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Pharmacist Continuing Education: Overview of Long-Acting Injectable Antipsychotics

15 May 2019 2:52 PM | Mandy Garion (Administrator)

Authors:  Andrea Prince, PharmD and Michelle Ndiulor, PharmD
PGY-2 Ambulatory Care Pharmacy Residents

Mentor:  Joshua Holland, PharmD, BCPP
Psychiatry Pharmacy Specialist
CoxHealth – Springfield, MO

Program Number:  2019-05-08
Approval Dates:  June 5, 2019 – December 4, 2019
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

  1. Review the mechanism of action and indication of antipsychotics
  2. Discuss advantages and disadvantages of long-acting injectable antipsychotics
  3. Identify the appropriate place in therapy for long-acting injectable antipsychotics in psychiatric conditions
  4. Identify various long-acting injectable antipsychotic agents available in the United States
  5. Explain the dosing, proper administration of long-acting injectable antipsychotics and how to address missed and late doses

Introduction

Schizophrenia and bipolar disorder are chronic disease states and complex disorders in which antipsychotics are utilized for treatment. Oral antipsychotics are known to have a high rate of poor adherence, which can result in relapse for the patient. Poor adherence is associated with mood relapses; increased risk for hospitalization and emergency room visits; and increased employee costs due to absenteeism, disability, and worker’s compensation. Some of the reasons for poor adherence may include side effects, poor efficacy, cognitive deficits, complexity of regimens, medication access, and an unstable living environment.1 Long-acting injectable antipsychotics (LAI APs) have shown similar efficacy and safety to oral antipsychotics and can be a treatment option for patients with adherence issues.

Overview of Antipsychotics

The use of antipsychotic agents in mental health disorders began around 1951 with chlorpromazine2,3. Prior to this period, chlorpromazine was used in patients due to its potential anesthetic effects during surgery. Psychiatrists during the time noticed its sedative effects and began using the medication in their patient populations2,3. Following this period, several oral first-generation or “typical” antipsychotic agents were introduced into the United States market for treatment of mental health disorders such as schizophrenia and bipolar disorder. Along with the effective mechanism of action that this class of medications brought came several adverse effects including extrapyramidal symptoms. In 1990, introduction of clozapine into the US market initiated the use of oral second-generation or “atypical” antipsychotics agents3. These agents showed a reduced potential for causing extrapyramidal symptoms.

In between the development of the various oral first- and second-generation antipsychotics, the first LAI AP was developed in 1966 by ER Squibb & Sons Ltd in the United Kingdom2,4. Fluphenazine enanthate appeared to show some potential advantages over oral antipsychotic agents including ensured contact with a provider and ease of administration. However, the medication was met with a great deal of adversity due to psychiatrists seeing it as a ‘threatening’ formulation for patients2,4.

With time, long-acting injectable antipsychotics made their way up treatment ladders for mental health conditions as prescribers and patients noticed its efficacy, tolerability, and simplified regimen. Currently there are several long-acting injectable antipsychotic agents available in the United States and other countries around the world2,4.

Mechanism of Action

Typical Antipsychotics5

The primary action of first-generation antipsychotics (FGA) is its pharmacological activity on the D2 (dopamine) receptor. This class of medication acts as an antagonist to the receptor, which is responsible for its antipsychotic effects. Unfortunately, this mechanism is also responsible for many of its various side effects. Neurolepsis results from D2 receptor antagonism. Patients that present with neurolepsis will appear apathetic and will lack motivation. Other adverse effects associated with the class’ D2 receptor antagonism include extrapyramidal symptoms (EPS) and hyperprolactinemia. Other actions of this class of medication include muscarinic cholinergic receptor antagonism, histamine receptor antagonism, and alpha-1 adrenergic receptor antagonism. Orthostatic hypotension may be seen with alpha-1 adrenergic receptor antagonism while side effects such as urinary retention and dry mouth may be seen due to anticholinergic effects.

Atypical Antipsychotics5

Atypical antipsychotics still have dopamine receptor blockade but also have serotonin-activity (5HT2-A antagonism). Having this second action leads to antipsychotic effects in addition to lower EPS and hyperprolactinemia risk through partial serotonin (5HT-1A) & D2 receptor agonism. Second generation antipsychotics (SGA) bind to dopamine receptors transiently and rapidly dissociate from receptors allowing dopamine to bind receptors. This is thought to be the reason why risk of extrapyramidal symptoms and hyperprolactinemia are lessened. Furthermore, some atypical antipsychotics exhibit serotonin agonism leading to increased release of dopamine and decreased release of glutamate which can potentially improve the side effect profile.

2014 National Institute for Health and Care Excellence (NICE) Guideline Recommendations for Long-Acting Antipsychotic Use in Schizophrenia Treatment6

Currently, the 2014 NICE guidelines recommend the consideration of a depot/long-acting injectable antipsychotic as maintenance therapy. In patients living with conditions such as psychosis or schizophrenia, LAI antipsychotics may be considered after an acute episode or when there is a desire to avoid intentional/non-intentional non-adherence. Oral antipsychotics are recommended during acute episodes alongside cognitive behavioral therapy.

The decision on which antipsychotic agent to use should be one that involves both the patient and/or caregiver and the healthcare professional. Furthermore, a discussion with the patient should include the likely benefits and potential side effects associated with the medication being initiated. Likely benefits to discuss with the patient would include less frequent administration potentially leading to improved adherence and potential for reduced relapse frequencies and rehospitalization rates7.  Furthermore, discussion of the potential side effects would include2:

  • Metabolic (including diabetes and weight gain)
  • Extrapyramidal symptoms (including dyskinesia, dystonia, and akathisia)
  • Cardiovascular (including prolonged QT interval)
  • Hormonal side effects (including hyperprolactinemia)

2014 NICE Guideline Recommendations for Long-Acting Antipsychotic Use in Bipolar Disorder Treatment8

For treatment of bipolar disorder, the 2014 NICE guidelines recommend the use of oral antipsychotic agents including haloperidol, quetiapine, olanzapine, or risperidone. Even, though the guidelines do not explicitly state the use of long-acting injectable antipsychotic agents, long-acting injectable antipsychotic agents are used in practice for bipolar disorder management.

According to the guidelines, it is recommended that before starting an antipsychotic agent, the patient’s weight, pulse, blood pressure, blood lipid profile, and fasting blood glucose or glycosylated hemoglobin A1c be measured and recorded. An electrocardiogram may also be necessary in the case that the patient has cardiovascular disease, has a family history of cardiovascular disease, is being admitted as an inpatient, or if it is specified with the specific antipsychotic being used2.  Monitoring recommendations for patients receiving antipsychotic treatment are listed in Table 1 below.

Table 1: Monitoring Recommendations for Patients Receiving Antipsychotic Treatment9

Place in Therapy: Long-Acting Injectable Antipsychotics

Adherence issues have been of growing concern. Despite having oral first and second-generation antipsychotics available for use, adherence to this formulation is lacking10. Some factors involved in nonadherence to antipsychotic therapy include lack of provider awareness of non-adherence, irregular daily routines, and complexity of the patient’s medication regimen. Evidence has shown that non-adherence rates of patients living with schizophrenia ranges from around 40 to 60% of all patients11-13. Furthermore, various studies have shown an association between non-adherence and increased rates of relapse, re-hospitalizations, worsening long-term prognosis, increased dependence on families, increased dependence on the healthcare system, and worsened functionality14-18. Long-acting injectable antipsychotics have exhibited efficacy, safety, and a more simplified medication regimen compared to some oral options4. Therefore, the use of long-acting injectables may be considered for use in this patient population.

Ideal Candidates7

Guidelines and literature suggest that ideal candidates for long-acting injectable antipsychotics include patients with recent-onset schizophrenia and individuals with risk factors for medication non-adherence. These risk factors include the following:

Advantages/Disadvantages of Long-Acting Injectable Antipsychotics7

When compared to oral antipsychotics, there are a number of potential advantages of long-acting injectable antipsychotics. One of the main advantages of LAIs APs compared to oral APs is there being no need for daily administration. Additionally with LAIs, there is less risk of intentional or unintentional overdose due to the guaranteed administration of the LAI and transparency of adherence. Benefits also include more consistent bioavailability and a more predictable correlation between dosage and plasma levels.  Moreover, when patients stop taking their medication, the plasma levels of the LAI decrease more slowly as compared to oral formulations. This gives the healthcare professionals time to intervene and reduce the probability of rebound symptoms and abrupt relapses.

One of the main disadvantages associated with LAI APs is the increased time it takes to achieve steady state levels and less flexibility of dose adjustments due to the long acting nature of the formulation. With injectable medications, there is the potential for injection-site reactions as well as pain at the injection site, which can be irritating to the patient. Depending on the patient’s lifestyle and socioeconomic factors, they may not be able to make frequent visits to clinics or pharmacies for administration due to job constraints, lack of or limited transportation, and/or work schedule. Lastly, the LAI APs are more expensive than the oral APs and may additionally require prior authorizations which can delay their use.

Overview of Long-Acting Injectable Antipsychotics Available in the United States

All the LAI APs have product specific dosing and dosing intervals. Additionally, some products require a trial of the oral formulation as well as an overlap period of oral and LAI formulations. Selecting an optimal LAI AP should be patient-centered and various practical considerations should be discussed. All of the LAI APs require administration by a healthcare professional. The side effect profile of the LAIs generally follows the known side effect profiles of the oral formulation. Pharmacokinetics of the LAIs varies among the different agents and is summarized below in Table 2. The advantages of the FGAs are cost and a lower metabolic side effect profile when compared to LAI SGAs. The disadvantages include a higher risk of EPS and greater interpatient variability regarding pharmacokinetics. Table 3 summarizes the clinical features of the LAI APs.

First-Generation LAI Aps19-27

Fluphenazine decanoate is indicated for treatment of psychotic disorders. Tolerability with oral fluphenazine should be established prior to initiation of injection. The drug vehicle for the injection is sesame oil thus close attention to the patient’s allergy profile is warranted. Initially, it is dosed at one to two-week intervals. Once steady state is reached, the dosing interval may be lengthened to four to six weeks.

Haloperidol decanoate is used for the treatment of schizophrenia. Tolerability with oral haloperidol should be established prior to use and overlap with oral haloperidol can be tapered and discontinued following the second or third injection. The vehicle for the injection is sesame oil similar to fluphenazine decanoate.

Second-Generation LAI Aps19-27

Abilify Maintena® (aripiprazole monohydrate) is indicated for the treatment of schizophrenia and maintenance of bipolar 1 disorder.  The drug vehicle is microparticles in water. Abilify Maintena® requires the patient to establish tolerability with 14 days of oral therapy and also requires a 14-day overlap of oral therapy. There are two types of kits one of which is a prefilled dual chamber syringe and the other contains vials of lyophilized powder which require reconstitution.

Aristada® (aripiprazole lauroxil) has an FDA-labeled indication for the treatment of schizophrenia. Tolerability should be established with oral aripiprazole prior to initiation treatment with Aristada®. Overlap with oral aripiprazole for 21 days is necessary with the first injection unless using Aristada Initio®. Aristada Initio® is a one-time injection that can be given on day 1 with a single 30mg dose of oral aripiprazole in addition to the first Aristada dose. When using Aristada Initio®, the 21 day oral aripiprazole overlap is not necessary. Aristada® is supplied as an off-white aqueous suspension in single-use pre-filled syringes.

Zyprexa Relprevv® (olanzapine pamoate) is indicated for the treatment of schizophrenia. It does not require overlap with the oral formulation but does require the establishment of tolerability with oral olanzapine prior to initiation. Zyprexxa Relprevv® is supplied as a microcrystalline suspension in vials. Zyprexa Relprevv® has a small risk for post-injection delirium/sedation syndrome which limits its use. The signs and symptoms associated with the reaction include: sedation, anxiety, confusion, aggressiveness, dizziness, ataxia and extrapyramidal symptoms. After an injection, patients require monitoring for three hours by a healthcare professional. Prescribers, facilities, and pharmacies must enroll in a national registry for documentation of this adverse event.

Invega Sustenna® (paliperidone palmitate) is indicated for treatment of schizophrenia and schizoaffective disorder. It does not require overlap with oral paliperidone; however, it does require establishment of tolerability with oral paliperidone. Invega Sustenna® requires two initiation doses during the first week to rapidly attain steady-state paliperidone concentrations.

Invega Trinza® (paliperidone palmitate) is indicated for the treatment of schizophrenia. Once patients are established on Invega Sustenna® for a least a four month duration, they may transition to Invega Trinza®, which has a three-month dosing interval. It is supplied as a suspension in a pre-filled syringe which requires vigorous shaking to ensure a homogenous suspension.

Risperdal Consta® (risperidone) is used for the treatment of schizophrenia and for the long-term treatment of bipolar 1 disorder. Tolerability with oral risperidone should be established prior to use of Risperdal Consta®. Overlap with oral risperidone for three weeks is necessary to establish adequate therapeutic plasma concentrations. Risperdal Consta® is supplied as a kit that requires reconstitution of a microsphere polymer suspension using a vial, vial adapter, and pre-filled syringe with diluent.

Perseris® (risperidone) is a once monthly injection indicated for the treatment of schizophrenia in adults. Tolerability with oral risperidone should be established prior to use of Perseris®. Perseris® is supplied as pre-filled liquid syringe carrying the delivery system and a prefilled powder syringe which contains risperidone.

Conclusion

Antipsychotic agents have been used for many years for the treatment of mental health conditions such as schizophrenia and bipolar disorder. First and second-generation antipsychotics have slightly different chemical profiles leading to reduced risk of certain adverse effects in second-generation (atypical) antipsychotics. Pharmacists can utilize their drug knowledge to assist in product selection, dosing, administration, missed doses, and drug-drug interactions. Additionally, some pharmacists are able to dispense and administer LAI APs to patients thus increasing medication access to patients.

Overall, long-acting injectable antipsychotic agents have been shown to be efficacious and relatively safe for use in patients living with mental health disorders. Long-acting injectable antipsychotics may be used to aid in the improvement of medication adherence by improving patient access to medications.

Supplemental Tables:

References:

  1. Correll CU, Citrome L, Haddad P et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry, 2016; 77[suppl 3]:1-24.
  2. Olivares JM, Pinal B, & Cinos C. Comparison of long-acting antipsychotic injection and oral antipsychotics in schizophrenia. Neuropsychiatry, 2011;1(3):275. http://www.jneuropsychiatry.org/peer-review/comparison-of-longacting-antipsychotic-injection-and-oral-antipsychotics-in-schizophrenia-neuropsychiatry.pdf.
  3. Shen WW. A history of antipsychotic drug development. Comprehensive psychiatry, 1999;40(6):407-414.
  4. Brissos, S., Veguilla, M. R., Taylor, D., & Balanzá-Martinez, V. (2014). The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Therapeutic advances in psychopharmacology, 4(5), 198-219.
  5. Stahl SM, & Stahl SM. (2013). Stahl's essential psychopharmacology: neuroscientific basis and practical applications. Cambridge university press.
  6. National Institute for Health and Clinical Excellence (NICE), National Collaborating Center for Mental Health, "Psychosis and Schizophrenia in Adults: Treatment and Management " March 2014.
  7. Guzman F. Long-Acting Injectable Antipsychotics: A Practical Guide for Prescribers. Psychopharmacology Institute website. https://psychopharmacologyinstitute.com/antipsychotics/long-acting-injectable-antipsychotics-a-practical-guide-for-prescribers/#fnref:1. Last Updated February 10, 2018.
  8. National Institute for Health and Clinical Excellence (NICE), National Collaborating Centre for Mental Health, “Bipolar Disorder: The Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care,” 2014.
  9. Chhim T, Chase P, Neumiller JJ. Antipsychotic-Induced Diabetes Mellitus. US Pharmacist website. https://www.uspharmacist.com/article/antipsychotic-induced-diabetes-mellitus. Published November 20, 2012.
  10. Schanda H, Stompe T: Is our clinical practice of antipsychotic relapse prevention in schizophrenia really evidence-based? Neuropsychiatr. 2010;24(1), 14–26.
  11. Zygmunt A, Olfson M, Boyer CA, Mechanic D: Interventions to improve medication adherence in schizophrenia. Am. J. Psychiatry 2002;159:1653–1664.
  12. Lacro JP, Dunn LB, Dolder CR, Leckband SG, Jeste DV: Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J. Clin. Psychiatry 2002;63:892–909.
  13. Perkins DO: Predictors of noncompliance in patients with schizophrenia. J. Clin. Psychiatry 2002;63:1121–1128.
  14. Kane JM: Treatment adherence and long-term outcomes. CNS Spectr. 2007;12:21–26.
  15. Leucht S, Heres S: Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J. Clin. Psychiatry 2006;67(5):3–8.
  16. Ayuso-Gutierrez JL, Rio JM: Factors influencing relapse in the long-term course of schizophrenia. Schizophr. Res.1997; 28:199–206.
  17. Weiden PJ, Olfson M: Cost of relapse in schizophrenia. Schizophr. Bull. 1995;21:419–429.
  18. Pennington, M. & McCrone, P. PharmacoEconomics. 2017;35:921. https://doi.org/10.1007/s40273-017-0515-3.
  19. Prescribing information: Prolixin Decanoate® (fluphenazine decanoate), APP, Dec 2010.
  20. Prescribing information: Haldol Decanoate® (haloperidol decanoate), Janssen, Feb 2014.
  21. Prescribing information: Abilify Maintena® (aripiprazole extended release), Otsuka, Dec 2014.
  22. Prescribing information: Aristada® (aripiprazole lauroxil), Alkermes, October 2015.
  23. Prescribing information: Zyprexa Relprevv® (olanzapine pamoate), Eli Lilly, Dec 2014.
  24. Prescribing information: Invega Sustenna® (paliperidone palmitate), Janssen, Feb 2015.
  25. Prescribing information: Invega Trinza® (paliperidone palmitate), Janssen, May 2015.
  26. Prescribing information: Risperdal Consta® (risperidone microspheres), Janssen, May 2014.
  27. Prescribing information: Perseris® (risperidone), Indivior, July 2018.
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