Safe Use of Long-acting Antipsychotic Injections

Inadequate adherence to antipsychotic therapies is one of the main barriers to optimal symptom control in schizophrenia. Discontinuation of antipsychotics is associated with an increased risk of disease relapse, hospitalisation, suicide, and reduced social functioning. While reported adherence for oral antipsychotics varies widely depending on the study and method used, adherence rates are consistently low for people with schizophrenia.

Factors associated with a higher rate of discontinuation include:

• Male gender
• Early phases of disease
• Poor education
• Intellectual disability
• Unemployment
• Low insight into disease
• More severe negative symptoms
• High number of previous psychiatric hospital admissions

Long-acting injectable (LAI) antipsychotics play an important role in the management of psychiatric disorders. They are most useful for improving compliance in patients who forget to take their doses or who have poor insight into their condition.

Other factors that may favour the use of LAI include:

• Where early warning of non-adherence is vital (e.g. patients who experience severe consequences when stopping antipsychotics, such as violence, self-harm, loss of employment/housing, etc.);
• Patients who respond well to a specific oral antipsychotic but have dose-dependent side effects. The more consistent blood levels provided by an LAI may be beneficial by avoiding the higher daily peaks often seen with oral therapy;
• Patients with poor or unpredictable absorption with oral therapies; and
• Patient preference. Some patients may prefer LAIs rather than taking oral medication each day.

While LAI antipsychotics can improve patient outcomes, they are high-risk medications that are prone to errors.

General considerations

Long-acting antipsychotics are administered intramuscularly (IM) and release the active ingredient slowly over time. This provides sustained therapeutic blood levels.

Ideally, the patient should be stabilised on an oral formulation of the same antipsychotic before an LAI is used. This is important to ensure the patient tolerates the medication before a long-acting form is used. However, this may not always be possible. For example, flupentixol is available as an LAI but has no oral formulation.

In addition, many orally administered antipsychotics do not have a LAI formulation. For patients taking one of these agents, it is recommended that they be switched to an oral agent that is available as an LAI and stabilised on that prior to initiation of the injectable form.

Table 1 shows the various antipsychotic formulations available.

Table 1. Antipsychotic formulations available (adapted from AMH)

Adverse effects associated with LAIs are typically similar to the corresponding oral agent. However, there may be some differences.

Injection site reactions such as pain, redness, swelling, or induration are unique to the injectable formulations. Older antipsychotics (e.g. flupentixol, haloperidol, zuclopenthixol) are formulated in oily vehicles which may result in a higher incidence of injection site reactions. Frequent large volume administration of these oily injections may also be associated with the development of muscle fibrosis and granulomas.

For all LAI antipsychotics, the injection site should be rotated to mininise injection site reactions. In all cases, care must be taken to avoid inadvertent intravenous administration.

As shown in Table 1, there are many antipsychotics formulations available. The presence of such a large range of products, some with similar names, increases the potential for medication selection errors. Therefore, great care is required when selecting and administering these products.

The following provides a summary of the LAI antipsychotics available.

Long-acting formulations

Aripiprazole

Aripiprazole has two modified-release injectable products:

• Abilify Maintena^® (monthly)
• Abilify Asimtufii^® (every two months).

Flupentixol

Flupentixol is available in two LAI formulations:

• Fluanxol Depot^® – 20 mg/mL
• Fluanxol Concentrated Depot^® – 100 mg/mL

The concentrated depot is preferred where volumes greater than 2-3mL of the lower strength product are required or where the patient complains of discomfort from a large injection volume.

Haloperidol

There are two brands of injectable haloperidol:

• Serenace^® (short-acting)
• Haldol^® (long-acting).

The haloperidol present in Haldol^® is the long-acting form, haloperidol decanoate. When given IM, haloperidol decanoate is hydrolysed by esterases in the blood and tissues to slowly release haloperidol into the systemic circulation. Plasma levels rise slowly, typically peaking 3-9 days after injection, with an apparent half-life of around 3 weeks. Steady state plasma levels are achieved in 2-4 months when given monthly.

Olanzapine

Olanzapine is available in two injectable forms:

• Zyprexa IM^® (short-acting)
• Zyprexa Relprevv^® (long-acting).

Zyprexa Relprevv^® contains olanzapine pamoate monohydrate, a crystalline salt that is insoluble in water and has very low solubility in muscle. When injected into the gluteal muscle, the salt slowly dissolves to allow a sustained release of olanzapine into the bloodstream over the dosing period. Following administration, plasma levels typically peak within the first week.

Post-injection syndrome has been reported to occur in 1.85% of patients. This syndrome most commonly presents with symptoms of sedation or delirium and can appear similar to alcohol intoxication. Other symptoms may also occur such as extrapyramidal symptoms, aggression, hypertension, or convulsions. This typically occurs within an hour of injection, although rare cases have occurred two hours or more after the injection. Full recovery was reported within 24-72 hours after injection in all cases. However, the potential for post-injection syndrome does necessitate additional monitoring. Following each injection of Zyprexa Relprevv, patients should be observed for at least two hours and actively monitored for alertness every 30 minutes. Patients should be educated about this potential effect and advised to abstain from activities that may be dangerous (e.g. operating machinery) the day after injection.

Paliperidone

There are three LAI forms of paliperidone, each with a different dosing interval:

• Invega Sustenna^® (monthly)
• Invega Trinza^® (3-monthly)
• Invega Hafyera^® (6-monthly)

These three LAI formulations all contain paliperidone palmitate. The palmitate salt has extremely low water solubility which allows for the extended dosing period. Following IM injection, paliperidone palmitate dissolves slowly before being hydrolysed to paliperidone and absorbed into the systemic circulation.

Paliperidone is the major active metabolite of risperidone. Tolerability should be established with oral paliperidone or oral risperidone prior to initiating a LAI form of paliperidone.

Risperidone

There are two LAI forms of risperidone:

• Risperdal Consta^® (every 2 weeks)
• Risvan^® (every 4 weeks)

Zuclopenthixol

Zuclopenthixol is available in two injectable formulations:

• Clopixol Acuphase^®
• Clopixol Depot^®

These products are not interchangeable. Clopixol Acuphase contains the acetate ester which is slowly released from the oil and then rapidly hydrolysed to zuclopenthixol. Maximum serum levels are reached within around 24-36 hours. Conversely, Clopixol Depot contains the decanoate ester which provides a slower release of zuclopenthixol from the oil depot. Maximum serum levels are reached within 3-7 days.

Clopixol Acuphase is only intended for short-term treatment (up to two weeks). The manufacturer recommends that the maximum accumulated dosage in a course should not exceed 400 mg, and the total number of injections should not exceed four. This is considered an intermediate-acting product and dose intervals are usually two to three days, although an additional injection may be required 24-48 hours after the first injection. One or two injections is usually sufficient to reduce symptoms prior to initiation of zuclopenthixol maintenance treatment (oral or depot).

Clopixol Depot is the LAI form of zuclopenthixol and is administered at intervals of two to four weeks. This product is intended for maintenance therapy.

Incorrect use of the intermediate-acting Clopixol Acuphase instead of the long-acting Clopixol Depot can result in severe adverse effects as the active ingredient is released much faster.

Medication errors

While LAI antipsychotics have demonstrated improvements in adherence and may improve clinical outcomes, they are not without their challenges.

Medication errors may occur with LAI antipsychotics for many reasons, including:

• Patients with mental health issues may transfer between facilities frequently
  • Inadequate medication reconciliation and communication between facilities can lead to missed or delayed doses, additional unnecessary doses, and confusion between formulations;
• Use of one-time orders instead of continuous orders may increase the risk of errors; and
• Availability of multiple formulations with different strengths, dosing intervals, and administration requirements
  • Many of these products fit the definition of look-alike sound-alike (LASA) medications.
  • For example, the name risperidone can be confused for paliperidone. It would also be very easy to confuse the brand names of Abilify, Abilify Maintena, and Abilify Asimtufii.
  • The outer packaging appears very similar for many of these LAI products.

The consequences of medication errors may be more significant for LAIs as their effects are long-lasting and administration via the incorrect route is associated with significant harm.

Strategies that may be considered to minimise selection errors include:

• Storage considerations
  • Physically separate look-alike products
  • Physically separate different strengths and formulations
  • Always keep medications in their original packaging
  • Do not store medication in a way that impairs recognition
• Verification
  • Query any order that seems ambiguous
  • Identify medicines by name and strength
  • Check appropriateness of therapy
• Minimise interruptions
• Report errors and near misses.

Summary

Long-acting injectable antipsychotics play an important role in the management of psychiatric conditions. They may improve compliance, particularly for patients who find it difficult to remember daily dosing.

There are many formulations available which may increase the risk of medication errors. Careful selection of products is required to ensure these medications are used safely and effectively.

The product information should be referred to as each product has unique instructions. For most LAI antipsychotics, the deltoid or gluteal sites are used (ventrogluteal site typically preferred for gluteal administration). A summary of LAI antipsychotics is shown in Table 2.

Table 2. Summary of LAI antipsychotic administration