This post was sponsored by Otsuka and Lundbeck.

ABILIFY ASIMTUFII® (aripiprazole) for the maintenance monotherapy treatment of bipolar I disorder in adults

Gustavo Alva, MD, DFAPA

Gustavo Alva, MD, DFAPA

Gustavo Alva is a paid consultant of Otsuka America Pharmaceutical, Inc and received an honorarium for participation in this program.

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INDICATIONS

ABILIFY ASIMTUFII® (aripiprazole) is an atypical antipsychotic indicated for:

  • Treatment of schizophrenia in adults
  • Maintenance monotherapy treatment of bipolar I disorder in adults

ABILIFY MAINTENA® (aripiprazole) is an atypical antipsychotic indicated for:

  • Treatment of schizophrenia in adults
  • Maintenance monotherapy treatment of bipolar I disorder in adults

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death (1.6 to 1.7 times) compared to placebo-treated patients. ABILIFY ASIMTUFII and ABILIFY MAINTENA are not approved for the treatment of patients with dementia-related psychosis.

Dr. Gustavo Alva is the Medical Director of ATP Clinical Research and a practicing psychiatrist at Pacific Neuropsychiatric Specialists in Costa Mesa, California. He is engaged academically as an Assistant Professor at the University of California, Riverside School of Medicine and a Visiting Professor in the Psychiatry International Program at UAG School of Medicine in Guadalajara, Mexico.

For patients living with bipolar I disorder, maintaining stability is crucial. I’d like to explore how ABILIFY ASIMTUFII, the first once-every-2-months long-acting injectable (LAI) for the maintenance treatment of bipolar I disorder, can help patients with long-term management of their bipolar I disorder.

Let’s review the efficacy and safety data of ABILIFY ASIMTUFII to give you a better idea of how to discuss this valuable treatment option with your patients.

What Sets ABILIFY ASIMTUFII Apart?

ABILIFY ASIMTUFII is unique as it is the first FDA-approved LAI that is administered once every 2 months for the maintenance monotherapy treatment of bipolar I disorder, using the same active molecule as ABILIFY MAINTENA, but with a longer duration of action.1

Pharmacokinetic Bridging Study and Efficacy Insights

A 32-week open-label, pharmacokinetic bridging study that established the similarity of aripiprazole plasma concentrations between ABILIFY ASIMTUFII and ABILIFY MAINTENA in adult patients living with schizophrenia or bipolar I disorder has shown that ABILIFY ASIMTUFII 960 mg maintains comparable plasma concentrations to ABILIFY MAINTENA 400 mg, providing consistent efficacy over 2 months.2 This finding supports the use of ABILIFY ASIMTUFII in providing sustained symptom control with six doses per year.

Aripiprazole plasma concentration over time, Graph
Aripiprazole plasma concentration over time, Graph

The efficacy of ABILIFY ASIMTUFII is based on the adequate and well-controlled study of ABILIFY MAINTENA for the treatment of bipolar I disorder in adults.1 Let’s review the data from a pivotal 52-week double-blind, placebo-controlled, randomized withdrawal study of ABILIFY MAINTENA.4

Phase 1 of the study involved switching patients from other antipsychotics to oral aripiprazole. In Phase 2, those patients who successfully switched to oral aripiprazole, along with patients already on this treatment for bipolar I disorder, were stabilized on a daily dose of 15 to 30 mg.4 Phase 3 involved a single-blind segment of at least 12 weeks and began with an initial dose of ABILIFY MAINTENA 400 mg while continuing daily oral aripiprazole for 2 more weeks.4 Finally, Phase 4 was a double-blind, placebo-controlled segment that lasted up to 52 weeks, where participants either continued ABILIFY MAINTENA or switched to a placebo via intramuscular depot.4

The primary endpoint was time from randomization to recurrence of any mood episode. In this study, recurrence was defined as one or more of the following: clinical worsening, psychiatric hospitalization, or increased risk of suicide.4

Results from this pivotal study showed that patients who were treated with ABILIFY MAINTENA remained free of any mood episodes significantly longer than those on placebo. More specifically, ABILIFY MAINTENA significantly delayed the time to recurrence of any mood episode with a P-value of less than 0.0001 and a hazard ratio, or HR, of 0.45.4

Proportion of patients with recurrence over 52 weeks, Graph
Proportion of patients with recurrence over 52 weeks, Graph

An analysis of an exploratory endpoint evaluated in the ABILIFY MAINTENA bipolar I disorder maintenance study found that ABILIFY MAINTENA significantly delayed time to recurrence for a manic episode (HR=0.259 [95% confidence interval, or CI, 0.136-0.495]) or mixed episode (HR=0.202 [95% CI, 0.044-0.939]) with no substantial difference in the time to a depressive episode (HR=0.932 [95% CI, 0.497-1.747]).5 Patients on ABILIFY MAINTENA experienced a 75% reduced risk of recurrence of mixed-/‌manic-mood episodes vs placebo (HR=0.249 [95% CI, 0.137-0.451]).5

Safety Data

Safety is a paramount consideration in any treatment modality. The safety of ABILIFY ASIMTUFII is based on an adequate and well-controlled 12-week study of ABILIFY MAINTENA in patients living with schizophrenia.1 In this study, the most observed adverse reactions associated with ABILIFY MAINTENA were increased weight, akathisia, injection site pain, and sedation. These most commonly observed adverse reactions occurred in at least 5% of patients and at a rate at least twice that of placebo.1 Importantly, no patients on ABILIFY MAINTENA or placebo discontinued due to these four adverse reactions.6

Percentage of patients reporting reaction in a 12-week study, Graph
Percentage of patients reporting reaction in a 12-week study, Graph

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.1

Please note, ABILIFY ASIMTUFII and ABILIFY MAINTENA have a BOXED WARNING: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death (1.6 to 1.7 times) compared to placebo-treated patients. ABILIFY ASIMTUFII and ABILIFY MAINTENA are not approved for the treatment of patients with dementia-related psychosis.

Administration of ABILIFY ASIMTUFII

If tolerability to aripiprazole has been established, the initial dose of ABILIFY ASIMTUFII 960 mg can be given. However, the patient must continue taking their oral aripiprazole or current oral antipsychotic for the next 14 days. After that, they don’t take any more medication until their next injection is due, 56 days after the first one. Patients may be given their injection up to 2 weeks before or 2 weeks after the scheduled timepoint.1

ABILIFY ASIMTUFII can be initiated from any oral antipsychotic. However, if the patient has never taken aripiprazole, the first step is to establish tolerability to oral aripiprazole, which may take up to 2 weeks due to its half-life. Then, the initial dose of ABILIFY ASIMTUFII can be administered. Additionally, the patient should continue their current oral antipsychotic for 14 consecutive days.1

For patients transitioning from ABILIFY MAINTENA, the switch can be made directly at the next scheduled dose without requiring re-establishment of tolerability, facilitating seamless continuity of care.1

A benefit of ABILIFY ASIMTUFII is its dosing flexibility—although maintaining a scheduled dosing regimen is recommended, if a patient misses an injection, they have up to 6 weeks from their scheduled dose in which they can receive the next injection without having to restart oral overlap.1

Please see the Full Prescribing Information for details about ABILIFY ASIMTUFII dosage adjustments and CYP450 considerations in dosing.

Concluding Thoughts

ABILIFY ASIMTUFII represents another treatment option in the management of bipolar I disorder. Its once-every-2-months dosing not only simplifies the treatment regimen, but also ensures consistent drug delivery,1 which is ideal for maintaining stability in bipolar disorder. As clinicians, we aim to offer treatments that control symptoms effectively and align with our patients’ lifestyles.

ABILIFY ASIMTUFII offers a potential option to many patients struggling with the challenges of bipolar I disorder. It is imperative that we remain committed to patient-centered care, ensuring that each person receives the most appropriate and effective treatment for them.

 

IMPORTANT SAFETY INFORMATION and INDICATIONS for ABILIFY ASIMTUFII® (aripiprazole) and ABILIFY MAINTENA® (aripiprazole)

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death (1.6 to 1.7 times) compared to placebo-treated patients. ABILIFY ASIMTUFII and ABILIFY MAINTENA are not approved for the treatment of patients with dementia-related psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including aripiprazole. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of aripiprazole, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. Prescribing should be consistent with the need to minimize TD. If antipsychotic treatment is withdrawn, TD may remit, partially or completely.

Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes mellitus should be regularly monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes), should undergo baseline and periodic fasting blood glucose testing. 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 should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
  • Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking aripiprazole. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping aripiprazole if such urges develop.

Orthostatic Hypotension or Syncope: ABILIFY ASIMTUFII and ABILIFY MAINTENA may cause orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue ABILIFY ASIMTUFII or ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Seizures: ABILIFY ASIMTUFII and ABILIFY MAINTENA should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: ABILIFY ASIMTUFII and ABILIFY MAINTENA 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 or ABILIFY MAINTENA does not affect them adversely.

Body Temperature Regulation: Use ABILIFY ASIMTUFII or ABILIFY MAINTENA with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with aripiprazole. Use caution in patients at risk for aspiration.

Alcohol: Advise patients to avoid alcohol while taking ABILIFY ASIMTUFII or ABILIFY MAINTENA.

Concomitant Medications: Dosage reductions are recommended in patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. Avoid concomitant use of CYP3A4 inducers with ABILIFY ASIMTUFII and ABILIFY MAINTENA for greater than 14 days. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

Most Commonly Observed Adverse Reactions: The most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence of ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation.

Injection Site Reactions:

  • ABILIFY MAINTENA: In a short-term, clinical trial with ABILIFY MAINTENA in patients with schizophrenia treated with gluteally administered ABILIFY MAINTENA, the percent of patients reporting any injection site-related adverse reaction was 5.4% and 0.6% for placebo. In an open-label study of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site pain was observed at approximately equal rates.
  • ABILIFY ASIMTUFII: In an open-label study in patients with schizophrenia or bipolar I disorder, the percent of patients reporting any injection site-related adverse reactions was 19% for ABILIFY ASIMTUFII and 9.0% for ABILIFY MAINTENA. In both treatment groups, the majority of the injection site pain events coincided with the first injection and were reported with decreasing frequency upon subsequent injections. Patient-reported rating of pain was similar in both treatment groups at the last injection.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ABILIFY ASIMTUFII and ABILIFY MAINTENA, during pregnancy.

Lactation: Aripiprazole is present in human breast milk. Monitor the breastfed infant for dehydration and lack of appropriate weight gain. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ABILIFY ASIMTUFII or ABILIFY MAINTENA and any potential adverse effects on the breastfed infant from ABILIFY ASIMTUFII or ABILIFY MAINTENA or from the underlying maternal condition.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1‑800‑438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

INDICATIONS

ABILIFY ASIMTUFII® (aripiprazole) is an atypical antipsychotic indicated for treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults.

ABILIFY MAINTENA® (aripiprazole) is an atypical antipsychotic indicated for treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults.

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING, for ABILIFY ASIMTUFII and ABILIFY MAINTENA.

References: 1. ABILIFY ASIMTUFII® (aripiprazole) Prescribing Information. 2. Harlin M, et al. A randomized, open-label, multiple-dose, parallel-arm, pivotal study to evaluate the safety, tolerability, and pharmacokinetics of aripiprazole 2-month long-acting injectable in adults with schizophrenia or bipolar I disorder. CNS Drugs. 2023;37:337-350. 3. Data on file. ABIASI-023. 4. Calabrese JR, Sanchez R, Jin N, et al. Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week randomized withdrawal study. J Clin Psychiatry. 2017;78(3):324-331. 5. Data on file. ABIMAI-178. 6. Data on file. ABIMAI-124. 7. Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(11):1254-1260.