August CE Article

August CPE Article

Review of Long-Acting Injectable Antipsychotics

Authors: Houston T. Williams, PharmD Candidate 2022; Hannah E. Johnson, PharmD, BCPS, BCPP; Kenneth E. Record, PharmD

The authors declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest.

Universal Activity #0143-0000-21-008-H08-P&T Contact Hour 1.0 KPERF offers all CE articles to members online at Expires: 8/5/2024 www.kphanet.org

Learning Objectives: At the conclusion of this knowledge-based article, the reader should be able to: 1. Describe the mechanism of action and adverse drug effect profiles of first- and secondgeneration antipsychotics 2. Discuss the indications and place for long-acting injectable antipsychotics in therapy 3. Review the administration and storage of long-acting injectable antipsychotics 4. Identify the pharmacists’ role in access and administration of long-acting antipsychotics

Introduction of Antipsychotics Since the early 1950’s, antipsychotics have played an important role in treating patients with mental health disorders. After the discovery of oral first-generation antipsychotics, such as chlorpromazine, a decline in hospitalizations and an increase in long-term psychiatric facility discharges was observed [1]. Soon after, long-acting injectable antipsychotics were being developed to help patients with adherence and reduce relapse from medication discontinuation [2]. In the 1980’s, oral second-generation antipsychotics emerged and long-acting injectable formulations of these were created shortly after [3]. Today, antipsychotics are used to help treat a variety of conditions including schizophrenia spectrum disorders, psychotic disorders, bipolar disorder, major depressive disorder, tic disorders, and autism spectrum disorder [4]. In the treatment of schizophrenia, both oral and long-acting injectable antipsychotics have shown efficacy, tolerability, and safety [5]. Schizophrenia Schizophrenia is a chronic disease that impacts the brain by affecting how a person feels, thinks, and behaves [6]. Chronic disease often requires medical assistance and is defined as a condition that persists long-term, may inhibit the ability to do everyday activities, and impact one’s quality of life (QOL) [7]. The median lifelong prevalence of schizophrenia is around 0.72%. The incidence of schizophrenia is higher in males with a ratio for males-to-females of 1.4:1. Males also develop symptoms earlier than females. Schizophrenia reduces life expectancy and increases the risk of mortality 2-3-fold [8]. In the United States, the total economic burden of schizophrenia is estimated to be 155.7 billion dollars annually. Patients who suffer from schizophrenia have an average cost of $44,773 per year [9]. |24| Kentucky Pharmacists Association | July/august 2021

Fluphenazine decanoate

(Prolixin D®)

Haloperidol decanoate

(Haldol®)

Aripiprazole (Abilify

Maintena®)

Aripiprazole lauroxil

(Aristada®)

Olanzapine pamoate

(Zyprexa® Relprevv™)

1st 6.25 - 25 mg every 2 weeks until steady state, then up to a max dose of 100 mg every 4-6 weeks Yes, at least until the 2nd injection No data

1st 10-20 times daily oral dose. If the initial dose requires more than 100 mg of injection, administer in 2 injections with a max dose of 100 mg for the first injection with remaining given 3-7 days later. Max: 450 mg every month Yes, for 2-3 months Adjust oral dose and rate of tapering based on clinical response and tolerability

2nd 400 mg every 4 weeks. Can consider 300 mg every 4 weeks if adverse events occur Yes, for 14 days No data

2nd 441-1,064 mg every 4-8 weeks Yes, for 21 days 10 mg/day = 441 mg per month 15 mg/day = 662 mg per month or 882 mg every 6 weeks or 1,064 mg every 2 months >/= 20 mg/day = 882 mg per month

2nd Up to 300mg every 2 weeks OR Up to 405 mg every 4 weeks 3 No 10 mg daily = Initial 210 mg every 2 weeks for 4 doses or 405 mg every 4 weeks for 2 doses 15 mg daily = Initial 300 mg every 2 weeks for 4 doses

Paliperidone palmitate

(Invega Sustenna®)

Paliperidone palmitate

(Invega Trinza®)

2nd 234 mg on the first day of treatment, then 156mg IM 1 week later. 5 weeks after initiation dose, start maintenance dose of 39-234 mg every month No 3 mg/day = 39-78 mg every month 6 mg/day = 117 mg every month 9 mg/day = 156 mg every month 12 mg/day = 234 mg every month

2nd Calculate every 3 months based on previous dose 2 No 3 mg/day = 273 mg every 3 months 6 mg/day = 410 mg every 3 months 9 mg/day = 546 mg every 3 months 12 mg/day = 819 mg every 3 months

Risperidone (Risperdal Con-

sta®)

2nd 25mg-50mg every 2 weeks Yes, for the first 3 weeks </= 3mg/day = 25 mg IM ER Q2 weeks >3 to </= 5 mg/day oral = 37.5 mg IM extended release every 2 weeks >5 mg/day = 50 mg IM ER every 2 weeks.1

Risperidone (Perseris™) 2nd 90mg-120mg once a month No Oral dose of 3mg/day is = to SQ injection of 90 mg once a month Oral dose of 4 mg/day is = SQ of 120 mg once a month

Table 1 shows LAIs and their dosing regimens, overlap requirements, and conversions [23-29] 1.

Manufacturer does not provide conversions. Recommendations are as listed [34]

2. To be used only after monthly IM injection has been established as adequate treatment for 4 months

Table 2 : Administration and Storage of LAIs [21, 23-29] Abbreviations: IM, Intramuscularly; SQ, Subcutaneously. Table 2 represents the administration location and storage recommendations

Drug (Brand) Administration (Location) Storage Protect from Light?

Fluphenazine decanoate (Prolixin

D®)

IM (gluteal) or SQ

Haloperidol decanoate (Haldol®) IM (gluteal)

Aripiprazole (Abilify Maintena®) IM (gluteal or deltoid

Aripiprazole lauroxil (Aristada®) IM (gluteal or deltoid)

Olanzapine pamoate (Zyprexa®

Relprevv™)

IM (gluteal)

Paliperidone palmitate (Invega IM (deltoid)

Paliperidone palmitate (Invega

Trinza®)

IM (gluteal or deltoid)

Risperidone (Risperdal Consta®) IM (gluteal or deltoid) Store at a temperature between 68-77° F; do not freeze or refrigerate

Store at a temperature between 59-86°F; do not freeze or refrigerate

Store prefilled syringe below 86° F; do not freeze Store unused vial at 77° F

Store at a temperature between 68-77° F Yes

No

Prefilled syringes: Yes

No

Store in a room temperature controlled area; do not exceed 86° F

Store at 77° F

Store at a temperature between 68-77°F

Store at a temperature between 36-46°F No

No

No

Yes

Risperidone (Perseris™) SC (abdomen)

The symptoms of schizophrenia are characterized into two main groups: positive and negative. Positive symptoms include alterations in the way a person thinks or acts, such as hallucinations and delusions [3, 10]. Negative symptoms cause a person to withdraw from everyday activities, lose interest, and appear to have no emotions [10]. Specific negative symptoms include social withdrawal, blunted affect, preoccupation, lack of insight, and motor retardation. There are also cognitive symptoms which impair memory, concentration, and attention [6]. Diagnosis of schizophrenia requires a men-

Store at a temperature between 36-46°F Unopened product may be stored at a temperature between 68-77° F, up to 7 days before administration; after removed from refrigeration use within 7 days No

tal health professional to determine if the criteria is met in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) [11]. For some patients, symptoms can begin years before they have their first episode of schizophrenia [10]. The exact cause of schizophrenia is still unknown. It is thought to be a combination of multiple factors including genetics, environment, and brain development [11]. Schizophrenia is an intricate disease that involves dysregulation among different neurotransmitter pathways. Dopaminergic, glutaminergic, GABAergic, and cholinergic systems have all been shown to play a role [12]. Treatment of schizophrenia must be individualized for each patient and focuses on optimizing the patient’s quality of life and adaptive functionality [13]. Treatment courses can include medications, psychotherapy (individual, group, or cognitive behavioral approaches), treatment programs that involve family support, and vocational rehabilitation [14]. A variety of members assist in the process, including the multidisciplinary healthcare team, case management, family/ caregivers, and the patient [13].

First-Generation vs Second-Generation Antipsychotics Antipsychotics are first-line treatment for schizophrenia and are divided into two categories: firstgeneration antipsychotics (FGAs) and secondgeneration antipsychotics (SGAs). The primary mechanism of action for both FGAs and SGAs is dopamine (D2) antagonism. However, they differ in D2-receptor binding affinity. Each antipsychotic within both classes has varying degrees of receptor binding including serotonin 5-HT1A and 5-HT2A, dopamine D1 and D2, histamine H1, adrenergic alpha1 and alpha2, and muscarinic M1 and M4, which lead to their differing adverse effect profiles. First-generation antipsychotics typically have strong D2-antagonism and weak serotonin (5HT2A) antagonism [14]. Extrapyramidal symptoms (EPS), including pseudoparkinsonism, dystonia, and akathisia, are side effects that arise due to the strong D2-receptor blockade. After taking medication in this class for an extended period, patients can also experience tardive dyskinesia [15]. In regard to schizophrenia, the FGAs are known to have some effect on the positive symptoms and limited to no effect on the negative symptoms [16]. Second-generation antipsychotics have varying degrees of D2-antagonism, with some having partial D2 agonism, and typically exhibit high 5-HT2A antagonism [17]. Because of the lower affinity for the D2 receptors and higher affinity for the 5-HT2A receptors, the SGAs are less likely to cause EPS and tardive dyskinesia [18]. However, the SGAs have the potential to cause metabolic syndrome, including the side effects of increased blood pressure, low high-density lipoprotein (HDL) cholesterol, elevated blood sugar, central obesity, and hypertriglyceridemia [1, 4].

Long-Acting Injectable Antipsychotics While they are under-utilized in real life practice, long-acting injectable antipsychotics (LAIs) have the potential to be one of the most effective treatments in psychiatry [19]. In the United States, there are a variety of LAIs that are used, including formulations of the FGAs haloperidol and fluphenazine and the SGAs aripiprazole, olanzapine, risperidone, and paliperidone [19, 20]. One-third of patients with schizophrenia report being non-adherent to their oral antipsychotics (OAPs). Medication non-adherence can lead to worsening function, progression of disease, increased cost, and hospitalizations. LAIs have been shown to improve adherence and help patients maintain their course of treatment for both acute and chronic schizophrenia [2, 19]. Research, including a meta-analysis of mirror studies, has shown that compared to OAPs, LAIs improve medication adherence and QOL, reduce adverse drug reactions and financial burden, and are superior for preventing hospitalizations/rehospitalizations [2, 5, 19,]. There is limited literature comparing the efficacy of individual LAIs to each other. LAIs are administered either intramuscularly or subcutaneously and slowly absorbed systemically. The frequency of administration varies by formulation, ranging from every two weeks to every three months. The absorption of LAIs can be impacted by drug properties including water solubility and patient-specific factors, including body habitus. LAIs have “flip-flop” kinetics due to absorption being |27| www.KPHANET.org

slower than elimination rates, thereby causing time to steady-state to be a function of absorption and concentration at steady-state to be a function of elimination. The extended half-lives of LAIs result from the very slow absorption and the prolonged duration of blood concentration. The LAIs avoid first-pass metabolism, leading to an increase in bioavailability. Fewer side effects and better tolerability can be seen with LAIs compared to OAPs due to slower absorption rate causing less variations in the peak to trough plasma concentration levels. [21]. Before starting an LAI, it is recommended to ensure tolerability to the oral formulation of that antipsychotic. Many LAIs then require a period of overlap with the oral formulation after the initial injection of the LAI. This data is summarized in Table 1.

Safety and Tolerability of LAIs in the Literature Safety and tolerability appear similar between LAIs and OAPs. A meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs showed no differences in adverse drug events [2]. However, there were differences seen among individual agents including risperidone and paliperidone LAI formulations with increased akinesia and weight gain, decreased prolactin changes, and other metabolic events observed with LAIs [2, 19]. Another study found that SGA LAIs and OAPs had similar occurrences of EPS and that the pharmacokinetic (PK) profiles are irrelevant to the side effects experienced [2]. However, potential dosage adjustments are warranted based on the drug-drug interactions, food-drug interactions, and type of metabolizer a patient is (i.e., a poor metabolizer) [21]. Some of the differences between the rates of akinesia, weight gain, EPS, anxiety, dosing interval, requirement for overlap with OAPs, and other differences can help guide the selection of the LAI [2, 19].

Advantages and Disadvantages of LAIs The use of LAIs provides health care professionals the ability to manage non-adherence and allows provider involvement to correct the issue. There is a lower risk of accidental or intentional overdose with LAIs compared to OAPs, as well as improved patient adherence, transparency, and confidence that the patient is receiving the dose. In addition, dosage and plasma levels correlations are more predictable when a patient is on a LAI. However, LAIs take longer to reach steady state levels, have a higher potential for injection site irritation, and are more difficult to titrate [22]. Additionally, stigma surrounding injection medications still exists for both healthcare providers and patients. Patients potentially receive the LAI recommendation poorly and see it as a form of punishment, a sign of progression of disease, or that the patient is severely ill. By making the recommendation in a way in which is not blaming the patient for the non-adherence but as a lifestyle benefit can potentially reduce the stigma [19].

Administration of LAIs The administration of long-acting antipsychotics varies for each specific agent (Table 2). Multiple LAIs can be administered via a gluteal or deltoid intramuscular injection, including fluphenazine, haloperidol, aripiprazole, olanzapine, paliperidone palmitate, and risperidone (Risperdal Consta®). In addition, both fluphenazine and risperidone (Perseris™) can be given in the abdomen via the subcutaneous route [23-29].

Pharmacists’ Role with LAIs With limited access for patients to mental health services in the state of Kentucky, pharmacists have the unique ability to help improve access to care for people with serious and persistent mental illness (SPMI). In the state of Kentucky, pharmacists are able to administer medications such as LAIs based on Kentucky law, which authorizes “administration of medications or biologics in the course of dispensing or maintaining a prescription drug order” [30]. Pharmacists administering LAIs in the community pharmacy setting may also help reduce stigma surrounding mental health. According to an observational study in the community pharmacy setting, patients were pleased with pharmacist administration of LAIs[31]. Pharmacists can also assist with assessing drug interactions, counseling on important aspects of the medications, assisting with insurance coverage and patient assistance, and moni-

toring for adverse effects, as well as providing missed dose recommendations to healthcare providers [32].

Navigating LAIs during COVID-19 During the global COVID-19 pandemic, many clinics transitioned from face-to-face interactions to virtual or telehealth appointments. Although many facilities have continued to allow in-person visits due to uncertainty of how to transition patients from their LAI back to an oral antipsychotic and desire to prevent patients from potentially discontinuing their medications, some have not [20,33]. It is imperative to continue providing access to administration of LAIs in medical facilities or expand LAI administration to community pharmacies to avoid potential hazards that could arise from missed doses or patient self-injection [20].

The Future of LAIs In the future, it would be beneficial to conduct more pragmatic studies that closely mimic clinical practice and look deeper into the efficacy of LAIs compared to the OAPs [2]. Head-to-head research studies between a variety of LAI formulations are needed to help ease the selection of LAIs in clinical practice. An increase in availability of the LAIs, utilization of home health, or assertive community treatments for antipsychotics would increase the likelihood for LAIs to be utilized. Pharmacists can play a crucial role by educating the public and healthcare providers, advocating for the use of LAIs and their role in treatment, and putting a focus on patient-centered care to maximize therapy. For LAIs to be optimized, there are some barriers that need to be addressed including the lack of provider knowledge, overall negative attitudes toward LAIs, resources, and cost [19].

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