Safety Issues with Long-Acting Injectable (LAI) Antipsychotics

Problem: Fourteen long-acting injectable (LAI) antipsychotic products are currently approved for use in the United States (Table 1). These products include seven active ingredients in various formulations and require different doses, injection intervals, titration schedules, and administration sites. Unlike oral antipsychotics that require one or more daily doses, LAI antipsychotics with longer dosing intervals can be a convenient option to help patients with schizophrenia maintain adherence to their treatment regimens and reduce relapses. However, despite guidelines that recommend early initiation of LAI antipsychotics for schizophrenia, lack of practitioner familiarity with LAI antipsychotics can often be a barrier for them to be initiated in the acute care setting. When they are used, LAI antipsychotic-related errors have occurred due to transitions of care handoffs and the product-specific nuances described below.

Table 1. Long-acting intramuscular (IM) and subcutaneous (SUBQ) antipsychotic injectable products

^{Content adapted from Lexicomp monographs.}

^{* Experts recommend administering in the gluteal muscle by deep IM injection; however, researchers have studied deltoid injection.}

^{† Z-track injection techniques are recommended to limit leakage of medication into the subcutaneous tissue.}

Medication Reconciliation Issues

It is common in many communities for patients/residents needing mental health services to transfer between home/outpatient care and acute or chronic residential care locations, resulting in different prescribers managing medication therapies. Prescribers may need to order multiple LAI antipsychotic formulations and doses for distinct phases of therapy (e.g., initiation, maintenance, subsequent initiation after missing maintenance doses). Based on product labeling, practitioners also prescribe different injection intervals (e.g., every 2, 4, or 8 weeks; every 3 months; every 6 months). Practitioners may document these medication orders in their respective paper medical records or nonintegrated electronic health records (EHRs), making record keeping for prescribed, dispensed, and administered doses a significant safety challenge. Also, initiation of LAI antipsychotics often requires patient tolerance to a corresponding oral formulation first. In fact, some regimens require an initial overlap of therapy after the first injection or require restarting concomitant oral therapy after long gaps in treatment. These variables can lead to patients receiving incorrect formulations or doses at inappropriate times.

A patient had missed several intramuscular (IM) maintenance doses of monthly INVEGA SUSTENNA (paliperidone). The prescriber ordered an initial one-time dose but was unaware that the recommended schedule for managing missed doses includes a booster dose to “re-load” the patient. Another practitioner discovered the discrepancy and prescribed the booster.

A patient transitioning from outpatient treatment to an acute residential facility received duplicate LAI doses in a single week. The acute care staff did not have information about the patient’s LAI antipsychotic as a result of inadequate medication reconciliation and paper medical records.

A prescriber ordered an IM dose of ABILIFY MAINTENA (ARIPiprazole, monthly) for a patient who had not received their LAI antipsychotic in the past year. During medication reconciliation, the prescriber did not verify the current medication list with the patient and did not know the patient was no longer taking an oral antipsychotic at home. The prescriber ordered the LAI antipsychotic dose without restarting the recommended concomitant oral therapy overlap or reassessing oral tolerance.

A patient’s medication history from an outside facility had documentation that the patient was taking 400 mg of Abilify Maintena (ARIPiprazole, monthly) IM monthly. When a pharmacist was reviewing the patient’s medication history, the patient said they were instead receiving ARISTADA (ARIPiprazole lauroxil) 1,064 mg IM every 2 months, and were 4 months past due on their dose. The pharmacist notified the prescriber of the discrepancy. Since the prescriber was not familiar with LAI antipsychotics, oral ARIPiprazole was ordered for inpatient therapy until the patient could be reevaluated by a comprehensive mental health services team.

Formulation Confusion

Some of the LAI antipsychotics (e.g., haloperidol decanoate) have corresponding short-acting injectable formulations (e.g., haloperidol lactate) that may contribute to a practitioner selecting an incorrect formulation. Other LAI antipsychotics are available in different formulations given at different intervals (e.g., ARIPiprazole, monthly; ARIPiprazole, every 2 months), which can lead to mix-ups as well.

A patient was admitted to an acute care hospital for treatment of coronavirus disease 2019 (COVID-19) infection. Since the patient had schizoaffective disorder, the admitting physician consulted a psychiatrist who recommended haloperidol 10 mg IM every 6 hours as needed. However, instead of the short-acting haloperidol lactate, a hospitalist inadvertently ordered haloperidol decanoate 50 mg every 6 hours as needed. The patient received three doses of the LAI antipsychotic formulation before another prescriber discovered the error. During event investigation, the medication safety pharmacist ran a report to capture haloperidol orders prescribed in the last year, which revealed that similar formulation mix-ups had occurred previously.

Overdoses with Multiple-Dose Vials

Most second-generation LAI antipsychotics, also known as atypical antipsychotics, work differently from first-generation antipsychotics and are provided in kits as exact doses. However, the first-generation products are available in multiple concentrations as single-dose (e.g., haloperidol decanoate 50 mg/mL, 100 mg/mL) and multiple-dose vials (e.g., haloperidol decanoate 500 mg/5 mL), or only as multiple-dose vials (e.g., fluPHENAZine decanoate 125 mg/5 mL). During preparation or administration, having multiple-dose vials can lead to overdose errors.

A prescriber ordered fluPHENAZine decanoate 25 mg/mL IM for a patient. The nurse, who was accustomed to administering full vials of other LAI antipsychotic single-dose formulations, administered the entire contents of a fluPHENAZine decanoate 125 mg/5 mL multiple-dose vial. When the overdose was discovered, the prescriber ordered diphenhydrAMINE 50 mg IM, and the patient was admitted for observation. No complications or adverse sequelae were identified.

Documentation and Communication Issues

Lack of documentation and communication during patient transfer between units or facilities can also lead to errors. This is especially true when prescribing LAI antipsychotics as one-time doses rather than continuous therapy with defined intervals (e.g., monthly).

A patient received a one-time IM dose of Abilify Maintena (ARIPiprazole, monthly) at a transferring facility. Since it was not a scheduled dose, the transfer documentation did not include the one-time order, nor was it communicated to the admitting facility. Unaware that the patient was receiving an LAI antipsychotic, the admitting prescriber ordered an alternative antipsychotic medication.

A prescriber ordered a one-time IM dose of RISPERDAL CONSTA (risperiDONE, 2-week) 50 mg for a patient who was later transferred to another unit before the dose was administered. The nurse documented the dose as “not given” in the EHR, thinking it would be administered when the patient was in the new unit. This resulted in an omission, as the dose fell off the medication administration record (MAR). During the patient’s transfer, the other scheduled medications were discussed. But this one-time dose was missed during the nurse handoff. When the patient showed increased psychosis, the prescriber discovered the omission error, and the LAI antipsychotic was administered. Due to the delay in treatment, the patient required an increased dose of oral risperiDONE.

Two nurses administered fluPHENAZine decanoate 50 mg IM on consecutive days after the first nurse experienced trouble scanning the barcode on the vial. The first nurse documented the dose administration in the progress notes but not in the MAR. The prescriber did not think that the nurse had administered the dose, so they reentered the order, which a pharmacist verified. The other nurse administered a second dose. Shortly after, the prescriber was contacted to evaluate the patient for tachycardia. At this time, the error was identified.

Duplicate Doses

Once a practitioner administers and documents a one-time dose in a patient’s MAR, if a prescriber orders an additional dose or another LAI antipsychotic too soon, EHR alerts often do not warn practitioners about the duplicate dose. Also, if a practitioner sets up their EHR setting to display a narrow timeframe (e.g., 48 hours), doses administered outside of this window are not even visible.

A prescriber ordered two one-time IM doses of RisperDAL Consta (risperiDONE, 2-week) 50 mg on consecutive days. A pharmacist verified and dispensed the first dose, which a nurse administered. The pharmacist verified the second dose, but prior to delivery, the pharmacist recognized the patient’s name from the previous day and identified the error. Though this LAI antipsychotic should be administered every 2 weeks, no alerts were generated to warn the prescriber or pharmacist of previously ordered and administered doses.

Difficult Dose Preparation

Manufacturers of second-generation LAI antipsychotics provide them as kits, with prefilled syringes, vials for reconstitution, separate diluent and powder syringes, or dual-chamber powder/fluid-filled syringes. The preparation instructions are often complex and time-consuming, requiring several types of preparation (e.g., shaking, tapping, flicking, reconstituting vials, combining liquid and powder syringes). In some cases, products are supplied with diluent syringes that are used as the final injection syringe, which may lead to inadvertent administration without reconstitution. 

Inappropriate Injection Site or Technique

Product labeling requires different doses to be injected in specific locations (e.g., only deltoid muscle for loading doses, deltoid or gluteal muscle for maintenance doses). Practitioners without knowledge about this can inject an LAI antipsychotic at the wrong injection site. Also, many of the LAI antipsychotics are provided with multiple IM needles intended for different sites (e.g., longer needles for gluteal injection) or patient characteristics (e.g., patients with obesity), and they may require different injection techniques (e.g., Z-track vs. standard), which may lead to administration errors.

Wrong Administration Route

The second-generation LAI antipsychotics are supplied in or with luer-lock syringes with separate IM or SUBQ needles, risking inadvertent administration via the intravenous (IV) route as an IV push. In addition, SUBQ doses risk administration by the IM route, or vice versa.

Safe Practice Recommendations: To promote patient safety with LAI antipsychotics, discuss their use in your organization and consider the following recommendations.

Reconcile medications. Patients’ lists of active medications may not include LAI antipsychotics. Since these agents are not administered daily and may be provided in outpatient/clinic and long-term care settings, it may be difficult to identify previous doses or administration dates. Add scripting to your medication reconciliation procedures that specifically ask patients about periodic injections, as patients inadvertently may omit these drugs when discussing their medication regimen. If the patient is not a dependable historian, ask family/caregivers or follow up with the patient’s primary care physician and/or their outpatient pharmacy.

Require last dose verification. Since LAI antipsychotics are intended for long-term maintenance therapy and not an emergent crisis, require practitioners to document when the last dose was administered before subsequent doses are ordered. Consider the use of short-acting oral/injectable agents if needed, until verifying this information.

Establish guidelines. Develop treatment guidelines and protocols that address both the initiation and continuation of these agents. Refer to guidelines such as The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia. Include recommendations for ensuring oral agent tolerance prior to LAI antipsychotic initiation, treatment overlap requirements, and monitoring parameters.

Create order sets. Build order sets to guide prescribers to select the appropriate doses, frequencies, and formulations. Automatically link products to the corresponding order sentences. If using one-time orders, ensure they are documented in the medication history and communicated during transitions of care. Check how long medication orders (e.g., one-time, administered, discontinued) remain visible on MARs and adjust timeframes if appropriate. Include the recommended administration site and technique information within the orders.

Restrict ordering. Restrict LAI antipsychotic ordering through an order set to prescribers who specialize in mental health or require that they be consulted prior to initiation or continuation of a patient’s outpatient regimen.

Differentiate formulations. Review naming conventions in your medication systems (e.g., EHR, automated dispensing cabinet [ADC]) for antipsychotics that are available in LAI and short-acting formulations. Review how the medication names appear in drug name searches and adjust if necessary (e.g., haloperidol decanoate may appear before haloperidol lactate if sorted alphabetically). Determine if it is feasible to include the generic name, brand name, and dose interval (e.g., paliperidone, 3-month [INVEGA TRINZA]; paliperidone, 6-month [INVEGA HAFYERA]) in the product description.

Dispense patient-specific doses. When possible, have the pharmacy prepare and dispense patient-specific doses of LAI antipsychotics, especially from multiple-dose vials (e.g., fluPHENAZine decanoate, haloperidol decanoate).

Employ barcoding. Use barcode scanning prior to dispensing and before administration.

Alert practitioners. EHR warnings should screen for antipsychotic agent therapeutic duplications and drug-drug interactions. Consider creating an alert to also warn practitioners of previously administered or discontinued LAI antipsychotic doses that may be outside of established order view timeframes.

Document and communicate. During handoffs, relay the last dose administered and confirm it is documented on the MAR. If an ordered LAI antipsychotic cannot be administered prior to transfer, educate nurses about the risk of documenting “not given” in the MAR. Explain that this action will remove the task from the MAR and could lead to omitting the dose. Consider running a report to identify one-time doses of LAI antipsychotics documented as “not given” and follow up appropriately.

Monitor patients. Ensure guidelines and order sets include LAI antipsychotic-specific patient monitoring. For example, a practitioner should directly observe patients receiving ZYPREXA RELPREVV (OLANZapine pamoate) injectable for a minimum of 3 hours after administration to monitor for signs of post-injection delirium/sedation syndrome, which is thought to be caused by inadvertent IV injection. This is characterized by the onset of sedation, confusion, ataxia, anxiety, and agitation, often within the first hour, and patients may become stuporous or comatose. Aspiration during injection for the appearance of blood is suggested to avoid inadvertent IV administration. If this occurs, care is supportive until symptoms resolve, typically within 24 hours. Because of this risk, Zyprexa Relprevv is available only through a Risk Evaluation and Mitigation Strategies (REMS) restricted distribution program called the Zyprexa Relprevv Patient Care Program, which requires prescriber, healthcare facility, patient, and pharmacy enrollment.

Educate patients. In addition to asking about LAI antipsychotics during the medication reconciliation process, educate patients and caregivers to proactively keep track of periodic medication injections and to share this information during transitions in care.

Educate practitioners. Educate practitioners who may handle LAI antipsychotics about the various formulations and guidelines. Ensure they understand the risk of harm associated with missed doses, duplicate doses, and wrong formulations, as well as the best workflow to reduce the risk of these error types. Review common adverse effects including extrapyramidal symptoms, tardive dyskinesia (especially with first-generation products), QT prolongation, neutropenia, akathisia, hyperprolactinemia, sedation, and metabolic effects (e.g., glucose dysregulation, hypertriglyceridemia, hypercholesterolemia, increased weight gain). LAI antipsychotics should never be administered to antipsychotic-naïve individuals, and the approval of new orders must include validation of the last dose administered and previous oral therapies.

Learn from errors. Review internally reported LAI antipsychotic-related errors as well as published external events, such as those described in this newsletter. Encourage staff to report close calls and actual errors that have occurred. Include a review of events from outpatient locations, focusing on errors that occur during transitions of care.

^{Suggested citation:}

^{Institute for Safe Medication Practices (ISMP). Safety issues with long-acting injectable (LAI) antipsychotics. ISMP Medication Safety Alert! Acute Care. 2023;28(16):1-6.}