US Pharm. 2024;49(5):HS1-HS6.
ABSTRACT: Long-acting injectable (LAI) antipsychotics are an important treatment option to help improve adherence in patients with schizophrenia and schizoaffective disorder. LAI antipsychotics are managed and dosed differently than oral antipsychotics. Multiple LAI formulations have come to market in recent years, each with unique pharmacokinetics and drug characteristics. Pharmacists should understand the nuances of the different formulations so that they can effectively guide patients in treatment selection and prevent medication errors. Pharmacists also have an opportunity to impact patient care by providing LAI antipsychotic administration and care-coordination services.
Long-acting injectable (LAI) antipsychotics were developed to address a key barrier of antipsychotic therapy: nonadherence. Although antipsychotics are foundational treatment for schizophrenia and schizoaffective disorder, nonadherence to oral antipsychotics has been observed in up to 50% of patients. Poor adherence in patients with schizophrenia is a risk factor for adverse outcomes such as relapse, hospitalization, arrest, violent behaviors, and substance misuse. LAI antipsychotics, an important treatment option for schizophrenia, eliminate the need for taking daily oral medication and provide a transparent method for identifying nonadherence.1,2
First-generation antipsychotics were the first LAI antipsychotics to be developed. Fluphenazine decanoate and haloperidol decanoate were approved in 1972 and 1986, respectively.1 Motor adverse effects, including drug-induced parkinsonism and the need for anticholinergic medications, were significant limitations to first-generation LAI antipsychotics. These agents were followed by second-generation LAI antipsychotics, which have better tolerability but are associated with metabolic syndrome. The first second-generation LAI antipsychotic approved in the United States was risperidone microspheres (Risperdal Consta), in 2003.3 Since then, an additional 10 formulations of second-generation LAI antipsychotics have been developed, each with unique pharmacokinetics and drug characteristics.
Clinical Outcomes
Evidence from large studies suggests that LAI antipsychotics may be more effective for improving long-term clinical outcomes and are similar in tolerability to oral antipsychotics. In a large meta-analysis of studies comparing oral and LAI antipsychotics across multiple study designs, LAIs were consistently associated with a lower risk of hospitalization and relapse.4 Additionally, LAI antipsychotics were superior to oral antipsychotics in 18% of 328 measured secondary efficacy and safety outcomes.4 A population-based Swedish study analyzed mortality rates with first-generation and second-generation oral and LAI antipsychotic use over 6 years.5 Second-generation LAIs were associated with the lowest mortality rate, and LAI antipsychotics overall were associated with 33% lower mortality than equivalent oral formulations.5 Finally, a meta-analysis comparing the safety and tolerability of oral and LAI antipsychotics in randomized, controlled trials identified similar rates between groups across 97% of reported adverse events.6 The frequency of treatment discontinuation due to adverse events, serious adverse events, and all-cause death was also similar between the groups.6
Place in Therapy
The American Psychiatric Association’s practice guideline for treatment of patients with schizophrenia recommends the use of LAI antipsychotics in patients who prefer this treatment or have a history of poor or uncertain adherence.7 LAI antipsychotics are commonly used in patients with chronic nonadherence or multiple relapses; however, experts suggest that patients with first-episode psychosis or early-stage schizophrenia may benefit most.1,2,8 Patients respond less well to antipsychotic therapy after experiencing a relapse.8 Early use of LAI antipsychotics may help increase treatment response, prevent relapse, and reduce structural neurologic changes in early disease. Patients at high risk for poor adherence or relapse should also be considered for LAI antipsychotics.2 Providers should openly discuss LAI antipsychotic treatment options with patients early in the disease. Advantages and disadvantages of LAI antipsychotics are listed in TABLE 1.
Pharmacokinetics
LAI antipsychotics utilize extended-release mechanisms and exhibit different pharmacokinetics than oral antipsychotics. LAI antipsychotics have higher bioavailability since they bypass the first-pass effect of the gastrointestinal tract. After IM or SC injection, LAI drugs form a depot at the site of injection and slowly release active drug into the systemic circulation over weeks to months. The rate of drug absorption depends on drug properties such as particle size, water solubility, delivery vehicle, and injection volume, as well as patient factors such as body weight, SC fat, and injection site. LAI antipsychotics exhibit “flip-flop” kinetics, as their drug-absorption rate is much slower than the elimination rate. Therefore, the time to achieve steady state is determined by the absorption rate rather than the elimination rate. Compared with oral antipsychotics, the slow absorption of LAI antipsychotics leads to more predictable and stable plasma drug concentrations.9,10
Drug Characteristics
Two first-generation antipsychotics (fluphenazine and haloperidol) and four second-generation antipsychotics (risperidone, paliperidone, aripiprazole, and olanzapine) are available in LAI form in the U.S. (TABLE 2). Different formulations with the same active drug molecule are also available. Each LAI formulation has unique pharmacokinetics, and the formulations differ based on dosage strengths, dosing interval, oral-supplementation requirements, injection site, needle size, storage, and reconstitution requirements. These practical differences should be discussed with patients as part of selecting the most appropriate LAI antipsychotic. Owing to the complexity of care, all LAI antipsychotics must be administered by a healthcare provider. Clinic infrastructure to support the administration of LAI antipsychotics should also be considered.3
Formulation
LAI antipsychotics utilize different designs to achieve drug depot and extended release from the injection site. The first-generation LAIs are formulated in an oil-based vehicle that slowly releases the decanoate ester into the systemic circulation. Second-generation LAIs are water-based and use low-solubility esters and salt forms (olanzapine, paliperidone), prodrug forms (aripiprazole lauroxil), and polymer and microsphere depot technology (risperidone) to achieve extended release. Once ester, salt, or prodrug forms of LAI antipsychotics are released into the systemic circulation, they are converted to the active form via various mechanisms.9 Patients may prefer water-based LAIs because they may be less painful during administration.10
LAIs antipsychotics are generally available in fewer and different dosage strengths than oral formulations. Oral dosing concepts cannot be directly applied to LAIs because of pharmacokinetic differences, as described previously. Within LAIs, dosage strengths for products with the same active molecule should be compared cautiously owing to the unique formulation and pharmacokinetics of each product. For example, monthly aripiprazole monohydrate is available in 300-mg and 400-mg dosage strengths, whereas aripiprazole lauroxil comes in strengths of 441 mg, 662 mg, 882 mg, and 1,064 mg. At first glance, the aripiprazole lauroxil dosages seem much higher, but this is because they are calculated based on the weight of the covalently bonded molecule rather than active drug.9,11,12 Both aripiprazole monohydrate 400 mg monthly and aripiprazole lauroxil 882 mg monthly are approximately equivalent to plasma concentrations achieved with oral aripiprazole 20 mg daily.11,12 Different serum concentrations are also achieved with these products; in pharmacokinetic studies, aripiprazole monohydrate attained higher serum concentrations than aripiprazole lauroxil across labeled dosing strategies.13
Initial Dosing
Patients should be established on and tolerate oral antipsychotics before they transition to an LAI formulation. Fluphenazine decanoate can be initiated at 12.5 mg to 25 mg.14 Haloperidol decanoate can be initiated at 10 to 20 times the previous daily oral dose, with a maximum dose of 100 mg.15 Oral-to-LAI dosing conversions are provided in the labeling for second-generation LAI antipsychotics or have been established in postmarketing pharmacokinetic studies.11,12,16-23 Notably, patients who are planning to start 3-month or 6-month paliperidone palmitate (Invega Trinza, Invega Hafyera) must first be established on and tolerate 1-month and 3-month paliperidone palmitate (Invega Sustenna, Invega Trinza), respectively.18,19 Other initial dosing considerations include patient comorbidities, pharmacogenomic results, concomitant medications, and renal function.13
In some cases, when a patient is starting an LAI antipsychotic, oral antipsychotics may need to be continued for a period of time owing to the extended time for the LAI to reach therapeutic or peak serum levels. First-generation and second-generation LAI antipsychotics, including the aripiprazole formulations (Abilify Maintena, Abilify Asimtufii, Aristada) and two risperidone formulations (Risperdal Consta, Rykindo), require oral supplementation ranging from 7 to 21 days.11,12,16,24,25 IM-injection loading doses are sometimes used in lieu of oral supplementation (Aristada, Invega Sustenna).12,17 Newer LAI antipsychotics have been able to overcome the need for supplementation by producing two absorption peaks, the first of which occurs within hours of injection (Perseris, Uzedy).20,21
Dosing Interval
The interval between LAI doses may be an important consideration for patients. Current LAI antipsychotics offer a wide range of dosing intervals, from every 2 weeks to every 6 months. Multiple equivalent doses or dosing intervals of aripiprazole lauroxil, olanzapine pamoate, and risperidone polymer (Uzedy) formulations have been studied. Dosing intervals of these formulations can be tailored further based on patient response or preference.12,21,22 Paliperidone palmitate (Invega Hafyera), which has the longest interval of currently available LAIs, may be given IM as 1,092-mg or 1,560-mg doses every 6 months.19 Owing to their extended half-lives and time to steady state, LAIs with longer dosing intervals take longer to reach their full effect when dose adjustments are made. Longer intervals offer more convenience but may prolong adverse effects, should they occur.9
Missed Doses
The labeling of most second-generation LAI antipsychotics provides guidance for missed doses. The missed dose should be administered as soon as possible, and patients may require oral or IM supplementation or may need to restart the initiation regimen, depending on the time elapsed since the last scheduled dose and last dosage strength given.11,12,16-22,24,25 In some cases, to avoid missed doses, LAI antipsychotic products may specify a dosing window for the original scheduled dose to be administered. For example, 6-month paliperidone palmitate (Invega Hafyera) may be administered up to 2 weeks before and 3 weeks following the scheduled 6-month dose.19 Aripiprazole monohydrate (Abilify Asimtufii) may be administered up to 2 weeks before or after the scheduled 2-month dose.16
Administration
All LAI antipsychotics must be administered by a healthcare provider trained in their use. Most LAI antipsychotics may be administered IM at the deltoid or dorsogluteal site.11,12,14,17,18,24 Some LAI antipsychotics that have a larger drug size or injection volume may be administered only at the dorsogluteal site (Rykindo, Invega Hafyera, Zyprexa Relprevv, Abilify Asimtufii, haloperidol decanoate).15,16,19,22,25 Risperidone polymer formulations (Perseris, Uzedy) are given by SC injection in the abdomen or the back of the arm.20,21 To limit drug leakage, it is recommended that the Z-track technique be utilized for administration of fluphenazine and haloperidol decanoate.26
The appropriate needle size should be used in order to reach the proper depth for injection and achieve the desired pharmacokinetics. Smaller-gauge (21G-22G) and longer-length (1.5-inch or 2-inch) needles may be needed for IM injection in obese patients.11,16,18,19 Second-generation LAI antipsychotic vial or syringe kits come with needles specifically to be used for administration; for example, the 3-month and 6-month paliperidone palmitate (Invega Trinza, Invega Hafyera) syringe kits come with specially designed thin-wall needles. Using other needles may cause drug blockage.18,19 The labeling for olanzapine pamoate (Zyprexa Relprevv) recommends aspiration to ensure that the needle was not accidentally inserted into a blood vessel.22
Monitoring
Postinjection monitoring is required only in the labeling for olanzapine pamoate (Zyprexa Relprevv) owing to the risk of postinjection delirum/sedation syndrome (PDSS). Risk Evaluation and Mitigation Strategy program requirements also apply.22 PDSS symptoms are consistent with olanzapine overdose symptoms and may occur when the drug is inadvertently injected into a blood vessel instead of muscle. The salt form of olanzapine dissolves quickly when it contacts blood or plasma, leading to symptoms including sedation, confusion, slurred speech, and altered consciousness. PDSS occurs in approximately 0.07% of olanzapine injections.3 Patients must be monitored for 3 hours at a healthcare facility and must be accompanied when leaving the facility.22
Storage and Preparation
Storage requirements and the complexity of dose preparation vary among LAI antipsychotics. First-generation LAI antipsychotics are available as vials or ampules; second-generation LAI antipsychotics are available as either syringe or vial kits. Most of them may be stored at room temperature, except for risperidone formulations.20,21,24,25 LAI antipsychotics may require reconstitution or vigorous shaking to homogenize the suspension.11,12,16-22,24,25 Institutions and healthcare providers administering LAI antipsychotics should be aware of the storage and preparation requirements for each product.
Medication Errors
Medication errors may occur with LAI antipsychotics because of their complexity and the numerous available formulations, dosage strengths, dosing intervals, dosing adjustments, and administration requirements. In August 2023, the Institute for Safe Medication Practices published an article highlighting commonly reported medication errors associated with LAI antipsychotics.27 Patients with mental health illnesses frequently transfer between inpatient and outpatient care facilities. Inadequate medication reconciliation and communication between facilities has led to missed doses, unnecessary doses, and confusion between formulations of the same active ingredient. Within facilities, ordering one-time doses of LAIs instead of continuous therapy has also resulted in errors because of the difficulty of tracking one-time orders over long periods of time. Further, reported administration errors included using the wrong injection site, using the incorrect needle size, and injecting via the wrong route.27 Pharmacists and prescribers should understand the nuances and risks associated with LAI antipsychotic therapy.
The Pharmacist’s Role
Pharmacists have the opportunity to play an important role in mental health services through LAI antipsychotic administration and care coordination. Although LAI antipsychotics are an effective treatment for schizophrenia and other serious mental health disorders, they remain underused partly because of costs, lack of infrastructure for their administration, and the complexity of care.28,29 As of 2016, at least 40 states allow pharmacists to administer injectable medications other than immunizations. In at least 28 states, pharmacists may broadly administer medications with no collaborative practice agreement.30 Pharmacists integrated into collaborative drug therapy management clinics for LAI antipsychotics have demonstrated improved care coordination, reduced hospitalizations, and institutional cost savings associated with pharmacist-driven services.31
Pharmacists can also make an impact in the community setting. In one study, patients who received an LAI antipsychotic at an alternative injection center—usually a community pharmacy—and remained in the program for at least 6 months were more than eight times more likely to achieve adherence than those not using the service.32 In a retrospective study of an LAI antipsychotic service at a supermarket-chain community pharmacy, 78% of enrolled patients achieved at least 80% adherence.33 Further documentation of pharmacists’ impact on clinical and economic outcomes of LAI antipsychotic treatment will be important as pharmacist services expand in this area.
Conclusion
Nonadherence is a key barrier for patients with schizophrenia and schizoaffective disorder. Compared with oral antipsychotics, LAI antipsychotics can help patients improve adherence and reduce the risk of hospitalization and relapse. With technological advancements, more complex LAI antipsychotics have been developed in recent years. Mental health providers and pharmacists should understand the nuances in the different formulations’ pharmacokinetics, initial dosing, dosing interval, missed doses, administration, storage, and preparation so that they can effectively guide patients in treatment selection and prevent medication errors. Pharmacists also have an opportunity to impact patient care by providing LAI antipsychotic administration and care-coordination services.
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