site Conditions | ||
| Injection Site Pain | 5 | 1 |
| Infections and Infestations | ||
| Upper Respiratory Tract Infection | 4 | 2 |
| Investigations | ||
| Increased Weight | 17 | 7 |
| Decreased Weight | 4 | 2 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia | 4 | 1 |
| Back Pain | 4 | 2 |
| Myalgia | 4 | 2 |
| Musculoskeletal pain | 3 | 1 |
| Nervous System Disorders | ||
| Akathisia | 11 | 4 |
| Sedation | 5 | 1 |
| Dizziness | 4 | 2 |
| Tremor | 3 | 1 |
| Respiratory, Thoracic and Mediastinal | ||
| Nasal Congestion | 2 | 1 |
| *This table does not include adverse reactions which had an incidence equal to or less than placebo. | ||
An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of Abilify Maintena patients at least twice the rate of placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial. This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few patients ≥65 years of age.
ABILIFY ASIMTUFII was evaluated in 266 patients with schizophrenia or bipolar I disorder in an open-label, multiple-dose, randomized, parallel-arm multi-center study.
The percentage of patients in the open-label study reporting any injection site-related adverse reactions (all reported as injection site pain) was 19% for patients treated with ABILIFY ASIMTUFII 960 mg and 9% for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of the injection site pain events coincided with the first injection of ABILIFY ASIMTUFII 960 mg (21/24 patients) or Abilify Maintena 400 mg (7/12 patients), was reported with decreasing frequency upon subsequent injections. The overall mean visual analog scale scores (0=no pain to 100=unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the ABILIFY ASIMTUFII 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group.
In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify Maintena-treated patients was 9.6% vs. 5.2% for placebo. The incidence of akathisia-related events for Abilify Maintena-treated patients was 11.5% vs. 3.5% for placebo.
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. In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of dystonia was 1.8% for Abilify Maintena vs. 0.6% for placebo.
In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for Abilify Maintena-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on Abilify Maintena and resolved spontaneously without any associated adverse reactions [see WARNINGS AND PRECAUTIONS].
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.
The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ABILIFY MAINTENA:
The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), hiccups, pathological gambling.
Table 7 presents clinically significant drug interactions with ABILIFY ASIMTUFII.
Table 7: Clinically Important Drug Interactions with ABILIFY ASIMTUFII
| Strong CYP3A4 Inhibitors AND/OR strong CYP2D6 inhibitors | |
| Clinical Rationale | Concomitant use of oral aripiprazole with strong CYP3A4 AND/OR CYP2D6 inhibitors increased the exposure of aripiprazole [see CLINICAL PHARMACOLOGY]. |
| Clinical Recommendation | Concomitant use of a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor |
| Reduce the dosage of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor for more than 14 days [see DOSAGE AND ADMINISTRATION]. | |
| Concomitant Use of a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor | |
| Avoid use of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor for more than 14 days [see DOSAGE AND ADMINISTRATION]. | |
| Strong CYP3A4 Inducers | |
| Clinical Rationale | Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see CLINICAL PHARMACOLOGY]. |
| Clinical Recommendation | Avoid use of ABILIFY ASIMTUFII in combination with a strong CYP3A4 inducer (e.g., carbamazepine) for greater than 14 days [see DOSAGE AND ADMINISTRATION]. |
| Antihypertensive Drugs | |
| Clinical Rationale | Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
| Clinical Recommendation | Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS]. |
| Benzodiazepines | |
| Clinical Rationale | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS]. |
| Clinical Recommendation | Monitor sedation and blood pressure. Adjust dose accordingly. |
Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY ASIMTUFII is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see CLINICAL PHARMACOLOGY].
In addition, no dosage adjustment is necessary for substrates of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 when coadministered with ABILIFY ASIMTUFII. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY ASIMTUFII [see CLINICAL PHARMACOLOGY].
Included as part of the "PRECAUTIONS" Section
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.
ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING and Cerebrovascular Adverse Reactions, Including Stroke In Elderly Patients With Dementia-Related Psychosis].
In placebo-controlled clinical studies (two flexible-dose and one fixed-dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with oral aripiprazole. ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see Increased Mortality In Elderly Patients With Dementia-Related Psychosis].
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex has been reported with antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global 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.
If NMS is suspected, immediately discontinue ABILIFY ASIMTUFII and provide symptomatic treatment and monitoring.
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 increases. The syndrome can develop, after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, ABILIFY ASIMTUFII 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 treated with ABILIFY ASIMTUFII, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY ASIMTUFII despite the presence of the syndrome.
Atypical antipsychotic drugs have been associated with metabolic changes including 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, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see ADVERSE REACTIONS]. 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 reactions 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, including ABILIFY ASIMTUFII, 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, including ABILIFY ASIMTUFII, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including ABILIFY ASIMTUFII, 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 atypical antipsychotic drug.
In a short-term, placebo-controlled randomized trial in adults with schizophrenia, the mean change in fasting glucose was +9.8 mg/dL (N=88) in the Abilify Maintena-treated patients (once monthly dosing) and +0.7 mg/dL (N=59) in the placebo-treated patients. Table 3 shows the proportion of Abilify Maintena-treated patients with normal and borderline fasting glucose at baseline and their changes in fasting glucose measurements.
Table 3: Proportion of Patients with Potential Clinically Relevant Changes in Fasting Glucose from a 12-Week Placebo-Controlled Monotherapy Trial with Abilify Maintena in Adult Patients with Schizophrenia
| Category Change (at least once) from Baseline | Treatment Arm | n/N* | % | |
| Fasting Glucose | Normal to High (<100 mg/dL to ≥126 mg/dL) |
Abilify Maintena | 7/88 | 8.0 |
| Placebo | 0/75 | 0.0 | ||
| Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) |
Abilify Maintena | 1/33 | 3.0 | |
| Placebo | 3/33 | 9.1 | ||
| *N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift. | ||||
During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena treatment, 1.1% with normal baseline fasting glucose experienced a shift to high while receiving Abilify Maintena and 9.8% with borderline fasting glucose experienced a shift to high. Combined, 2.9% of these patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during this trial.
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Table 4 shows the proportion of adult patients from one short-term, placebo-controlled randomized trial in adults with schizophrenia taking Abilify Maintena (once monthly dosing), with changes in total cholesterol, fasting triglycerides, fasting LDL cholesterol and HDL cholesterol.
Table 4: Proportion of Patients with Potential Clinically Relevant Changes in Blood Lipid Parameters From a 12-Week Placebo-Controlled Monotherapy Trial with Abilify Maintena in Adults with Schizophrenia
| Treatment Arm | n/N* | % | |
| Total Cholesterol Normal to High (<200 mg/dL to ≥240 mg/dL) |
Abilify Maintena | 3/83 | 3.6 |
| Placebo | 2/73 | 2.7 | |
| Borderline to High (200~<240 mg/dL to ≥240 mg/dL) |
Abilify Maintena | 6/27 | 22.2 |
| Placebo | 2/19 | 10.5 | |
| Any increase (≥40 mg/dL) |
Abilify Maintena | 15/122 | 12.3 |
| Placebo | 6/110 | 5.5 | |
| Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) |
Abilify Maintena | 7/98 | 7.1 |
| Placebo | 4/78 | 5.1 | |
| Borderline to High (150~<200 mg/dL to ≥200 mg/dL) |
Abilify Maintena | 3/11 | 27.3 |
| Placebo | 4/15 | 26.7 | |
| Any increase (≥50 mg/dL) |
Abilify Maintena | 24/122 | 19.7 |
| Placebo | 20/110 | 18.2 | |
| Fasting LDL Cholesterol Normal to High (<100 mg/dL to ≥160 mg/dL) |
Abilify Maintena | 1/59 | 1.7 |
| Placebo | 1/51 | 2.0 | |
| Borderline to High (100~<160 mg/dL to ≥160 mg/dL) |
Abilify Maintena | 5/52 | 9.6 |
| Placebo | 1/41 | 2.4 | |
| Any increase (≥30 mg/dL) |
Abilify Maintena | 17/120 | 14.2 |
| Placebo | 9/103 | 8.7 | |
| HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) |
Abilify Maintena | 14/104 | 13.5 |
| Placebo | 11/87 | 12.6 | |
| Abilify Maintena | 7/122 | 5.7 | |
| Any decrease (≥20 mg/dL) |
Placebo | 12/110 | 10.9 |
| *N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift. | |||
During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena, shifts from baseline in fasting cholesterol from normal to high were reported in 2.1% (total cholesterol) and 2.2% (LDL cholesterol) and shifts from baseline from normal to low were reported in 8.5% (HDL cholesterol). Of these patients with normal baseline triglycerides, 3.6% experienced shifts to high, and 0.0% experienced shifts to very high. Combined, 1.0% of these patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during this trial.
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
In one short-term, placebo-controlled trial in adult patients with schizophrenia with Abilify Maintena (once monthly dosing), the mean change in body weight at Week 12 was +3.5 kg (N=99) in the Abilify Maintena-treated patients and +0.8 kg (N=66) in the placebo-treated patients.
Table 5 shows the percentage of adult patients with schizophrenia with weight gain ≥7% of body weight in a short-term, placebo-controlled trial with Abilify Maintena.
Table 5: Percentage of Patients From a 12-Week Placebo-Controlled Trial with Abilify Maintena in Adult Patients with Schizophrenia with Weight Gain ≥7% of Body Weight
| Treatment Arm | N* | Patients n (%) | |
| Weight gain ≥7% of body weight | Abilify Maintena | 144 | 31 (21.5) |
| Placebo | 144 | 12 (8.5) | |
| *N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. | |||
During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena, 1.8% discontinued Abilify Maintena treatment due to weight increase. Abilify Maintena was associated with mean increase from baseline in weight of 1.0 kg at Week 52. In this trial, 21.4% of these patients demonstrated ≥7% increase in body weight and 15.4% demonstrated a ≥7% decrease in body weight.
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 to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
ABILIFY ASIMTUFII may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Associated reactions related to orthostatic hypotension can include dizziness, tachycardia, and in some patients, syncope. In the short-term, placebo-controlled trial in adults with schizophrenia, the adverse reaction of presyncope was reported in 1/167 (0.6%) of patients treated with Abilify Maintena (once monthly dosing), while syncope and orthostatic hypotension were each reported in 1/172 (0.6%) of patients treated with placebo. During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, orthostasis-related adverse events were reported in 4/576 (0.7%) of patients treated with Abilify Maintena, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%).
In the short-term placebo-controlled trial of Abilify Maintena in adults with schizophrenia, there were no patients in either treatment group with 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 bpm when comparing standing to supine values). During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, the incidence of significant orthostatic change in blood pressure was 0.2% (1/575).
Use ABILIFY ASIMTUFII with caution in patients with known cardiovascular disease (heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Antipsychotics, including ABILIFY ASIMTUFII, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related 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.
In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported [see ADVERSE REACTIONS].
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) absolute neutrophil count (ANC) and a 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 ABILIFY ASIMTUFII 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 treat promptly if such symptoms or signs occur. Discontinue ABILIFY ASIMTUFII in patients with severe neutropenia (ANC<1000/mm3) and follow their WBC counts until recovery.
As with other antipsychotic drugs, use ABILIFY ASIMTUFII cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
ABILIFY ASIMTUFII, like other antipsychotics, may impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that therapy with ABILIFY ASIMTUFII does not affect them adversely.
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY ASIMTUFII 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).
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. ABILIFY ASIMTUFII and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact a health care provider or report to the emergency room if they experience signs and symptoms of NMS [see WARNINGS AND PRECAUTIONS].
Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, increased urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking ABILIFY ASIMTUFII. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see WARNINGS AND PRECAUTIONS].
Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see WARNINGS AND PRECAUTIONS].
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 ABILIFY ASIMTUFII [see WARNINGS AND PRECAUTIONS].
Inform patients that ABILIFY ASIMTUFII has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that ABILIFY ASIMTUFII therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].
Educate patients regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see DRUG INTERACTIONS].
Advise patients that ABILIFY ASIMTUFII 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 ABILIFY ASIMTUFII during pregnancy [see Use In Specific Populations].
No carcinogenicity studies were conducted with intramuscular aripiprazole suspension.
Lifetime carcinogenicity studies were conducted with oral aripiprazole in Swiss albino mice, Sprague-Dawley (SD) rats, and F344 rats. Oral 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 oral MRHD based on mg/m2, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m2). Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidence of pituitary gland adenomas, mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the oral 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 (3 times the oral 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 (19 times the oral 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.
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.
No mating and fertility studies were conducted with intramuscular aripiprazole suspension.
Female rats were treated with aripiprazole oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the oral 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 and 20 mg/kg/day and decreased fetal weight was seen at 20 mg/kg/day.
Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the oral MRHD on 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.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
Neonates exposed to antipsychotic drugs, including ABILIFY ASIMTUFII, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (see Clinical Considerations). There are insufficient data with ABILIFY ASIMTUFII use in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 11 times, respectively, the maximum recommended human oral dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the oral MRHD produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data). Consider the benefits and risks of ABILIFY ASIMTUFII and possible risks to the fetus when prescribing ABILIFY ASIMTUFII to a pregnant woman. Advise pregnant women of potential fetal risk.
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.
Fetal/Neonatal Adverse Reactions
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, including oral aripiprazole, during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.
Animal Data
No developmental toxicity studies were conducted with intramuscular aripiprazole suspension.
In animal oral or intravenous 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 which are approximately 1 to 10 times the oral 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). 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 rats treated with aripiprazole intravenously at doses of 3, 9, and 27 mg/kg/day, which are 1 to 9 times the oral MRHD on mg/m2 basis, during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose which also caused 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 of aripiprazole on mg/m2 basis 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 pregnant rabbits receiving aripiprazole injection intravenously at doses of 3, 10, and 30 mg/kg/day, which are 2 to 19 times the oral MRHD on mg/m2 basis during the period of organogenesis, the highest dose caused pronounced maternal toxicity that resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD on mg/m2 basis.
In rats treated with oral doses of 3, 10, and 30 mg/kg/day, which are 1 to 10 times the oral MRHD of aripiprazole on a mg/m2 basis, peri- and post-natally (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.
In rats treated with aripiprazole intravenously at doses of 3, 8, and 20 mg/kg/day which are 1 to 6 times the oral MRHD on mg/m2 basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the oral MRHD on mg/m2 basis, and decreases in early postnatal pup weight and survival were seen at the highest dose; these doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.
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 ABILIFY ASIMTUFII and any potential adverse effects on the breastfed infant from ABILIFY ASIMTUFII or from the underlying maternal condition.
Safety and effectiveness of ABILIFY ASIMTUFII in pediatric patients have not been established.
No juvenile animal studies were conducted with intramuscular aripiprazole suspension. A study with oral aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.
Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.
Clinical studies of ABILIFY ASIMTUFII did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In single-dose and multiple-dose pharmacokinetic studies with oral aripiprazole, there was no detectable age effect in the population pharmacokinetic analysis in schizophrenia patients. No dosage adjustments are recommended based on age alone. ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and WARNINGS AND PRECAUTIONS].
Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3% to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see DOSAGE AND ADMINISTRATION].
No dosage adjustment for ABILIFY ASIMTUFII is required on the basis of a patient’s renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see DOSAGE AND ADMINISTRATION].
No dosage adjustment for ABILIFY ASIMTUFII is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15).
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.
Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.
ABILIFY ASIMTUFII is contraindicated in patients with a known hypersensitivity to aripiprazole, or any of the excipients. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see ADVERSE REACTIONS].
The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown.
The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM, respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 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). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).
ABILIFY ASIMTUFII 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 about 29% of the parent drug exposure in plasma.
ABILIFY ASIMTUFII delivers aripiprazole over a 2-month period. ABILIFY ASIMTUFII has linear PK in the approved dose range. Steady-state aripiprazole exposures were reached by the fourth dose. Plasma exposures at steady state were compared between ABILIFY ASIMTUFII (960 mg, once every 2 months) and Abilify Maintena (400 mg, once every month). The average plasma concentrations (Cavg) of aripiprazole were 263 ng/mL and 280 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively. The Cmax of aripiprazole were 342 ng/mL and 344 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively.
Figure 9: Mean Plasma Concentration of Aripiprazole Following the Fourth Administration of ABILIFY ASIMTUFII 960 mg versus the Eighth Administration of Abilify Maintena 400 mg
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Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with Tmax ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.
Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
Metabolism
Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. Following administration of multiple doses of ABILIFY ASIMTUFII, dehydro-aripiprazole, the active metabolite, represents approximately 30% of aripiprazole AUC in plasma.
Excretion
Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.
No specific drug interaction studies have been performed with ABILIFY ASIMTUFII. The information below is obtained from studies with oral aripiprazole.
The effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 10 and Figure 11, respectively. Based on simulations, 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 10: The Effect of Other Drugs on Aripiprazole Pharmacokinetics
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Figure 11: The Effect of Other Drugs on Dehydro-aripiprazole Pharmacokinetics
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The effect of oral aripiprazole on the exposures of other drugs are summarized in Figure 13. A population PK 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.
Figure 13: The Effect of Oral Aripiprazole on Pharmacokinetics of Other Drugs
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No specific pharmacokinetic studies have been performed with ABILIFY ASIMTUFII in specific populations. All the information is obtained from studies with oral aripiprazole or is based on the pharmacokinetic modeling of oral aripiprazole and/or ABILIFY ASIMTUFII.
Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 14 and Figure 15, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with oral aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.
Figure 14: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics
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Figure 15: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics
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The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. In dogs, repeated intramuscular dosing of the 2-month aripiprazole extended release injectable suspension over a period of 52 weeks produced no clinical evidence of significant local irritation, and resulted in slight foreign-body type of localized granulomatous inflammatory reaction to deposited drug at the injection site. These effects gradually resolved with discontinuation of dosing.
Oral 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 and 60 mg/kg. The 40 and 60 mg/kg/day doses are 13 and 19 times the maximum recommended human oral dose (MRHD) based on mg/m2 body surface 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.
The efficacy of ABILIFY ASIMTUFII (once every 2 month dosing) for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena (once monthly dosing). The results of these adequate and well-controlled studies are presented below.
The efficacy of Abilify Maintena (once monthly dosing) for treatment of schizophrenia was established in:
In the short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1), the primary measure used for assessing psychiatric signs and symptoms was the Positive and Negative Syndrome Scale (PANSS). 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 primary endpoint was the change from baseline in PANSS total score to week 10.
The inclusion criteria for this short-term trial included adult inpatients who met DSM-IV-TR criteria for schizophrenia. In addition, all patients entering the trial must have experienced an acute psychotic episode as defined by both PANSS Total Score ≥80 and a PANSS score of >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, unusual thought content) at screening and baseline. The key secondary endpoint was the change from baseline in Clinical Global Impression-Severity (CGI-S) assessment scale to week 10. The CGI-S rates the severity of mental illness on a scale of 1 (normal) to 7 (among the most extremely ill) based on the total clinical experience of the rater in treating patients with schizophrenia. Patients had a mean PANSS total score of 103 (range 82 to 144) and a CGI-S score of 5.2 (markedly ill) at entry.
In this 12-week study (n=339) comparing Abilify Maintena (n=167) to placebo (n=172), patients were administered 400 mg Abilify Maintena or placebo on days 0, 28, and 56. The dose could be adjusted down and up within the range of 400 to 300 mg on a one-time basis. Abilify Maintena was superior to placebo in improving the PANSS total score at the end of week 10 (see Table 8).
Table 8: Efficacy Results of Abilify Maintena in Short-term Schizophrenia Study 1 (Adults)
| Primary Efficacy Measure: PANSS Total Score | ||||
| Study Number | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference* (95% CI) |
| Study 1 | Abilify Maintena (400 to 300 mg) |
102.4 (11.4) | -26.8 (1.6) | -15.1 (-19.4, -10.8) |
| Placebo | 103.4 (11.1) | -11.7 (1.6) | -- | |
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. *Difference (drug minus placebo) in least-squares mean change from baseline. |
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The change in PANSS total score by week is shown in Figure 16. Abilify Maintena also showed improvement in symptoms represented by CGI-S score mean change from baseline to week 10. The results of exploratory subgroup analyses by gender, race, age, ethnicity, and BMI were similar to the results of the overall population.
Figure 16: Weekly PANSS Total Score-Change in the 12-Week, Placebo-Controlled Study with Abilify Maintena in Schizophrenia - Study 1 (Adults)
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| n = the number of patients remaining in the respective study arm at each time point |
The efficacy of Abilify Maintena in maintaining symptomatic control in schizophrenia was established in a double-blind, placebo-controlled, randomized-withdrawal trial in adult patients (Study 2) who met DSM-IV-TR criteria for schizophrenia and who were being treated with at least one antipsychotic medication. Patients had at least a 3-year history of illness and a history of relapse or symptom exacerbation when not receiving antipsychotic treatment.
In addition to the PANSS and CGI-S, clinical ratings during this trial included the:
This trial included:
The primary efficacy endpoint was time from randomization to relapse. Relapse was defined as the first occurrence of one or more of the following criteria:
A pre-planned interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Abilify Maintena group compared to placebo-treated patients and the trial was subsequently terminated early because maintenance of efficacy was demonstrated. The final analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Abilify Maintena group than compared to placebo-treated patients. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for Abilify Maintena and placebo groups are shown in Figure 17.
Figure 17: Kaplan-Meier Estimation of Cumulative Proportion of Abilify Maintena-Treated Patients with Relapse* (Adults) Study 2
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| *This figure is based on a total of 80 relapse events. |
The key secondary efficacy endpoint, percentage of patients meeting the relapse criteria, was statistically significantly lower in patients randomized to the Abilify Maintena group (10%) than in the placebo group (40%).
The efficacy of ABILIFY ASIMTUFII (once every 2 month dosing) for the treatment of maintenance monotherapy treatment of bipolar I disorder in adults is based on an adequate and well-controlled study of Abilify Maintena (once monthly dosing). The results of the adequate and well-controlled study are presented below.
The efficacy of Abilify Maintena (once monthly dosing) for the maintenance treatment of bipolar I disorder was established in a 52-week, double-blind, placebo-controlled, randomized withdrawal trial in adult patients who were experiencing a manic episode at trial entry, met DSM-IV-TR criteria for bipolar I disorder, and had a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and/or treatment with an antipsychotic agent.
Clinical ratings during this trial included:
Young Mania Rating Scale (YMRS)-an 11-item, clinician-rated scale used to assess the degree of manic symptomatology, in a range with 0 representing no symptoms, and 60 representing worst symptoms; Montgomery-Asberg Depression Rating Scale (MADRS) – a 10-item clinician-related scale used to assess the degree of depressive symptomatology, with 1 representing no symptoms, and 60 representing worst symptoms; Clinical Global Impression Bipolar Version Severity of Illness (CGI-BP-S) a scale of 1 (normal, not at all ill) to 7 (very severely ill patient) based on the patient’s severity of illness mania, depression, and overall bipolar illness.
This trial included:
The primary efficacy endpoint was time from randomization to recurrence of any mood episode. Recurrence was defined as the first occurrence of one or more of the following criteria:
1) Hospitalization for any mood episode OR 2) Any of the following: a. YMRS total score ≥15 OR b. MADRS total score ≥15 OR c. Clinical Global Impression - Bipolar Version-Severity (CGI-BP-S) score >4 (overall score) OR 3) Serious adverse event (SAE) of worsening disease (bipolar I disorder) OR 4) Discontinuation due to lack of efficacy or discontinuation due to an adverse event (AE) of worsening disease OR 5) Clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, and/or increase greater than the allowed benzodiazepine doses for treatment of symptoms of an underlying mood disorder OR 6) Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of “yes” on question 4 or 5 on the C-SSRS
Analysis demonstrated a statistically significantly longer time to recurrence of any mood episode in subjects randomized to the Abilify Maintena group than compared to placebo-treated subjects. The Kaplan-Meier curves of the time of recurrence to any mood episode during the double-blind treatment phase for Abilify Maintena and placebo groups are shown in Figure 18.
Figure 18: Kaplan-Meier Estimation of Cumulative Recurrence Rate for Any Mood Episode* in Abilify Maintena-Treated Adults
 |
| *This figure is based on a total of 103 recurrence events. |
Analysis by type of mood recurrence demonstrated a statistically significantly longer time to recurrence for both manic and mixed mood episodes in subjects treated with Abilify Maintena compared to those treated with placebo. There was no substantial difference between treatment groups in delaying time to recurrence of depressive mood episodes.
An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.
ABILIFY ASIMTUFII®
(a-BIL-i-fy AH-SIM-TUH-FYE)
(aripiprazole) for extended-release injectable suspension, for intramuscular use
What is the most important information I should know about ABILIFY ASIMTUFII?
ABILIFY ASIMTUFII may cause serious side effects, including:
What is ABILIFY ASIMTUFII?
ABILIFY ASIMTUFII is a prescription medicine given by injection by a healthcare provider:
It is not known if ABILIFY ASIMTUFII is safe and effective in children under 18 years of age.
Do not receive ABILIFY ASIMTUFII if you are allergic to aripiprazole or any of the ingredients in ABILIFY ASIMTUFII.
See the end of this Medication Guide for a complete list of ingredients in ABILIFY ASIMTUFII.
Before receiving ABILIFY ASIMTUFII, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription medicines and over-thecounter medicines, vitamins, and herbal supplements.
ABILIFY ASIMTUFII and other medicines may affect each other causing possible serious side effects. ABILIFY
ASIMTUFII may affect the way other medicines work, and other medicines may affect how ABILIFY ASIMTUFII works.
Your healthcare provider can tell you if it is safe to receive ABILIFY ASIMTUFII with your other medicines. Do not start or stop any medicines during treatment with ABILIFY ASIMTUFII without first talking to your healthcare provider.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I receive ABILIFY ASIMTUFII?
What should I avoid while receiving ABILIFY ASIMTUFII?
What are the possible side effects of ABILIFY ASIMTUFII?
ABILIFY ASIMTUFII may cause serious side effects, including:
Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with ABILIFY ASIMTUFII:
The most common side effects of ABILIFY ASIMTUFII include: weight gain, restlessness or feeling like you need to move (akathisia), injection site pain, or sleepiness (sedation).
These are not all the possible side effects of ABILIFY ASIMTUFII.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of ABILIFY ASIMTUFII.
If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ABILIFY ASIMTUFII that is written for healthcare professionals.
What are the ingredients in ABILIFY ASIMTUFII?
Active ingredient: aripiprazole monohydrate
Inactive ingredients: carboxymethylcellulose sodium, polyethylene glycol 400, povidone, sodium chloride, sodium phosphate monobasic monohydrate, sodium hydroxide and water for injection.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
