Learning objectives

1. 1. Identify common clinical challenges encountered when prescribing LAI antipsychotics.

2. 2. Discuss strategies for addressing adherence, dosing, and missed injections with LAIs.

3. 3. Evaluate approaches for managing adverse effects, drug interactions, and optimizing patient-centered outcomes.

Storage and reconstitution requirements

LAIs have a range of storage requirements (Table 1). Some formulations, such as certain risperidone products, require refrigeration to maintain stability. ^{12 , 13} In contrast, others, including paliperidone palmitate, ^{6 – 9} aripiprazole, ^{3 , 4} aripiprazole lauroxil, ^{1 , 2} olanzapine, ⁵ and different risperidone formulations, ^{10 , 11} require storage at controlled room temperature (15 °C–30 °C). Specific products may have allowances for short-term storage outside their primary recommended range. ^{12 , 13} Compliance with each product’s storage instructions is essential to maintain the drug’s stability and intended slow-release properties. These requirements are important not only for pharmacy and clinic storage but also for patients with planned travel that includes a prearranged injection site, as international travel may present additional concerns.Reference Halsey and Evans ¹⁴

Table 1. Storage and Reconstitution Requirements

Controlled room temperature is defined by the US Pharmacopeia (USP) to be thermostatically maintained between 20 °C and 25 °C (68 °F and 77 °F), with brief excursions from 15 °C to 30 °C (59 °F to 86 °F).

Some LAIs are formulated as lyophilized powders or liquids that require reconstitution prior to injection. ^{3 , 5 , 10 , 11 , 13} The reconstitution process often involves product-specific techniques, such as vigorous shaking or the use of vial adapters, to ensure proper suspension. For example, olanzapine LAI necessitates a specific diluent and technique, including wearing gloves to prevent skin contact and eye protection from potential aerosolization. ^{5 , 15} Conversely, many newer LAI formulations are available in prefilled syringes and do not require reconstitution. ^{1 – 4 , 6 – 9 , 12} The type and volume of the diluent and the mixing protocol are critical and differ between products. Using multiple LAIs that need reconstitution in a single clinic can lead to errors; therefore, the clinician should review the specific product’s instructions before each use. Incorrectly reconstituted medications must be discarded.

Injection site selection and technique

The appropriate injection site is an important aspect of LAI administration, as it can influence the rate of drug absorption.Reference Rossenu, Cleton and Hough ^{16 ,} Reference Raoufinia, Peters-Strickland and Nylander ¹⁷ Injection volume and patient preference are key considerations. Most LAIs are given intramuscularly (IM) in either the deltoid or gluteal muscle. Some formulations with smaller volumes are specified for subcutaneous (SC) injection.

Since deltoid has significantly greater blood flow per volume of muscle than gluteus, initiating paliperidone palmitate in deltoid provides therapeutic drug concentrations sooner. Some LAIs, like olanzapine (Relprevv), are given by gluteal injection only. Higher doses of aripiprazole lauroxil and the paliperidone palmitate 6-month formulation require the gluteal muscle due to their large injection volume. Recording and rotating the injection site is advised (Table 2).

Table 2. Injection Sites, Technique, and Initiation Regimen

Tolerability testing with the same oral medication for at least a few days is recommended to determine efficacy before using the LAI formulation. While aspiration to check for blood return before an IM injection is routinely recommended, it should be avoided with aripiprazole lauroxil products as this can clog the needle. ^{1 , 2} If an aripiprazole lauroxil needle clogs, it should be replaced, and the injection administered rapidly at a different site. Recommendations for needle gauge and length depend on the specific LAI, the injection site, and patient factors like body weight.

Oral overlap and initiation regimens

For several LAIs, an initial period of oral antipsychotic supplementation, or “oral overlap,” is required to ensure adequate therapeutic concentrations are maintained as the injectable medication is slowly released.Reference Correll, Kim and Sliva ¹⁸ Examples include risperidone, aripiprazole monohydrate, and aripiprazole lauroxil. Some risperidone LAIs do not need an oral overlap due to an early-release “double peak” property. ^{6 , 12} For most LAIs, the initiation of treatment involves loading doses to achieve therapeutic concentrations more rapidly. The aripiprazole-based formulations offer optional initiation methods that avoid the need for an oral overlap. ^{1 – 4} Proper adherence to these regimens is essential to bridge the interval until the LAI reaches therapeutic concentrations (Table 2).

Postinjection monitoring

The administration of olanzapine (Relprevv) carries a <0.1% risk of post-injection delirium/sedation syndrome (PDSS), necessitating a 3-hour observation period in a registered healthcare facility with ready access to emergency response services. ⁵ This monitoring allows for the detection of symptoms like excessive sedation or delirium due to rapid absorption. While PDSS is a unique risk to olanzapine (Relprevv), routine postinjection monitoring for acute adverse effects and injection site reactions is important for all LAIs.

Management of missed doses

Maintaining a consistent schedule for LAI injections is critical, and missed appointments are a common issue. A good clinician–patient relationship is foundational to avoiding missed doses. Proactive strategies can lessen patient barriers and improve adherence. These include implementing reminder systems (phone calls, text messages), involving family or caregivers, and helping with transportation. For LAIs with long intervals between doses, reminders become even more important. Scheduling the next appointment immediately after the current one and providing a reminder card can improve follow-through. Proactive scheduling around holidays and vacations reinforces the importance of timely injections. Having a clear policy for managing missed appointments and promptly following up with patients is essential.Reference Velligan, Weiden and Sajatovic ¹⁹

Rescheduling and managing delayed injections

When patients miss scheduled injections, a plan should be available to explain to the patient. Recommendations for managing missed doses vary depending on the LAI and the interval since the last injection (Table 3). Many products have a dosing window, allowing the injection to be given before or after the scheduled date. To manage a missed dose, clinicians need to know the time since the last dose, the specific product, and the dose. The appropriate action may involve administering the next injection as soon as possible, sometimes with supplemental oral antipsychotics. For certain LAIs, like paliperidone palmitate, specific re-initiation guidelines exist based on the interval since the last dose. ^{7 – 9} Similarly, aripiprazole LAIs have distinct recommendations. Using pharmacy or medical records to determine the product, dose, and date of the last injection will ensure the correct catch-up protocol is used.

Table 3. Management of Missed Doses for Common LAIs

Table 4. Invega Trinza 4- to 9-month Missed Dose Reinitiation Regimen

Addressing insufficient duration of the effect

Some patients may experience symptoms returning before their next scheduled injection.Reference Correll, Kim and Sliva ^{18 ,} Reference Correll, Sliwa, Najarian and Saklad ²⁰ This can be due to several factors, including absorption rate, metabolism, dosing, and timing. The absorption rate is a function of the product formulation, dose, injection site, and needle size. Drug interactions and genetic polymorphisms can alter the elimination rate. In most cases, the reason for early loss of effect is too low a dose, too long an injection interval, or both.

Management of clinically significant drug interactions

Drug interactions with LAIs can lead to symptom breakthrough, increased adverse effects, or altered duration of action. These can occur through pharmacokinetic mechanisms (affecting absorption, distribution, metabolism, or excretion) or pharmacodynamic mechanisms (additive or antagonistic effects).Reference Correll, Kim and Sliva ¹⁸

Many antipsychotics are metabolized by cytochrome P450 (CYP) enzymes. CYP inhibitors can increase plasma concentrations, while CYP inducers can accelerate metabolism, leading to decreased concentrations and reduced efficacy. ² Some LAIs are also substrates of P-glycoprotein (P-gp) transporters.Reference Moons, de Roo, Claes and Dom ²¹ Clinically significant interactions include the reduction of aripiprazole and risperidone concentrations by carbamazepine and the increase in olanzapine concentrations by fluvoxamine.Reference Correll, Kim and Sliva ¹⁸ Pharmacodynamic interactions can also occur, such as the additive QTc prolonging effects with paliperidone. ⁷ A thorough review of the patient’s complete medication history, including prescription, over-the-counter, and supplemental products, is crucial. Drug interaction databases and pharmacist consultations can aid in management (Table 5).Reference Moons, de Roo, Claes and Dom ²¹

Table 5. Clinically Significant Drug Interactions with Common LAIs

Addressing recreational drug use

The co-occurrence of substance use disorders is common in patients receiving LAIs and can worsen the course of illness, impact adherence, and increase relapse risk. Recreational drugs can interact with LAIs, reducing their effectiveness or exacerbating symptoms.Reference Coles, Knezevic and George ²² For example, cannabis can worsen psychotic symptoms, while alcohol can amplify sedative effects. Regular, nonjudgmental assessment of substance use allows clinicians to monitor for interactions, manage symptom exacerbation, and tailor treatment strategies.Reference Coles, Knezevic and George ²²

Management of common adverse effects

Drug-induced Parkinsonism

Drug-induced Parkinsonism (DIP) is characterized by motor symptoms like tremor, rigidity, and bradykinesia.Reference Ali, Sisay and Tariku ²³ While less common with second-generation agents, it can still occur, particularly at higher doses. Management strategies include reducing the LAI dose, switching to an agent with a lower risk (eg, aripiprazole-based products), adding amantadine, or short-term use of an anticholinergic medication. Long-term anticholinergic use should be avoided due to adverse effects on cognition and an increased risk of tardive dyskinesia (Table 6).Reference Ogino, Miyamoto, Miyake and Yamiguchi ²⁴

Table 6. Management Strategies for Common Adverse Effects of LAIs

Addressing patient requests to return to oral antipsychotics

Patients may request to return to oral antipsychotics for various reasons, including a mistaken belief they are “cured,” discomfort with injections, a desire for more autonomy, or concerns about adverse effects. Understanding the patient’s reasoning through a collaborative discussion is the first step. The risks and benefits of switching should be reviewed, including the increased likelihood of symptom return. The decision on when to initiate the oral medication should consider the pharmacokinetic properties of the LAI. For many second-generation LAIs, the corresponding oral medication can be started around the time of the next scheduled injection. Close monitoring for symptom recurrence is essential during the transition.

Managing symptoms not effectively covered by an LAI

Patients on an LAI may still experience breakthrough symptoms. A systematic approach involves assessing for contributing factors like medical illness, substance use, or stressors. Optimizing nonpharmacological treatments and addressing co-occurring conditions is important. If the LAI is being administered correctly, adjusting the dose or frequency may be considered. For rapid relief, supplementation with a low dose of the corresponding immediate-release oral antipsychotic can be used.

Integrating an oral antipsychotic for added activity

While combining antipsychotics can be viewed as inappropriate polypharmacy, judiciously adding a second medication to target specific, inadequately controlled symptoms can be a best practice. For example, patients with bipolar depression may benefit from an added oral medication, as this is not effectively covered by any current LAI (Table 7).Reference Carvalho, Firth and Vieta ²⁸ In a patient with refractory schizophrenia on clozapine with adherence issues, an LAI can provide a safety net. A comprehensive treatment plan should also integrate nonpharmacological therapies.

Table 7. Medications Approved for Bipolar Disorder

Conclusion: Optimizing LAI treatment

Successful maintenance of LAI treatment requires a comprehensive, proactive approach. This begins with a collaborative treatment plan, careful attention to preparation and administration, and effective strategies to enhance adherence. Clinicians must be prepared to manage insufficient duration of effect, potential drug interactions, and common adverse effects. Addressing patient preferences, including requests to return to oral medication, requires a non-judgmental, collaborative process. By managing these common issues, healthcare professionals can optimize LAI treatment, leading to improved clinical outcomes, enhanced quality of life, and a reduced risk of relapse for individuals living with serious mental illness.