Aripiprazole/Adherence to Treatment Plans Materials

ARIPIPRAZOLE AND ADHERENCE TO ANTIPSYCHOTIC TREATMENT PLANS

ANNA SHURTLEFF SMITH, MPH, BSN-RN

Anna Shurtleff Smith is a graduate of the University of North Texas Health Science Center, School of Public Health with a community health focus, and Texas Tech University School of Nursing. She has clinical experience in both inpatient and outpatient settings. Anna is passionate about patient education, health literacy, and health communications. When not writing, she can be found enjoying the outdoors and enjoying family time.

AMANDA MAYER, PharmD

Amanda Mayer is a graduate of the University of Montana, Skaggs School of Pharmacy. She has clinical experience working in inpatient mental health, which is her passion. She has also done fill-in work at retail pharmacies throughout her career. Amanda appreciates the wide variety of professional opportunities available to pharmacists. Amanda loves spending time with her family and spends most of her free time exploring new restaurants, hiking in the summer, and snowboarding and cross-country skiing in the winter.

Topic Overview

Aripiprazole is an atypical, second-generation antipsychotic indicated for the treatment of schizophrenia, bipolar disorder, and treatment-resistant major depressive disorder. It is also used to manage irritability associated with autism spectrum disorder and treat Tourette syndrome. Antipsychotic medications can be an important component of treatment plans for patients with mental health disorders. Antipsychotic medications have historically been linked to poor adherence, sometimes due to adverse effects or poor insight. Studies have shown that aripiprazole is associated with a lower risk of several adverse effects compared to other antipsychotic medications, which may possibly lead to better patient adherence to treatment plans.

Accreditation Statement:

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-075-H01-P

Pharmacy Technician  0669-0000-23-076-H01-T

Credits: 2 hours of continuing education credit

Type of Activity: Knowledge

Media: Internet Fee Information: $6.99

Estimated time to complete activity: 2 hours, including Course Test and course evaluation

Release Date: May 26, 2023 Expiration Date: May 26, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From May 26, 2023, through May 26, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the basic indications of aripiprazole treatment

List the different aripiprazole dosage forms and dosing frequencies

Discuss essential psychiatric assessment specific to aripiprazole

Identify the potential side effects of antipsychotics, including aripiprazole

Outline strategies to mitigate common side effects to reduce non- adherence

Disclosures

The following individuals were involved in the development of this activity: Anna S. Smith, MPH, BSN-RN, Amanda Mayer, PharmD, Yasmine S. Ali, MD, Jeff Goldberg, PharmD, BCPP, and Pamela M. Sardo, PharmD, B.S. Pamela Sardo, PharmD, BS, was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

The percentage of patients who fail to adhere to treatment plans involving antipsychotics is extremely high. Non-adherence is primarily caused by patients stopping their antipsychotic medications because of their associated side effects. Non-adherence to treatment plans can trigger many problems for patients, including illness relapse and re-hospitalization. Many healthcare professionals have a suboptimal working knowledge of antipsychotic medication side effects, which may compromise patient care. Healthcare professionals may assist patients in mitigating common side effects to reduce non-adherence. One option is the selection of aripiprazole as the antipsychotic treatment choice. Aripiprazole can have a more favorable profile regarding side effects generally seen with antipsychotics, which could lead to better patient adherence to treatment plans.

Antipsychotics and Non-adherence to Treatment Plans

Antipsychotic medications can be an important component of treatment plans for patients with mental health disorders.1 In many instances, antipsychotics are considered first-line treatment options for patients with psychosis.1 Antipsychotic medications can potentially cause adverse effects, and their safety and tolerability are unclear when they are used over the long term.1 These adverse events can be so serious that they outweigh the benefits to the patient. For example, studies show that patients taking certain antipsychotics may be three times more likely to die suddenly from cardiac arrest or stroke than the general population.2 Patients taking antipsychotics may experience higher rates of cardiac arrhythmias, weight gain, neuroleptic malignancy, and serotonin syndrome, and in some cases, these events may be fatal.1

Antipsychotic medications may also cause a neuropsychiatric syndrome, e.g., akathisia.1 Akathisia is a movement disorder that may be symptomatic of an underlying health condition or antipsychotic medications.1,3 Misdiagnoses of akathisia are common because restlessness and pacing can be found in other developmental disorders (e.g., ADHD) and

untreated anxiety or agitation. 1 As a result of misdiagnosis, many clinicians may increase the medication, which worsens the symptoms and can lead to suicide, increased aggression, and violence. Overprescribing or inappropriately prescribing antipsychotic medication may lead to polypharmacy.1

All these adverse events result in high proportions of patients not adhering to their treatment plans, which include antipsychotics. Non- adherence rates have been reported to be as high as 90%.1 Against this backdrop, aripiprazole may offer an alternative that improves patient treatment plan adherence.

History of Aripiprazole

Aripiprazole is an atypical, second-generation antipsychotic indicated for treating schizophrenia, bipolar disorder, and treatment-resistant major depressive disorder.4-6 It sometimes acts as an agonist at presynaptic dopamine D2 autoreceptors, which prevents extrapyramidal side effects.6 This action has led clinicians to refer to aripiprazole as a third-generation antipsychotic.5-8

It is typically well-tolerated, and its use has been extended to other psychiatric conditions in children and adults.6,7 Studies suggest aripiprazole is superior to placebo and many first- and second-generation antipsychotics for various indications.9,10

Aripiprazole, under the brand name Abilify, received FDA approval in 2002.4,5,11 At that time, aripiprazole had a unique chemical structure that differentiated it from other available antipsychotics.4 It was initially approved as an oral tablet for treating schizophrenia.5 The patent expired in 2015, and oral aripiprazole has since been available as a generic medication.5 Abilify Maintena®, a long-acting, extended-release injectable, was approved for the treatment of schizophrenia in 2013.4,12

Extended-release aripiprazole lauroxil injectable formulations were FDA-approved in 2015.13 Aristada® (aripiprazole lauroxil) was approved for treating schizophrenia.6,13 Aristada Initio® was FDA-approved as an extended-release injectable used when aripiprazole treatment is initiated.14 On April 27, 2023, the FDA approved Abilify Asimtufii (aripiprazole) extended-release injectable suspension.15 The oral, extended-release, and long-acting injectable forms of aripiprazole each provide unique pharmacokinetic profiles. Clinicians must consider these profiles when creating a treatment plan.

Clinical Pharmacology

Mechanism of Action

Like other antipsychotics, the exact mechanism of action of aripiprazole is unclear. Aripiprazole is classified as a second-generation, atypical antipsychotic.7,8 As mentioned above, it is also known as a “prototypical third-generation antipsychotic” due to its unique characteristics.5 Aripiprazole exhibits high affinity for D2, D3, 5-HT1A, and 5- HT2A receptors and moderate affinity for D4, 5-HT2C, 5-HT7, alpha1 adrenergic, and H1 receptors.7 It is classified as a dopamine partial agonist due to its agonist activity at certain receptor targets, most notably D2 autoreceptors.7 This distinguishes it from the first-generation dopamine antagonists.5 Therapeutic activity is presumed to result from aripiprazole’s partial agonist activity at D2 and 5-HT1A receptors and its antagonism at 5- HT2A receptors.9 Aripiprazole lauroxil is a prodrug of aripiprazole.6,10

Pharmacokinetics

Oral Aripiprazole

The activity of oral aripiprazole is via the parent drug (aripiprazole) and, to a lesser extent, its major metabolite, dehydroaripiprazole.9 The tablet and oral solution formulations are well-absorbed.7,9 Peak concentrations occur between 3-5 hours post-ingestion, and it has an

absolute bioavailability of 87%.7,9 Aripiprazole is highly protein-bound (>99%) and has a volume of distribution of 4.9 L/kg.7,9 Metabolism occurs via three mechanisms: hepatic dehydrogenation and hydroxylation via CYP2D6 and CYP3A4, as well as N-dealkylation via CYP3A4.9 The half-lives of aripiprazole and dehydroaripiprazole are 75 hours and 94 hours, respectively.7,9 Excretion occurs primarily via feces (55%) and, to a smaller extent, through the urine (25%).7,9

Long-acting Injectable

Aripiprazole dual chamber or vial (Abilify Maintena®) is a long-acting injectable. Similar to the oral formulation, the activity of the LAI is mainly due to the parent drug (aripiprazole) and, to a smaller extent, dehydroaripiprazole.12 Due to aripiprazole’s low solubility, absorption of this formulation is slow and prolonged.7 The time to peak plasma concentration following multiple doses is 4 days after deltoid administration and 5-7 days following gluteal administration.7,12 The half-life elimination is dose- dependent and approximately 30 days for the 300 mg dose and 47 days for the 400 mg dose.12

Long-acting injectable antipsychotics have a unique pharmacokinetic profile, making them particularly beneficial in treating psychiatric conditions such as schizophrenia.12 Long-acting injectable medications help patients adhere to their antipsychotic regimen as they provide a more stable and predictable plasma level of an active drug when compared to taking oral antipsychotics. This helps lower the chances of side effects that can happen with inconsistent dosing and increase therapeutic outcomes.12

It is important for clinicians to understand the pharmacokinetic differences between the oral and LAI forms of aripiprazole, as misunderstanding these differences may lead to poorer patient outcomes.12 For example, the LAI or extended-release forms of aripiprazole exhibit “flip- flop” kinetics that impact the time it takes for the drug to reach a steady state because of its slower rate of absorption.13-17 ‘Flip-flop’ kinetics is an

unusual situation where the rate of absorption, or the rate to enter the blood, is slower than its elimination.18

Correll, et al. (2021) discuss the importance of individualizing a treatment plan, utilizing an oral antipsychotic before switching to a long- acting form, knowing when it is best to make dose adjustments, understanding the different dosing schedules for the distinctive forms of aripiprazole, e.g., aripiprazole lauroxil versus aripiprazole, etc., and understanding that if adverse effects do present with aripiprazole, the use of a long-acting drug may prolong their duration.16

Extended-release Injectable: Aripiprazole lauroxil extended-release suspension Aripiprazole Lauroxil (Aristada® and Aristada Initio®)

Aripiprazole lauroxil is a prodrug of aripiprazole, with activity mainly due to aripiprazole and, to a lesser extent, dehydroaripiprazole.13,14 Aripiprazole lauroxil is available in two intramuscular injectable formulations

- Aristada Initio® (aripiprazole lauroxil prodrug injection (675 mg/2.4 mL), and Aristada® (441 mg, 662 mg, 882 mg or 1064 mg).14 Aristada Initio® is indicated for the initiation (not repeated dosing) of Aristada treatment for schizophrenia in adults and is given with oral aripiprazole.14 The single dose can be used to re-initiate Aristada treatment if a dose is missed. However, using Aristada Initio® for repeated dosing of Aristada is not recommended. The Aristada Initio® formulation appears in the systemic circulation on the day of injection, with peak plasma exposure being about 27 days.14 The Aristada® formulation appears in the systemic circulation between 5 and 6 days post-injection and is released for 36 more days.13 When both formulations are administered together, i.e., a single intramuscular injection of Aristada Initio, combined with 30 mg oral aripiprazole, at the time of the first Aristada dose, aripiprazole concentrations reach relevant levels within 4 days, instead of 5 to 6 days. Similarly, aripiprazole concentrations reach relevant levels within 4 days if oral aripiprazole is taken for 21 days at the time of the first Aristada dose.14

The volume of distribution of aripiprazole lauroxil is 268 L.13,14 It undergoes hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes water-mediated hydrolysis to aripiprazole.13 Hepatic metabolism involves CYP3A4 and CYP2D6.13 The half-life elimination is approximately 53 to 57 days for Aristada® and 15 to 18 days for Aristada Initio®.13,14

Abilify Asimtufii, a long-acting injectable formulation that provides a dosing option of once every two months, was approved by the FDA on April 27, 2023.15 This medication is approved for the treatment of schizophrenia in adults and as maintenance monotherapy treatment of bipolar I disorder in adults. This medication results in a sustained plasma concentration over 2 months following a gluteal injection. Although the once-every-two-month dosing provides convenience for patients, injection site reactions (reported as pain in all instances) were reported as higher with Abilify Asimtufii (19%) compared to Abilify Maintena (9%). Most of the injection site pain was associated with the first injection of both formulations, and subsequent injections had fewer injection site pain reports.15

Labeled and Off-Label Uses

Aripiprazole was initially approved to treat schizophrenia but has since been approved for numerous other conditions.

Labeled Uses

The following Table 1 contains labeled uses of aripiprazole and aripiprazole lauroxil.7,10,11-15 Agitation associated with schizophrenia or bipolar mania has also been listed as a labeled use; however, this indication is only listed for the intramuscular injection that has been taken off the market and will not be discussed further.

Table 1: Labeled Uses of Aripiprazole and Aripiprazole Lauroxil

Off-Label Uses

Aripiprazole has also been used off-label for delusional disorder, delusion infestation (delusional parasitosis), Huntington disease-associated chorea, and treatment-resistant obsessive-compulsive disorder.7 All of these uses have level C evidence, meaning evidence from observational studies (such as retrospective case series/reports providing a significant impact on patient care), unsystematic clinical experience, or from potentially flawed randomized, controlled trials (such as when limited options exist for a condition). This evidence means that any estimate of the drug’s effect on these medical conditions is uncertain. Use of treatment-resistant obsessive-

compulsive disorder has Level C evidence along with Level G. Level G means use has been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline.7 Some evidence suggests aripiprazole may be useful as an add-on in the treatment of antipsychotic- induced hyperprolactinemia.19

Dosage and Administration

Labeled Uses

Table 2 contains the dosing regimens that are recommended for labeled uses of aripiprazole and aripiprazole lauroxil.7,10-15 Dosing for off- label uses will not be stated.

Table 2: Dosing Regimens of Aripiprazole and Aripiprazole Lauroxil

Table 3: Converting oral aripiprazole to IM aripiprazole lauroxil (Aristada)13

Dosage Forms and Strengths

The following dosage forms of aripiprazole and aripiprazole lauroxil are available in the strengths noted.7,9,11-15

Table 4: Dosage Forms and Strengths

Administration

Pharmacists should be familiar with administering the various dosage forms of aripiprazole appropriately.7,9-11,15

Oral formulation

The oral form of aripiprazole can be administered with or without food. The orally disintegrating tablet (ODT) should be placed on the tongue as soon as the tablet is removed from the packaging. Patients can take ODT aripiprazole with or without liquids. When counseling patients on the ODT formulation, patients should be told not to push a tablet through the foil as this could damage the tablet. If patients miss a dose, they can take the missed dose as soon as they remember. However, if the patient’s next dose is almost due skip the missed dose and take the next dose on the regular schedule. Under no circumstances take two doses of the aripiprazole at the same time.

Tablet with Sensor

Patients should be advised to swallow tablets whole and may take them with or without food. The tablets are embedded with an ingestible event marker (IEM), and they come with a wearable sensor patch. This sensor can detect a signal from the IEM after the tablet is ingested. It then transmits data to a smartphone between 30 minutes to 2 hours after tablet ingestion. Patients will need to download the MyCite app to transmit data.20

The patch should be applied to the left side of the body just above the lower edge of the rib cage. This should only be done when instructed by the app. Patches should not be placed where the skin is scraped, cracked, inflamed, or irritated, or in a location that overlaps the area of the most recently removed patch. Patches need to be changed weekly. The app prompts patients to change the patch and can direct patients to apply and remove the patch correctly.

Oral Solution

The oral solution may be administered with or without meals. Calibrated oral measuring device should be used to draw up the dose. Once a bottle is opened, it can be stored for up to 6 months, but not beyond the manufacturer-labeled expiration date.11

Aripiprazole for extended-release injectable suspension, dual-chamber syringe, or vial (Abilify Maintena®)

Clinicians should ensure patients tolerate oral aripiprazole prior to initiating the LAI form.12 This aripiprazole formulation is given intramuscularly (IM) and should not be administered subcutaneously or intravenously. A 1-inch needle with deltoid administration can be used for nonobese patients. For obese patients, a 1.5-inch (38 mm) needle with deltoid administration or a 2-inch (51 mm) needle with gluteal administration should be used. Patients should be instructed not to massage the area after administration. The injection site should be rotated between the two gluteal or deltoid muscles. Pre-filled syringes and powders come in boxes with all components needed and detailed instructions. A healthcare professional must administer injections.12

Aripiprazole for extended-release injectable suspension every 2 month dosing (Abilify Asimtufii)

Oral tolerance should be established before use, and it is to be prepared and administered by a healthcare professional.15 This formulation should only be administered by intramuscular injection into the gluteal muscle. After removing the pre-filled syringe from the package, the syringe should be tapped on the administrator's hand at least 10 times and then shaken vigorously for at least 10 seconds until the medication is uniform. Two needles are provided in the packaging (a 22-gauge, 1.5-inch for non- obese patients and a 21-gauge, 2-inch needle for obese patients.) Expel the air from the needle before administering the dose. The dose may be slowly injected into the gluteal muscle. Do NOT massage the injection site after dose is given.15

Aripiprazole lauroxil extended-release

Aripiprazole lauroxil extended-release injectable suspension (Aristada®). Clinicians should ensure patients tolerate oral aripiprazole before initiating aripiprazole lauroxil. Aripiprazole lauroxil is administered intramuscularly.13 The 441 mg dose and the 675 mg nanocrystal dispersion dose (Aristada Initio) should be administered via the deltoid or gluteal muscle. Other strengths should be administered in the gluteal muscle. Administration of Aristada Initio and Aristada concurrently in the same muscle should be avoided.13,14 Before administration, the syringe should be tapped at least 10 times to dislodge any settled material and then shaken vigorously for ≥30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, it needs to be shaken again for 30 seconds. A healthcare professional must administer injections.

Contraindications

Aripiprazole treatment is contraindicated in cases where patients have any sensitivities to aripiprazole or formulation components.7

Warnings

Important warnings and precautions should be noted before the use of aripiprazole.7,9-11,15 A boxed warning states that elderly patients with dementia-related psychosis who use antipsychotics are at an increased risk of death. The safety of aripiprazole for use in this patient population has not been established and it is not an FDA-approved treatment.9 Additionally, patients treated with aripiprazole for dementia-related psychosis may be at an increased risk of cerebrovascular events, including stroke and transient ischemic attack, which may lead to fatalities.9

Patients who discontinue aripiprazole therapy are at risk of withdrawal and rebound symptoms.7 These patients may experience various symptoms, including myalgia, psychosis, restlessness, and tremors.7

Aripiprazole may cause orthostatic hypotension and should be used cautiously in patients with cardiovascular disease. Heart rate and blood pressure should be monitored, and patients should be warned of the risks of dehydration or syncope.7 Differences in autonomic nervous system (ANS) dysfunction have been observed between long-acting, injectable aripiprazole and the oral form in patients with schizophrenia, with the once-monthly injection having fewer ANS adverse effects.13

Aripiprazole should be used cautiously in patients with Parkinson’s disease, as they may experience worsening motor disturbances. Aripiprazole should be used cautiously in those with a history of seizures or in patients with conditions that may lower the seizure threshold. Patients who develop neuroleptic malignant syndrome can be managed by immediately discontinuing aripiprazole and close monitoring, sometimes in an inpatient or intensive care setting.7

Neuroleptic malignant syndrome is a rare situation but deadly. It is unique to patients taking antipsychotic medications. The symptoms progress over 1-3 days. Mild symptoms are mild rigidity, mild confusion or catatonia, fever of less than 100.4, and heart rate of less than 100 beats per minute.

Severe progression results in severe rigidity, severe catatonia, or confusion with a fever above 104 and a heart rate above 120. Report any of these emerging symptoms to a physician immediately.21

Aripiprazole has numerous additional warnings for clinicians to consider, including altered cardiac function, blood dyscrasias, CNS depression, esophageal dysmotility, falls, impulse control disorders, and temperature regulation.7,10 The full prescribing information should always be consulted for comprehensive safety and efficacy information.

Drug Interactions

Aripiprazole is a major substrate of both CYP2D6 and CYP3A4.9,11 Use of aripiprazole concomitantly with strong CYP2D6 or CYP3A4 inhibitors may increase aripiprazole concentrations and oral aripiprazole dose reductions of half the usual dose should be considered.9 Reductions in the LAI can be considered when the use of inhibitors occurs concomitantly for more than 14 days.12-15 Use of aripiprazole with strong CYP3A4 inducers can lead to decreased levels of aripiprazole and may require double the usual oral dose over 1 to 2 weeks.9,12-15 Use of Abilify Maintena® should be avoided with strong CYP3A4 inducers (such as carbamazepine).12

Aripiprazole can increase the effects of some antihypertensive drugs due to its alpha-adrenergic antagonism when used concomitantly.9,11 Blood pressure should be monitored closely in these cases.9,11 Dose reductions may also be warranted. Additionally, aripiprazole should be used cautiously in patients taking lorazepam due to the potential for increased sedation and orthostatic hypotension.9,11 Blood pressure and sedation should be monitored closely and dose adjustments should be considered.

Administration of aripiprazole with the following medications is contraindicated: brexpiprazole, cisapride, dextromethorphan with quinidine, dronedarone, fluconazole, ketoconazole, levoketoconazole, metoclopramide, pimozide, posaconazole, quinidine, and thioridazine.

Adverse Reactions

While aripiprazole has a favorable side-effect profile compared to first- generation antipsychotics and other atypical antipsychotics, important adverse reactions must be considered. The most common side effects noted in adult patients during clinical trials (those occurring at rates of 10% or higher) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.7,9,22 For pediatric patients, the most common side effects included somnolence, headache, vomiting, extrapyramidal symptoms, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight gain.7,9

In general, side effects of aripiprazole can occur on a spectrum running from sedating effects (drowsiness) to activating effects (restlessness and akathisia).7,9,11 These effects are dose-related, and risks are higher in younger children. Aripiprazole may also cause dyslipidemia, hyperglycemia, and hematologic abnormalities, including leukopenia, neutropenia, and agranulocytosis.7 The extent of metabolic side effects is generally lower than other antipsychotic medications.23 Additionally, its use can lead to extrapyramidal symptoms (EPS), including drug-induced Parkinsonism, akathisia, acute dystonia, and tardive dyskinesia.7 Previously, second- generation antipsychotics were thought to have decreased risk of movement symptoms; however, this difference was not seen in recent studies that compared second-generation antipsychotics to low-potency first-generation antipsychotics.24

Post-marketing reports have found an association between the use of aripiprazole and compulsive behaviors, including gambling, binge eating, shopping, or engaging in sex.25 These effects are rare, could affect any patient regardless of history of compulsive behaviors, and may stop once aripiprazole therapy is discontinued or the dose is reduced.25 This information is included in the package inserts for aripiprazole under patient counseling information.11

Adverse Reaction Case Report

Oculogyric crisis (OGC) is an acute dystonic reaction that is a relatively uncommon EPS side effect of antipsychotics and is reported as a rare potential adverse effect of aripiprazole.26 Oculogyric crisis presents with sustained, bilateral, and upward deviation of the eyes. Episodes of OGC can last seconds to hours with associated symptoms including restlessness, agitation, malaise, fixed stare, pain, increased blinking, and neck dystonia. Risk factors for OGC include male gender, young age, use of atypical antipsychotics, and initiation or up-titration of an antipsychotic.26

A clinical case report from January 2023 describes a 19-year-old male who had been psychiatrically hospitalized with symptoms of his first episode of psychosis.26 He was initiated on 5 mg of aripiprazole. Three days after initiating aripiprazole, the patient was anxious and pacing around his room. Upon physical exam, the patient was found to have intermittent eye-rolling, sustained upward conjugate gaze, and limited downward gaze. Other symptoms included frontal headache, bilateral eye pain, and anxiety. Symptoms improved within one hour of administration of 50 mg of oral diphenhydramine.26 Oral aripiprazole was initially held upon recognition of symptoms, and the patient declined to reinitiate antipsychotic medications.26

Baseline Assessments and Labs Before Prescribing Aripiprazole

Many adverse effects associated with aripiprazole can be prevented by collecting correct baseline assessments and labs. Healthcare practitioners can compare those values for potential contraindications for taking the drug.

In adults, the following vitals should be monitored: Electrocardiogram (EKG), blood pressure, weight, height, BMI, and waist circumference.27,28 Laboratory tests should include CMP, CBC, Liver Transaminase Levels, BUN, creatinine, and A1C.27,28 Screening may include an Abnormal Involuntary Movement Scale (AIMS) for extrapyramidal symptoms,29 and an ocular examination.30 In appropriate cases, a patient may be screened for suicide

ideation. Suicide screening tools may be obtained from the National Institute of Mental Health.31

Pediatric patients should receive the same vitals and laboratory testing as adults, as discussed above.32 In appropriate cases, a pediatric patient may be screened for suicide ideation. Suicide screening tools for youths may be obtained from the National Institute of Mental Health.33

Following the collection of baseline assessments and labs, the healthcare team members should consult with the patient’s primary physician before administering the aripiprazole. The physician can confirm whether the patient is sensitive to aripiprazole and has lab results outside the normal range, especially leukopenia or neutropenia.27 “Mild leukopenia [white blood cell (WBC) count of 3500–3000/mm3 or absolute neutrophil count (ANC) of 2000–1500/mm3 of blood], moderate leukopenia (WBC count of 3000–2000/mm3, ANC 1500–1000/mm3), or severe leukopenia (WBC count < 2000/mm3, ANC < 1000/mm3) are descriptions used for defining the severity of leukopenia.”34 Neutropenia is a blood neutrophil count to < 1500/mcL (< 1.5 × 109/L) in White people and < 1200/mcL (< 1.2 × 109/L) in Black people.35 The primary physician will also want to know if the patient is breastfeeding or has a seizure disorder. These special populations are discussed at greater length below.

Management of Patients taking Aripiprazole

The team should monitor common side effects from aripiprazole. Antipsychotic-related constipation can occur and lead to life-threatening complications. Prescribing polyethylene glycol as a first-line laxative has been found to prevent these complications.36 Assessments, labs, examinations, and screening, discussed above, should be ongoing.27-30,32

Aripiprazole overdose is rare. There is no known antidote for aripiprazole overdose. Charcoal administration has been found to help prevent the absorption of orally ingested drugs. Obtain an EKG on admission

to identify any cardiac arrhythmias.37 Focus needs to be on supportive therapy.37

Specific Populations

Pregnancy

Given its safety and efficacy profile, aripiprazole is frequently used in women of childbearing age.38 Thus, clinicians need to understand the risks and benefits of use during pregnancy. Animal studies suggest risks of adverse effects on the fetus, but benefits may outweigh risks in certain patients.10 There exists no randomized, placebo-controlled data pertaining to the use of aripiprazole in pregnancy; however, animal data and exposure/outcome data for human fetuses is available. Studies suggest children exposed to aripiprazole during pregnancy are not at a higher risk than those exposed to other SGAs.38-41 However, the use of antipsychotics in the third trimester has been associated with a risk of extrapyramidal and withdrawal symptoms in newborns post-delivery.7 The American College of Obstetricians and Gynecologists (ACOG) recommends that treatment with psychiatric medications during pregnancy be individualized and overseen by a multidisciplinary care team, which includes an obstetrician, mental health practitioner, primary care practitioner, and pediatrician.42

Lactation

Aripiprazole and dehydroaripiprazole were found in breast milk.7 Generally, breastfeeding while taking any medication is typically deemed acceptable when the relative infant dose (RID) of the medication is less than ten percent.43 For aripiprazole, the RID can vary between 0.7% to 8.3%. Breastfed infants should be monitored for excessive drowsiness, lethargy, and developmental delays. In deciding whether to breastfeed while taking aripiprazole, the benefits of breastfeeding should be weighed against potential risks to the infant.

Pediatric

Aripiprazole is approved for use in pediatric patients for the management of the following disorders: schizophrenia in adolescents ages

13 to 17, acute treatment of manic or mixed episodes associated with bipolar 1 disorder in pediatric patients ages 10 to 17, irritability associated with autism spectrum disorder in pediatric patients ages 6 to 17, and treatment of Tourette Syndrome in pediatric patients ages 6 to 18 years.11 The number of US pediatric patients receiving aripiprazole between 2014 and 2016 was found to be half a million per the FDA’s pediatric focus safety review.44 Data from meta-analyses suggest aripiprazole is superior to placebo in the treatment of behavioral impairments associated with autism, but no difference was demonstrated between aripiprazole and risperidone for this treatment.44 The results of four other meta-analyses found aripiprazole to be superior to placebo but not to other antipsychotics in the management of tics.44

Weight gain, neurological effects, extrapyramidal effects, and drowsiness are common side effects.45 Mankoski, et al. (2018) found weight gain is more common in younger pediatric patients and those without previous exposure to antipsychotic medications.45 Adverse effects such as EPS, weight gain, metabolic effects, and drowsiness may be considered more important to monitor in children and adolescents than adults.44

Aripiprazole does come with a boxed warning of increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. These populations should be monitored for worsening and emergence of suicidal thoughts or behaviors.11

Geriatric

For geriatric patients, careful monitoring and initiation doses of aripiprazole in the low range, then titrating doses slowly, is recommended.7 In older patients, aripiprazole has the potential to cause or exacerbate hyponatremia or the syndrome of inappropriate antidiuretic hormone

(SIADH).46 Sodium levels should be monitored when the drug is started and during any dose adjustments.46 If use is required in the geriatric population, reducing other CNS depressants and implementing fall risk strategies should be considered. Treating dementia-related psychosis in geriatric patients with antipsychotics is not approved, and use should be avoided if possible due to increased morbidity and mortality.

Renal Impairment

No dose adjustment of aripiprazole is recommended for patients with any degree of renal impairment.7,9 Because aripiprazole has a large volume of distribution and is protein-bound, it is unlikely to be removed via hemodialysis, and no dose adjustments are recommended for these patients.7,9 Additionally, dose adjustment is not recommended for patients undergoing peritoneal dialysis, continuous renal replacement therapy, or sustained, low-efficiency diafiltration.7,9

Hepatic Impairment

No dose adjustments are recommended for patients with hepatic impairment.7,9

Clinical Studies

Bipolar I Disorder

The initial clinical trials of aripiprazole as an acute treatment for the onset of manic episodes in patients with bipolar I disorder established its effectiveness for this purpose. Subsequent research, published literature, authoritative reviews, and meta-analyses have confirmed this and have reported significant efficacy in reducing the severity of manic episodes in patients who have bipolar disorder.47-50

Long-acting injectable aripiprazole (Abilify Maintena) was approved in July 2017 by the FDA as a maintenance monotherapy treatment for adults who have bipolar I disorder.50 Long-acting injectable aripiprazole can address the high rates of non-adherence to antipsychotic medication treatment plans among bipolar patients.51 Adherence is defined as the extent to which a patient’s behaviors follow a health provider’s medical advice.51 The use of LAI, or extended-release aripiprazole may promote adherence, as discussed below under the subsection on schizophrenia.

A double-blind, placebo-controlled, 52-week randomized withdrawal study was conducted in which patients with Bipolar 1 who were currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and LAI aripiprazole 400 mg. They were then randomized to either long-acting aripiprazole 400 mg or placebo.52 This study found that a once-a-month 400 mg IM dose of aripiprazole significantly decreased the time to recurrence of mood episodes and the rate of mood episodes.52

Major Depressive Disorder

Atypical antipsychotics are recommended as adjunctive agents for treating major depressive disorder. Aripiprazole has been approved by the FDA as an adjunctive agent for the treatment of major depressive disorder and has a comparatively favorable benefit and risk profile.11 Initial clinical trials and later research established that aripiprazole is effective and that the clinical benefits are long-lasting.53-56

A network meta-analysis of 65 randomized trials investigated the effectiveness of medications for augmentation of depression. Results included direct comparisons between medications and medications compared to placebo.55 Aripiprazole demonstrated low rates of discontinuation and great benefit as an augmentation agent.55 In another study, aripiprazole demonstrated better remission rates at week 6 over bupropion but overall similar efficacy and tolerability as augmentation therapy for patients treated for major depressive disorder who did not respond to SSRI treatment.56

Schizophrenia

Aripiprazole has been proven to be an effective treatment for schizophrenia.57-63 Comparative studies of atypical antipsychotics have low to very low-quality evidence and are difficult to use clinically. However, there are definite and important differences between antipsychotics in their adverse effect profiles and their suitability for a specific patient.57-63 A 2018 review of aripiprazole use in the treatment of schizophrenia suggests it has similar efficacy when compared to both atypical and typical antipsychotic drugs, with the exception of olanzapine and amisulpride.58 Notably, in this review, aripiprazole was found to cause lower weight gain and fewer changes in cholesterol levels compared to risperidone, olanzapine, and clozapine and less extrapyramidal side effects than typical antipsychotics and risperidone.58

Long-acting injectable antipsychotics, including aripiprazole, have been effective at reducing the symptoms of schizophrenia.61,62 Long-acting injectable antipsychotics have inherent advantages over oral formulations, such as the need for less frequent dosing that would intuitively seem to help increase patient adherence.61,62 Aripirazole LAI formulations are administered monthly or every 2 months; whereas, the oral formulations are taken daily.61 Long-acting injectable aripiprazole therapy results in improved symptoms for patients with a favorable safety profile.62,63

A study published in December 2022 discusses the use of aripiprazole and its therapeutic and metabolic effects associated with gene polymorphisms.62 Currently, a reduced dose is recommended for individuals who metabolize CYP2D6 poorly. It has been postulated that other polymorphisms can influence the therapeutic effect of aripiprazole, including CYP3A4, CYP3A5, ABCB1, DRD2, and 5-HTRs genes. Genetic variants may also help explain the increased levels of prolactin, C-peptide, insulin, and cholesterol seen in some patients.62 Authors of this study suggest that a specific genetic profile can help determine the predicted effectiveness and tolerability of aripiprazole; however, they do admit that further extensive

pharmacogenomic studies are needed to assess the true relevance of gene polymorphisms in regard to aripiprazole.62

Autism Spectrum Disorder

Aripiprazole has FDA approval and has been recommended for treating irritability in children who have autism spectrum disorder.65-67 Multiple clinical trials found that aripiprazole significantly improved the Aberrant Behavior Checklist (ABC) and Clinical Global Impressions – Improvement (CGI-I) scale of children and adolescents.66-68

One 52-week, open-label study of aripiprazole flexible-dosing of 2– 15 mg/day focused on treating irritability associated with autism spectrum disorder in children and adolescents.69 An estimated 38.2% of the study subjects were given concomitant antidepressants (13.4%), psychostimulants (11.5%), and antiepileptics (5.9%).69 At week 52, the authors reported a mean change from baseline in Aberrant Behavior Checklist Irritability subscale scores was −8.0 in de novo subjects and −6.1 in prior placebo subjects; subjects who were previously on aripiprazole maintained symptom improvement that was achieved with treatment in the prior study.69 Most subjects reportedly had a Clinical Global Impressions–Improvement score of 2 (much improved) or 1 (very much improved).69

The evidence suggests aripiprazole may be an effective maintenance treatment for symptoms of irritability in children with autism spectrum disorder.68,69 Clinicians should be informed that aripiprazole use has been associated with significant side effects, including aggression, extrapyramidal symptoms, increased appetite, sedation, and weight gain.68,69

Tourette Syndrome

Aripiprazole was approved by the FDA for the treatment of Tourette syndrome in 2014.70 Case reports found aripiprazole was effective in treating tics in children and adolescents with Tourette syndrome, and a clinical study measuring its effectiveness with the Yale Global Tic Severity Scale (YGTSS)

and the Clinical Global Impression – Tourette Syndrome (CGI-TS) confirmed the data from earlier research.70,71 In this study, a significant reduction was seen in the YGTSS in the treatment with aripiprazole group of total tic score compared to placebo and the CGI-TS showed ‘much improved’ and ‘very much improved’ in the treatment group. A subsequent study suggested aripiprazole could be a treatment option for children and adolescents with tic disorders.72 Adverse events common to this age group in this study were somnolence, headache, sedation, nausea, and vomiting.72

Suicidal Ideation

The FDA requires a U.S. Boxed Warning about antidepressants and suicide. Aripiprazole is not categorized as an antidepressant; however, atypical antipsychotics are often prescribed for patients who have unipolar major depression. Although the FDA data analysis used as the basis for the

U.S. Boxed Warning about antidepressants and suicide did not include information about the atypical antipsychotics, the prescribing information for aripiprazole and other atypical antipsychotics is required to include the U.S. Boxed Warning about suicide.9,11

There is some evidence that atypical antipsychotics may reduce the risk of suicide. To this end, certain atypical antipsychotics have a labeled use for reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder.73 The strength of this effect and whether it truly occurs is unclear, which is also true of aripiprazole. There is encouraging evidence that aripiprazole decreases the risk of suicide, but the evidence is not conclusive.74 Ringbäck, et al. (2014) reported that patients prescribed aripiprazole, along with patients prescribed clozapine or olanzapine, had a reduced risk of suicide compared to patients administered other antipsychotics.73 Weisler, et al. (2011) reported on study subjects prescribed aripiprazole 2 mg, 10 mg, or a placebo for six weeks, and suicidal ideation was noticed more in subjects who had taken the placebo.74 A 2019 study in JAMA Psychiatry found no association between aripiprazole and self-harm or suicide in a study of more than 1600 patients treated with aripiprazole.75

Dementia-Related Psychosis

The prescribing information for many of the atypical antipsychotics has a U.S. Boxed Warning that advises clinicians that the use of these drugs in elderly patients who have dementia increases the risk of death.9,11 This Boxed Warning was added to the prescribing information because an analysis by the FDA of 17 placebo-controlled trials found that the risk of death in the treated patients was 1.7 times that of the patients who received a placebo.76 A systematic review evaluated data from meta-analyses focused on use of antipsychotic agents in patients with dementia.77 Results found while these medications have some efficacy in managing aggression and agitation in this patient population, their adverse effect profile limits use.77 In particular, aripiprazole has demonstrated some benefit in the treatment of aggression and psychosis in patients with Alzheimer's disease.77

Rubino, et al. (2020) stated that “several studies reported a decreased prevalence of antipsychotic medication use by elderly patients with dementia after the 2005 warning.78 However, the warning’s long-term association with health outcomes in elderly patients remains unknown.”78 The authors attempted to compare the use of atypical antipsychotics with other psychiatric medications and opioids by looking at health events, cardiovascular and cerebrovascular events, falls, fractures, and mortality. According to Furey and Wilkins (2016), no FDA-approved treatment options are available for prescribers to reference in the treatment of dementia- related behavioral disorders, such as agitation and psychosis, but there are randomized controlled trials supporting atypical antipsychotic use in cautious amounts to help control symptoms.79 Expert consensus and professional guidelines reference second-generation antipsychotics for certain cases involving elderly patients where another treatment has failed.79 The off-label atypical antipsychotic use for elderly patients, including those diagnosed with dementia, has reportedly increased over the recent years.79

Look-alike/Sound-alike Concerns

The Institute for Safe Medication Practices publishes a List of Confused Drugs Names that contain look-alike, sound-alike (LASA) name pairs of medications.80 Medications included on this list should have special safeguards in place to minimize the risk of harm. The Institute for Safe Medication Practices notes that “ARIPiprazole” could be confused with “proton pump inhibitors,” RABEprazole, or omeprazole.80,81 Pharmacists are encouraged to take steps to prevent medication errors due to these similarities.

Storage and Handling

The following storage requirements are noted for aripiprazole dosage forms.7,10-15

Table 5: Storage Recommendations

Patient Counseling

Patients who are receiving aripiprazole treatment and their caregivers should be counseled on its purpose using patient-friendly language. They should be instructed on how to take the medication appropriately and what to do in the event they miss a dose of medication. Patients need to be informed to take missed doses as soon as they remember. However, if they are close to the next scheduled dose, they should skip the missed dose and take the next dose. Patients need to be advised to never take two doses at once. Potential side effects of the medication, including common and serious adverse reactions, should be discussed. Pharmacists should also counsel patients on ways to mitigate these side effects. Patients should be instructed to contact their prescriber if they experience serious side effects and to go to the closest emergency room if they experience highly concerning effects, including anaphylaxis, trouble controlling body movements, seizures, or blurred vision. Patients should be instructed to store aripiprazole under appropriate conditions and to refill the medication on time in order to not interrupt therapy. Healthcare professionals are encouraged to use the teach- back method to ensure patient understanding. Pharmacy technicians can aid in adherence by making the refill process as smooth as possible and

facilitating phone calls to patients if medication has not been picked up but is ready to be dispensed.

Case Study

Castanheira, et al. (2019) reported the first aripiprazole-induced liver injury (hepatitis).82 The patient was a 28-year-old Black female with no previous psychiatric history who had developed persecutory and reference delusions that began two weeks before admission.82 The patient also had Capgras delusion: she believed an imposter had replaced her brother. The patient appeared anxious and suspicious. She claimed that people had been following her and were following her at the hospital.82 The patient’s family did not have a history of mental illness. The patient had no known medical diseases. She did have a history of cocaine use, but she had not used any other drugs, including alcohol.82

The patient was given a Positive and Negative Symptom Scale (PANSS) test.82 The PANSS contains 30 items rated on an underlying seven-point Likert scale (1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5

= moderate-to-severe, and 6 = severe, 7 = extreme).83 The scores from each item are added together to determine a PANSS total score, consisting of three subscales with seven items measuring positive (psychotic) symptoms (P1–P7), seven items measuring negative symptoms (N1–N7), and 16 items measuring more general psychopathology (G1–G16).83

The patient scored 15 for the positive subscale, 7 for the negative subscale, and 31 for the general psychopathology subscale on the Positive and Negative Symptom Scale (PANSS).82 The patient’s score was not high enough for a diagnosis of a psychotic disorder using the criteria of Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), so the patient was provisionally diagnosed with brief psychotic disorder using DSM- 5.82

Laboratory tests were normal. These included negative urine toxicology and hepatitis B and C serologies.82 Electrocardiogram showed no significant alterations. The patient underwent cranial magnetic resonance imaging and an electroencephalogram with normal results.82

The patient was administered aripiprazole, 10 mg per day, and lorazepam 2.5 mg, three times per day.82 After 12 days of treatment, the patient’s delusions persisted, and the dosage of aripiprazole was increased gradually to 20 mg per day. The patient showed significant improvement after a few days.82 However, on her 21st day in the hospital, the patient became nauseous, vomited once, and presented with sclerotic jaundice.82 Laboratory tests were performed, and the patient’s tests showed AST levels of 176 U/L, ALT 745 U/L, GGT 437 U/L, ALP 224 U/L, total bilirubin 1.14 mg/dl, direct bilirubin 0.79 mg/dl, and C-reactive protein (CRP) 0.66 mg/dl.82 The patient’s hepatitis A serology was negative. An abdominal ultrasonography did not detect any significant changes.82

Aripiprazole was discontinued, and the patient was started on paliperidone, titrated to 6 mg per day. Lorazepam 2.5 mg three times per day was maintained.82 The patient’s liver tests were closely monitored and showed improvement.82

On day 35 of hospitalization, the patient was discharged. Her psychiatric symptomatology had improved markedly. Her PANSS scale scores were 9 on the positive subscale, 7 on the negative subscale, and 18 on the general psychopathology subscale, and her liver function tests were AST levels of 22 U/L, ALT 72 U/L, ALP 155 U/L, GGT 252 U/L, total bilirubin

0.49 mg/dl, and direct bilirubin of 0.30 mg/dl.82 Follow-up treatments and monitoring showed that the patient’s psychotic symptoms continued to improve, and her laboratory tests remained normal.82

The import of this case report is that despite aripiprazole’s good tolerance and side effect profile, it can lead to severe drug-induced liver injury.82 The authors suggest that patients with known hepatic disease or who are taking medications that can provoke liver injury, or consuming

alcohol, be monitored for liver function before starting atypical antipsychotics and then that they be monitored on a regular basis.82

Summary

Aripiprazole is a second-generation, atypical antipsychotic that is best known under the brand name Abilify®. It was originally approved for the treatment of schizophrenia and bipolar I disorder, but it has also been used for other psychiatric conditions in children and adults.

Aripiprazole is available in oral and long-acting injectable forms, which have unique pharmacokinetic profiles that must be considered when formulating a treatment plan. It is important for clinicians to understand the pharmacokinetic and other differences between the oral and long-acting forms of aripiprazole. A misunderstanding of these differences may lead to poorer outcomes for patients.

Aripiprazole has a favorable side-effect profile when compared to other antipsychotics. However, children and adolescents have reported increased extrapyramidal side effects when treated with aripiprazole. There are also recommendations clinicians should follow when switching to a long-acting antipsychotic.

Course Test

Antipsychotic medications may cause , a movement disorder whose symptoms include restlessness and needing to pace.

neuroleptic malignancy

serotonin syndrome

cardiac arrhythmia

akathisia

Aripiprazole is classified as a second-generation, atypical antipsychotic but it is also known as a                  due to its unique mechanism of action.

anticonvulsant

third-generation antipsychotic

benzodiazepine

first-generation antipsychotic

The long-acting injectable (LAI) forms of aripiprazole exhibit

           kinetics that impact the time it takes for the drug to reach a steady state because of its slower absorption rate.

polypharmacy

placebo

flip-flop

peak–trough

Aripiprazole is classified as a dopamine partial agonist due to its

        activity at certain receptor targets, most notably D2 autoreceptors.

partial agonist

antagonist

blocking

full antagonist

Aripiprazole is FDA-approved as an adjunctive therapy to treat

major depressive disorder.

akathisia.

delusional disorder.

elderly patients with dementia-related psychosis.

True or False: Aristada Initio and Aristada should be injected into the same muscle when administered concurrently.

True

False

The long-acting injectable (LAI) aripiprazole may help promote adherence to antipsychotic medication treatment plans because

there are no adverse events with LAIs.

the dosing for LAIs is less frequent.

LAI formulations only use dehydroaripiprazole as the parent drug.

LAIs are administered daily.

Aripiprazole has FDA approval for treating irritability in children who have

bipolar 1.

schizophrenia.

autism spectrum disorder.

akathisia.

Patients taking aripiprazole should be counseled that

there is no risk of metabolic side effects or weight gain.

only children are at risk of extrapyramidal symptoms.

oculogyric crisis (OGC) is relatively common and self-resolving.

an association between the use of aripiprazole and compulsive behaviors, including gambling, binge eating, shopping, or engaging in sex has been reported.

Women of childbearing age should be informed of the following about taking aripiprazole during pregnancy:

children exposed to aripiprazole during pregnancy are at a higher risk of adverse effects than those exposed to other antipsychotics.

antipsychotics in the third trimester pose no risk of adverse effects.

animal studies suggest risks of adverse effects on the fetus, but benefits may outweigh risks in certain patients.

aripiprazole is contraindicated in pregnant women.

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