Comparing Leuprolide Formulations in Advanced Prostate Cancer

Melanie McGilloway, NP-C, an advanced practice provider at Genesis Urology in San Diego, discusses the various formulations of leuprolide, a gonadotropin-releasing hormone (GnRH) agonist used for treating advanced prostate cancer, during her conversation with Urology Times®. There are two categories, leuprolide acetate and leuprolide mesylate. The former has both intramuscular (IM) and subcutaneous versions, each with different dosing durations and storage requirements. Leuprolide mesylate is notable for its prefilled, pre-mixed syringe format, which needs refrigeration but is simpler to administer and has a longer post-mixing shelf life, attributed to its methylated salt composition. When deciding on which leuprolide to use, McGilloway considers clinical factors, such as patient adherence, and non-clinical ones, like reimbursement. Patients chosen for leuprolide treatments typically have advanced but non-metastatic prostate cancer, avoiding those with metastatic disease due to an initial surge in testosterone levels post-administration.

Melanie McGilloway, NP-C: My name is Melanie McGilloway. I'm an advanced practice provider. I work at Genesis Urology in San Diego, and I've been in urology about 5 years with a subspecialty in prostate cancer. Today we are going to talk about clinical pearls with leuprolide.

UROLOGY TIMES®:Could you discuss the different leuprolide formulations and the dosing schedule and the storage for each formulation? Are there any benefits to a prefilled syringe?

Melanie McGilloway, NP-C: They're all GnRH agonists (gonadotropin-releasing hormone), more commonly referred to as leuprolides. In fact, there is one that is not technically leuprolide, and that is triptorelin. But it’s a GnRH agonist, so we're going to loop that 1 in as well.

As far as leuprolide acetate goes, there are 2 in this category. One is an IM [intramuscular] injection that comes in a prefilled syringe that's kept at room temperature. It is available in a 1-month, 3-month, 4 month, and 6-month dosing. The next one is a subcutaneous injection that comes in a prefilled refrigerated syringe that's also available in 3-month, 4-month and 6-month dosing. Another leuprolide which is a little different is known as leuprolide mesylate, and leuprolide mesylate is a prefilled, refrigerated, pre-mixed syringe that has to be taken out about 30 minutes prior to injection and it's only available on a 6-month dosing for now. The final one is the triptorelin. This is a pre-filled room temperature syringe available in 1-month, 3-month and 6-month injections.

So, when we talk about the leuprolides as a whole, we can appreciate that they are all prefilled syringes. However, it is important to note that only leuprolide mesylate is available as pre-filled and pre-mixed. It's administered within 30 minutes of reaching room temperature and is good for about 7 days after reaching room temperature.

Now, they all come in comprehensive packs with everything you need to administer the medication. However, each have a step-by-step process that can be challenging in a busy clinic or with new staff. For instance, one formulation of leuprolide acetate is a prefilled dual chamber syringe that needs to be administered immediately after mixing and discarded, if not used within 2 hours. The other is a part of a 2-syringe mixing system requiring reconstitution and agitation. After the medication has come to room temperature, it's administered immediately and needs to be discarded within 30 minutes, if not given. Triptorelin is a mixed set. It has a syringe, a vial, a mixing adapter, and the medication can be kept at room temperature, but it also needs to be administered within 2 minutes of mixing.

Leuprolide mesylate is a prefilled, pre-mixed syringe, which again, sets it apart because there's really no mess with mixing it. It's pretty easy, and you open up the package, put the needle on and it's ready to go. The reason it can be stored as a pre-filled and pre-mixed is because of the methylated salt which actually sets it apart from the acetate, which is less stable. Leuprolide mesylate is what I consider an “easy button.” That being said, it is only for patients who are going to be on long term ADT as it's a six-month injection. I do find that patients sometimes, especially when they're first getting started on their hormone ablation, they're a little hesitant to take an injection that they're stuck with for six months.

UROLOGY TIMES®:Could you talk about any differences in the administration of the formulations, if it's hard for the staff to administer, and if patients might experience any injection site reactions?

Melanie McGilloway, NP-C: As far as administering either of the leuprolides, they all sort of have their own nuances. For instance,leuprolide acetate comes in a powder. It has to be reconstituted with sterile water and is an IM injection. IM injections obviously have a little bit more risk involved. They're more painful for the patients. The other formulation of leuprolide acetate is a subcutaneous injection. However, not only does it have to be reconstituted, but it has to be agitated. It is a pretty large needle that's subcutaneous. It does form a small capsule underneath the subcutaneous skin, which patients, if they don't have a lot of subcutaneous tissue, they often are bothered by the little nodule underneath the skin. As far as far as triptorelin goes, that one actually has a syringe, a dilutant, and has a vial with a vial adapter. And really it has a pretty lengthy administration or setup, making it pretty cumbersome in a busy clinic. Leuprolide mesylate is already pre-filled, pre-mixed; it does have to be refrigerated, and both of these have to be administered at room temperature. So, you do have to plan ahead a little bit, but leuprolide mesylate, once it hits room temperature, is still good for 7 days; leuprolide acetate, once it's mixed, actually has to be discarded within 30 minutes.

Now, as far as injection site reactions, I see more injection site reactions with the subcutaneous injections, but you could really have an injection site reaction with any of these. The most common I see is just redness and pain. Once in a while there's some bleeding if you hit the capillary beds in such a way. Leuprolide acetate is an IM injection, as is triptorelin. So, these 2 I typically don't see as many injection site reactions, but you certainly are at higher risk with a more vigorous blood supply, not to mention a lot of nerve pathways in the dorsal gluteal.

UROLOGY TIMES®:Could you comment on the salt isomers of leuprolide, the difference between mesylate and acetate and the attributes of each, and how that might impact patient outcomes?

Melanie McGilloway, NP-C: The difference between the two leuprolides, leuprolide acetate and leuprolide mesylate, is the salt isomer with which it is made. And for years the leuprolide acetate was certainly efficient and safe, but it also has not as great of a shelf life. So, the other, leuprolide mesylate, is a bit more stable. When we talk about our patients, they may not have a big difference in their clinical outcome, but on the back side in office, we know that things don't always go according to plan. Sometimes patients come in for a leuprolide acetate injection, but they’re having flu like symptoms, they've been around people with COVID, and we decided to not give the injection for safety reasons. But if the medication was already pre-filled, now the office is financially responsible for that. That's the biggest difference when we talk about the salt isomers, not how it affects the patient or their tolerability as they're both very tolerable, very safe, and they've been proven effective. But it's more about the convenience and that could be on the backside really for the office to feel comfortable knowing that we can make the right decision for the patient without having to worry about the financial impact on the on the company.

UROLOGY TIMES®:Can you speak to the efficacy data for leuprolide mesylate and leuprolide acetate?

Melanie McGilloway, NP-C: Going back to the fact that these two both are leuprolides, it's really just the salt isomer that sets them apart. All of these leuprolides have been around since the 1940s. They have proven efficacious, and their safety and tolerability are well established. The data is there for testosterone, castration, and super castration. The difference sometimes is that if you're mixing drugs, some of that medication can be left behind if it's not mixed appropriately. And so, the leuprolide mesylate really is the one that there's really not a thought process. There is no -- well, I wouldn't say no -- but there is little to no room for error. I'm sure most of us can agree that there's been a lot of staffing shortages, particularly with medical assistance. So, if you have a very busy clinic, a new medical assistant opens up an administration kit with 3 or 4 items in there and they're unsure of exactly how to mix it appropriately, there is room for error there, and that is where the patients will suffer. We've seen testosterone breakthroughs that are attributed to a dose reduction from the medical assistance being not trained well.

UROLOGY TIMES®:Could you talk about your specific experience with people leuprolide acetate and leuprolide mesylate? What clinical and non-clinical factors do you consider when choosing them? In which patients do you typically use leuprolide?

Melanie McGilloway, NP-C: When I'm trying to decide as to which leuprolide to choose for the patient, clinical factors include their adherence. If somebody has been known to be lost to follow-up on occasion, that I'm certainly going to go with any of the options that offer a longer interval dosing. But otherwise, the non-clinical factor is really the reimbursement side of things. Medicine, unfortunately, is a business and we do have to think about that. I don't ever choose 1 or the other based on price alone. But if the price is similar, then I typically will go with whichever medication is going to be more financially lucrative for the company. Now, as far as the patients that I use for leuprolide, these are any patients with advanced prostate cancer. But that being said, I'm certainly not using any leuprolide on patients who already have metastatic disease because GnRH agonists cause a transient increase in serum levels of testosterone within the first week. So, if they've got mets or micro mets, this is essentially providing a last supper for the cancer. So, the patients that I use leuprolide on have advanced prostate cancer, but non-metastatic cancer for sure.