The first and oldest method of formulating an LAI version of an oral antipsychotic was to dissolve the active drug in an oil to form a clear solution (known as a depot neuroleptic; Fig. 1A). Oil-based products can be stored in their final presentation and do not need mixing before use because the medication remains dissolved in the solution. However, drug-delivery technologies have evolved away from oil-based solutions and towards aqueous-based suspensions. Depending on drug solubility, two primary approaches are utilized for aqueous suspensions: powders for reconstitution and ready-to-use suspensions.
Active drug particles that have higher aqueous solubility than ready-to-use formulations or are less stable when exposed to an aqueous environment during storage can be formulated as powders for reconstitution. In addition, drug particles encapsulated in a biodegradable microsphere also require the addition of a liquid for reconstitution before administration (Fig. 1B). The properties of the microsphere determine the release rate into systemic circulation.
Ready-to-use suspensions take advantage of the low solubility of the drug to prevent the particles from dissolving. When mixed properly with a liquid, solid particles are uniformly distributed, and the suspension will appear cloudy or opaque (Fig. 1C). Following standing or storage, the solid particles will pack at the bottom of the container due to settling (Fig. 1D). Before injection, the drug particles will need to be resuspended by shaking. For these formulations, release into the systemic circulation following injection is dictated by the size of the drug particles.
There are several challenges during the development of LAIs that need to be overcome to create a successful formulation. A disadvantage of oil-based solutions is their viscosity, which makes them difficult to inject, and once injected, the oil may be irritating to surrounding tissues and cause injection-site pain.5–7 Therefore, practice has moved away from oil-based formulations to more commonly used aqueous suspensions.
Although aqueous suspensions may be easier to use than oil-based solutions, there are technical challenges that need to be considered. One challenge is that over time, the drug particles tend to settle to the bottom of the container into a dense mass, known as sediment. The sediment needs to be dispersed so that the active drug is uniformly distributed within the suspension before injection. Therefore, all aqueous LAI suspensions need to be mixed shortly before injection, but there are important differences in how this is performed.
Differences in LAI formulations affect specific instructions concerning how to resuspend drug particles. Variations in instructions include differences in tapping, shaking, and timing. The different instructions are not interchangeable among individual LAIs, and instructions for one LAI cannot be used for another.
Another challenge is to ensure that the drug particles in the aqueous suspension flow through the needle bore of the syringe. The injection needle is the narrowest part of the syringe that the LAI suspension flows through and is often the bottleneck. Needle clogs may happen when drug particles are not fully resuspended or when they clump in the needle during the injection procedure. An important aspect of the development of LAI suspensions is to lower the risk of needle clogs.
What Is Aripiprazole Lauroxil?
Aripiprazole lauroxil is an LAI atypical antipsychotic approved by the US Food and Drug Administration in 2015 for the treatment of patients with schizophrenia.8,9 The drug particles consist of aripiprazole lauroxil, a prodrug of aripiprazole, that following intramuscular injection is slowly released into the bloodstream and converted into aripiprazole.10
Aripiprazole lauroxil is supplied as a kit that contains a single-use prefilled syringe with the sterile aqueous suspension of the drug, along with a range of needles for administration.9 The injection volume is proportional to the dose, as detailed later in the article in the section on the “Injection Volume of Aripiprazole Lauroxil.”
Formulation Development of Aripiprazole Lauroxil
A novel approach in the formulation of aripiprazole lauroxil was to use inactive ingredients that promote loose association of drug particles and minimize sedimentation. The less dense the sediment, the easier it is to get solid particles into suspension. Figure 2 illustrates the differences in ease of resuspension for formulations that are designed to loosely associate versus those that do not. The settling of discrete particles leads to the formation of a densely packed sediment as opposed to the settling of loosely associated particles, which are not susceptible to dense packing due to their bulkiness.
Aripiprazole lauroxil has been developed so that the drug particles are loosely associated, with the formulation exhibiting a property known as shear-thinning. A formulation that is shear-thinning becomes less viscous when high force is applied via rapid injection. The reduction in viscosity is due to the loosely associated particles breaking up with rapid injection, allowing the suspension to flow through the needle as if it had the properties of a low viscosity fluid (eg, water or milk). In contrast, slow injection of aripiprazole lauroxil does not decrease the viscosity, and the suspension flows through the needle as if it had the properties of a high viscosity fluid (eg, oil).
As injection-site reactions are common adverse events seen with LAIs,11–13 the tolerability of aripiprazole lauroxil was studied during clinical trials, and the rate of injection-site reactions was low with rapid injection.8,14
Injection Volume of Aripiprazole Lauroxil
The volumes of aripiprazole lauroxil delivered by prefilled syringes are 1.6 mL (aripiprazole lauroxil, 441 mg), 2.4 mL (aripiprazole lauroxil, 662 mg), 3.2 mL (aripiprazole lauroxil, 882 mg), and 3.9 mL (aripiprazole lauroxil, 1064 mg).9,14 The formulation and design features of aripiprazole lauroxil allow for deltoid (441 mg) or gluteal (441, 662, 882, and 1064 mg) administration from a prefilled syringe, which provides a convenient option for practitioners.
Importance of Proper Resuspension and Rapid Injection Speed
Two of the most essential steps to mitigate the risk of needle clogs with aripiprazole lauroxil are resuspension by tapping and shaking and giving the injection rapidly (Fig. 3). Tapping in addition to shaking before administration disperses any clumps of material that may stick to the sides of the syringe barrel. Practitioners who have experience with using other atypical LAIs should be familiar with the tapping and shaking part of the procedure. However, the instructions for injecting rapidly may seem counterintuitive because other LAI instructions often recommend injecting slowly. Shaking with insufficient vigor and/or administering with a slow injection rate or hesitant manner can result in inadequately resuspended material and increased viscosity, thereby increasing the risk of a needle clog.
Steps in Aripiprazole Lauroxil Injection Administration
The following steps should be taken when administering aripiprazole lauroxil9:
- Resuspension of aripiprazole lauroxil drug particles into solution:
- ○ Tap the prefilled syringe at least 10 times to dislodge any settled material and shake vigorously for at least 30 seconds to ensure a uniform suspension (if the syringe is not used within 15 min, shake again for 30 s).
- Select the injection site and then select the appropriate needle length.
- Attach the injection needle securely with a clockwise twisting motion, being sure not to overtighten because this could cause the needle hub to crack.
- Holding syringe in an upright position, lightly tap to bring air bubbles to the top.
- Remove air by depressing the plunger rod (just enough to expel the air and allow a tiny drop of the suspension to appear at the tip of the needle).
- Holding the syringe at a 90-degree angle, insert the syringe rapidly up to the hub of the needle, with a dart-like motion.
- Inject rapidly to lower the viscosity of the suspension and decrease the risk of needle clogs.
- ○ Administer intramuscularly in a rapid and continuous manner, and without hesitation.
- Dispose of the needle safely by pressing the safety device and placing it in a sharps waste container.
RECENT ADVANCES IN PRACTICE
LAIs are often administered intramuscularly because muscle tissue is less prone to irritation than subcutaneous tissue.15 There are several factors to consider when determining the injection site, including the type of medication being injected, the volume of medication, and the patient’s age, condition, and preferences. The gluteal site is most commonly used for intramuscular injections because it can accommodate large volumes, while the deltoid muscle (Fig. 4A) is smaller and can generally accommodate lower volumes of fluid.15 The site used for intramuscular injection is one of the most important factors in minimizing complications and ensuring correct delivery of the medication.16 In general, many practitioners use the dorsogluteal site for intramuscular injections; however, current practice and literature recommend the ventrogluteal site because it is free of major nerves and blood vessels, has a larger muscle area, and allows for better uptake of medication (Fig. 4B).15,16 The practitioner administering a ventrogluteal injection must be familiar with the anatomic landmarks to determine this site, including the greater trochanter of the femur and the iliac crest. Unless there are extenuating circumstances, the injection sites should always be rotated.
The length of the needle is also an important factor in the administration of intramuscular antipsychotics and is determined by the weight of the patient and the site of the injection. Muscle mass, adipose tissue, and the patient’s body mass index should be taken into account. The needle needs to be of a sufficient length to pierce through subcutaneous fat and into the muscle layer. One-inch or 1.5-inch needles are recommended for deltoid injections, whereas 1.5-inch or 2-inch needles are recommended for gluteal injections. Longer needles should be used for patients with a large amount of subcutaneous tissue overlaying the injection site.
MANAGING PATIENT ANXIETY
It is important to consider that some patients may have concerns about receiving an LAI injection, particularly those who are initiating LAI treatment for the first time. A patient may be anxious about an LAI injection due to a fear of needles, issues with pain, concerns over modesty, or cultural attitudes.
Signs of anxiety include rapid breathing, agitation, sweating, tense muscles, nausea, and dizziness. It is important for the patient to remain as relaxed as possible. Tensing the muscle can make it difficult to depress the plunger, causing a delay in the injection and increasing the chances of a needle clog.
At the beginning of the procedure, the practitioner should engage the patient and assist in managing the patient’s anxiety. Time should be allocated for the patient to ask questions about the injection and be involved in the decision-making process. When at all possible, the patient should be allowed to choose the injection site. The practitioner should explain the rationale if unable to accommodate the patient’s request with regard to injection site. Some patients prefer to lie down, whereas others may feel more comfortable sitting. Patients should be allowed to position themselves, depending on the site of the injection and whether their chosen position impedes medication administration. In addition, the patient should be allowed to bring a support person if desired.
A patient may present with a severe fear of needles, have extreme anxiety about the potential pain caused by the needle stick, or both. It is also important to remember that there are sex differences around pain and intramuscular injections (eg women have higher mean pain scores than men).17 Manual pressure can reduce pain, by using the hand to apply 10 seconds of pressure to the injection site before performing the injection.18,19 Relaxation techniques, such as deep breathing exercises or mindfulness, can help ease patient anxiety. Progressive muscle relaxation can help prevent a vasovagal response (ie, fainting).20 If the patient is concerned about pain, topical anesthetics can be applied to the injection site.19 The practitioner should discuss the patient’s concerns about pain and possible techniques to help reduce pain in advance.
Patients may feel uncomfortable disrobing to receive the injection. Considering a patient’s culture and personal preferences and respecting his or her modesty will help to relieve some anxiety concerning the injection process. The patient should be advised to wear comfortable clothing that can be easily adjusted to allow access to the injection site. All efforts should be made to keep the patient covered and only expose the area necessary for the injection.
Utilizing best practices and being respectful of patient preferences can help to minimize the perception of pain. In addition, encouraging the patient to participate in health care decisions may help to develop the therapeutic relationship by building trust and also influence adherence to future injections.
Advances and variability in formulation technology provide several LAI antipsychotic treatment options for practitioners and patients, with a wide range of doses and dose intervals for the treatment of schizophrenia. The injection technique, including speed of injection, and specific steps involved in administering each LAI are unique and depend on the formulation and characteristics of the drug product. In other words, learning how to give an injection for one LAI will not mean that the same instructions will work for other LAIs.
Aripiprazole lauroxil is an example of a currently available LAI formulation that requires rapid injection, whereas some other LAIs require slow-speed injection. Therefore, practitioners should be knowledgeable about the differences in formulation design and best practices for the administration of the LAI being used to treat patients with schizophrenia. Special consideration should be given to nuances and practices related to administration technique as new LAIs are developed.
The authors acknowledge medical writing and editorial support for the preparation of this manuscript (under the guidance of the authors) by Mia Cahill (ApotheCom, UK).
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
long-acting injectable antipsychotic; formulation development; injection speed; aripiprazole lauroxil; schizophrenia