Allergic to Zoladex (Goserelin)

Spoonie77

For those that know me on the boards, I've posted about my experience with Zoladex quite a bit on the thread: Starting/Declining Hormone Therapy (Nov, Dec, Jan 2018) so please forgive the duplicity and length, but I did want to create a thread specifically for this topic, for future members to find if/when needed.

I've been the rare unicorn in the medical world, accruing a majority of the odd, weird reactions, syndromes, etc over the years since the age of 13 as I've battled my various medical conditions. I've come to expect it but I sure hoped it would not continue on into the Cancer World but here I am: a patient who is allergic/hypersensitive to the ovarian suppression medication Zoladex (Goserelin). Very nearly unheard of, unicorn status achieved.

While rare, it can and does happen. (Chart: pg 3, occurring in 1-10% of patients)

There are 4 types of hypersensitivity to medications: Immediate, Cytotoxic, Immune Complex, and Delayed (T-Cell Mediated).

I fall into Type IV Delayed, as I was dxd with D.R.E.S.S. / Eosinophilia (elevated Eosinophils) after exposure to Zoladex. (FYI: D.R.E.S.S. is VERY different than the medical term Anaphylaxis, which is a life-threatening condition.)

"Drug Rash with Eosinophilia and Systemic Symptoms syndrome (DRESS) is a severe idiosyncratic drug reaction with a long latency period. It has been described using many terms; however, drug rash with eosinophilia and systemic symptoms syndrome appears to be the most appropriate. This syndrome causes a diverse array of clinical symptoms, anywhere from 2 to 8 weeks after initiating the offending drug."

It took over a month and a half to get my diagnosis. It was exhausting, physically and mentally.

I was given my first injection of Zoladex on 07/02, in my left hip/love handle.

These were my symptoms, in order of onset, beginning after 07/04:

Fever, Rash, Neck/Throat Swelling, Neck/Throat Pain, Itchiness/Redness, Nausea, and Trouble Swallowing. These began appearing about a week AFTER the injection. Of note, Zoladex releases extremely slowly during the first 8 days after the injection. (pg 19)

""Goserelin (Zoladex) is released from the depot at a much slower rate initially for the first 8 days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period."

(NOTE: I've included a mountain of drug info, half life info, ingredients, etc, plus my own Timeline and Photos at the end of this post that hopefully will be helpful to anyone else following this path.)

The main difficulty I ran into is that there just aren't any medical tests recommended for determining an allergic reaction to Zoladex. They cannot run a skin patch/prick test. They cannot run a lab/antibody test. There is nothing, tests just do not exist.

The only way to arrive at an allergy confirmation is to run down the differential diagnosis.

As my Allergist put it during my appt with him, since this happens so very rarely there's not a demand for testing to be developed.AKA Supply vs Demand. No demand, no test. Makes sense but sure makes the journey that much more difficult. UGGGH.

In fact, an allergic reaction happens so rarely my MO actually DENIED the possibility of an allergy outright to my face and instead blamed my immune system. To make matters worse, even though they were the ones that administered the Zoladex depot/injection to me, they refused to have anything to do with what I was experiencing and help solve the problem. There only "attempt" to help was to say "Go to Urgent Care or see your Primary. We can't help you with this.". At one point two weeks later, I asked for a referral to Immunology to help get to the bottom of this and they wouldn't even do that one thing for me. Helpful. NOT.

With my MO and her nurses leaving me alone, high and dry, I'm thankful I had a supportive team elsewhere to navigate through this nightmare. I'm not sure what would have happened without them by my side.

My Cancer Rehab/Breast Lymphedema Specialist ruled out Lymphedema as a cause of the new neck swelling.

My PCP ruled out Enlarged Lymph Nodes and Mono and other basic infections/viruses/causes through lab work and a Head/Neck Ultrasound. (Side note, the US found a pea sized mass on the right lobe of my Thyroid which now gets to be followed up on in 2 months in regards to a FNA or Biopsy. With a strong history of Thyroid Cancer in my family this is worrying. Another doctor, an Endocrinologist, to add to "Team Spoonie". Oh joy. SMH)

My PCP also prescribed 3 tablets Claritin 2 times daily along with Prednisone 20 MG Tabs 2 x daily to manage symptoms. The Claritin only controlled the itching to some extent, it did nothing for the neck/throat swelling. Prednisone, two different courses of 5 days, was the only thing that managed the symptoms involving my neck/throat. Swelling decreased rapidly within 24 hours of beginning the drug and vice versa increased rapidly within 48 hours of stopping the Prednisone.

I was referred to Immunology and they too ruled out any Immune System Disorders, especially of concern where Hereditary Angioedema and Aquired Angioedema. Thankfully I was negative for those and other abnormalities. (Labs were CH50, C1, C4, and C5 tests for immune deficiencies/abnormalities)

In the end, after 6 weeks spent jumping through various hoops, referrals, and undergoing multiple tests/imaging to eliminate all other causes, I was finally able to get to an Allergist that specifically understood what was going on and say that yes indeed I AM ALLERGIC to Zoladex (Goserilin).

Hallel-freakin-uljah!!!!!!!

Again, sorry for the length of the post but hopefully this will spare some other cancer patient some day. I truly would not want anyone else to under go what I went through to get these answers. It was weeks of physical pain, enduring unrelenting symptoms, trusting my gut, googling and researching, calling Astro Zeneca (drug manufacturer), and continuing to advocate for myself despite doctors telling me otherwise.

During this debacle, I talked to one of the makers of Zoladex (Astra Zeneca) asking about its half life. All they could tell me is, "[I]t leaves the system "rapidly" after the final dose." This would make the final dose the 28th day after implantation. However, I've found on the internet, according to the FDA that it takes at least 2 months for the depot (materials used to implant the Zoladex) to be degraded and reabsorbed into your body. Since there is no way to medically tell if it's the Zola or the materials ("totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose)") used to make the depot implant that I'm reacting to I have no way to know when my body will stop being symptomatic. More fun. At least I know there will be an end in sight at some point. IMO I believe it's the Zola since I've had medical sutures that biodegrade (which are made of the same materials as the depot) and have never had a reaction prior to now.

While talking to Astra Zeneca because I had informed them (AZen) of my side effects, they were required to open a case report. I had to give them my MO's name and phone number. I'm guessing they (my MO's staff) will not be happy with me but hey it was their legal responsibility (according to AZen) to report all negative, possibly allergic side effects such as this to AZen. I doubt they did since they denied this was an allergic reaction to my face multiple times.

Now that I know I cannot take Zoladex, I'm hesitant to even try an alternative, one of which is Lupron (Leuprolide). There are proven cases of patients, who having been allergic to one LHRH antagonist, were found to also be allergic to others as well. Sooooo, if I am not on a ovarian suppression medication, I can't take an Aromatase Inhibitor like Arimidex since I am pre-menopausal and have a history of 5 mg of Tamoxifen daily being intolerable due to SEs. My risk of Recurrence/METs is 28-35% according to my MO if I'm not on systemic therapy. My Allergist did suggest a "challenge" exposure to a medication chosen as an alternative to the Zoladex. I have to give this plenty of thought before agreeing to it, as there are high risks at stake. Re-exposure can be multiple times worse than the first exposure. Scary facts.

"DPT involves administering the drug using slow, incremental dose escalations at fixed time intervals and observing for the presence or absence of an objective reaction. It is not without risk to the patient and should be done only under the strict supervision of clinicians/nurses with allergy training and with resuscitative equipment available." (DPT: Drug Provocation Challenge Test)

He suggested if I do decide that I need to try another ovarian suppression med, I should be given 1:1000 of the full dose, wait a full half life of the med, if no reaction, proceed to 1:100 of full dose, wait again, if no reaction, proceed to full dose. However, since these are injectable "implant" meds, I'm not sure if there are oral versions or liquid injections available to try these lower doses. If not, there is likely no way I'm going to try it and then I'm left with.....do I do surgery to remove ovaries etc? Le Sigh. Heavy questions.

The journey ahead will definitely involve some ginormous decisions but I've made it this far so I know I will just continue to take it day by day, being the amazingly unique unicorn that I am.

That's all any of us can do, right? Indeed. Anyway, I am wishing everyone a completely allergy free experience with Zoladex. However, if you happen to a unicorn like me, feel free to PM or to post here to spread the word and share your experience.

Remember that knowledge is power so keep passing it along and NEVER EVER stop being your own best advocate.

Hugs and healing to all.

Spoonie

------- Drug Information, Timeline and Photos -------

Here is the timeline of my onset of symptoms if anyone is interested. This is why we have to be our own detectives. Seriously.

* According to FDA, "Goserelin (Zoladex) is released from the depot at a much slower rate initially for the first 8 days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period." and also "[chart] Time to peak concentration (days) FEMALE: 8-22 Days".

(This is shown by the green and the orange vertical sections on my timeline)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019726s050s051s052lbl.pdf

07/18: First day the seatbelt was like, "Yo, neck, you in my territory. Back the F up, k?!"

07/18: Rash First Appears (left side neck)

07/19: Rash Worsens. Left side with spreading redness down my neck towards clavicle

07/19: Rash Appears on Right side. Behind/under ear. Redness seen on Right swollen clavicle

07/24: Just me and my "lymphies" chilling

(normal for my compression bra a small indent on shoulders, no lumps, etc. obviously NOT the case here)

07/24: Continuing to enjoy The Rock neck. NOT.

07/31: The Rock neck can get bigger. Who knew?

08/02 and 08/03: Prednisone Day 1 and Day 2 (First Round)

08/05: Day 4 Prednisone

A side by side (left Prednisone, right 3 days prior) is just crazy to me....

08/10: 4 Days Past Prednisone (continued with 3 tabs Claritin 2 times daily)

08/13: Saw Primary. Do 3 days JUST Claritin. If no improvement, then restart Prednisone.

Photos:No PRED. Just Claritin 48 Hrs and 72 Hrs

Excerpt from Starting/Declining Hormone Therapy (Aug 21, 2019 03:34PM)

HELLLLLLLOOOOOO EVERYBODY!!!

I am in the BEST mood!!! Know why????

Welp, I finally have answers. Super duper answers and my MO can just suck it!!!!

LOL, sorry not sorry am just relieved to finally have an answer, even though it may not be the best for my cancer treatments going forward, but it IS AN ANSWER!

According to my Allergist am I am completely and totally ALLERGIC TO ZOLADEX!

Whoooopity doooo! I thought I was going to pass out from joy walking out of that appt, I tell ya what!

My labs corroborated the allergic reaction with the elevated Eosinophils, neck swelling, rash, and response to Prednisone. He is going to run follow-up testing after I'm off of the Pred for a week. Even if they are not elevated at this time, he is quite sure I am allergic and would DEFINITELY NOT FEEL COMFORTABLE with me ever having Zoladex, and most likely any other ovarian suppression medication.

I am walking on Cloud 9 - he was just an amazingly helpful doctor and told me "You have been through alot. Just breathe. We have time and I am listening." So much compassion. I was impressed.

Anyway, that is my GRRRRREAT update for the day! I'm all smiles.

Can't wait to send his report to my Oncologist and let them choke on it. Allergies happen, maybe not to many but they DO happen to a few, and I am one of them. Shame on them for the way they handled this and I expect they will be highly embarrassed (or should) be by how the treated me over the past month and a half."

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Zoladex Description

"Zoladex® (goserelin acetate implant) is a GnRH agonist. Goserelin acetate is chemically described as an acetate salt of [D-Ser(But)6, Azgly10]. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O14(C2H4O2)x where x = 1 to 2.4].

Goserelin acetate is an off-white powder with a molecular weight of 1269 Daltons (free base). It is freely soluble in glacial acetic acid. It is soluble in water, 0.1M hydrochloric acid, 0.1M sodium hydroxide, dimethylformamide and dimethyl sulfoxide. Goserelin acetate is practically insoluble in acetone, chloroform and ether.

Zoladex is supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin. Zoladex is designed for subcutaneous injection with continuous release over a 28-day period. Goserelin acetate is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose)[PLGA] containing less than 2.5% acetic acid and up to 12% goserelin-related substances and presented as a sterile, white to cream colored 1-mm diameter cylinder, preloaded in a special single use syringe with a 16-gauge x 36 +/- 0.5 mm siliconized needle with protective needle sleeve (SafeSystem™ Syringe) in a sealed, light- and moisture-proof, aluminum foil laminate pouch containing a desiccant capsule. Studies of the D,L-lactic and glycolic acids copolymer have indicated that it is completely biodegradable and has no demonstrable antigenic potential."

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Pharmacodynamics

"In females, a similar down-regulation of the pituitary gland by chronic exposure to Zoladex leads to suppression of gonadotropin secretion, a decrease in serum estradiol to levels consistent with the postmenopausal state, and would be expected to lead to a reduction of ovarian size and function, reduction in the size of the uterus and mammary gland, as well as a regression of sex hormone-responsive tumors, if present. Serum estradiol is suppressed to levels similar to those observed in postmenopausal women within 3 weeks following initial administration; however, after suppression was attained, isolated elevations of estradiol were seen in 10% of the patients enrolled in clinical trials. Serum LH and FSH are suppressed to follicular phase levels within four weeks after initial administration of drug and are usually maintained at that range with continued use of Zoladex. In 5% or less of women treated with Zoladex, FSH and LH levels may not be suppressed to follicular phase levels on day 28 post treatment with use of a single 3.6 mg depot injection. In certain individuals, suppression of any of these hormones to such levels may not be achieved with Zoladex. Estradiol, LH and FSH levels return to pretreatment values within 12 weeks following the last implant administration in all but rare cases."

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PLGA (depot ingredient of Zoladex) Info Below:

"PLGA (co-polymer material used to make the Depot for Zoladex) is one of the most common and important polymers for medical applications because of its long-term clinical use and suitable properties. Thus far, there are 11 types of commercially available PLGA produces (Summarized above in Table 1). They are formulated in different forms, including membranes (mesh), sponge, powers, gel, and suture with different LA/GA ratio.Their degradation time varies from a couple of weeks to 48 weeks. Some membranes products such as Vicryl and Resolut can remain integrity for at least 12 weeks, which meets the requirement for GTR or GBR."

"[located in Table 1] Zoladex and Lupron degradation time: 4 weeks. Zoladex: 'good biocompatability, nontoxicity in MOST tissues. Lupron: Minimal toxicity and minimal mechanical irration to the surrounding tissues.'." (my understanding is that this is the degradation time/half life for the DRUG itself, not for the ingredients that make up the depot for implantation/injection)

Also of note: PLGA is available not only in different combination percentages, but also in different "endings". Some PLGA will end in a ESTER or a Hydroxy and ACID terminated molecule form. (I'm also going to call AsZen to find out which one is what I received)

"Table 2 Approximate resorption times of commercially available lactide and glycolide homopolymers and copolymers":

"[see chart] DL-PLGA (50 : 50) 1–2 [months] "

(according to Table 3 Zoladex is a DL-PLGA polymer which comes in various percentages mix. I will call Ast Zeneca to find out which is in the One Month injection and the 3 month and update later.)

** other tags: Goserelin (generic name for Zoladex), PLA (polylactic acid), PGA (polyglycolic acid), PLGA ( Poly Lactic-co-Glycolic Acid), DL-PLGA (<-- Zoladex polymer type), co polymer, depot, , biodegradable lactide-glycolide copolymer matrix, GnRH, Gonadotropin Releasing Hormone Receptor Agonist, LHRH, Hypersensitivity, Allergic Reaction, Allergy, Half Life Zoladex **

Cpeachymom

Hi Spoonie!

I’ve been following your saga on the os board. I’m glad you got to the bottom of it! And I’m always impressed by the links and research you post! I’m sure it’s very helpful to others as well.

So, little tidbit I picked up a while ago is that Lupron is also used in ivf. There are microdose schedules for some ivf, so I’m guessing there is a microdose available somewhere. You may have better luck finding info if you look in that direction.

Good luck!

Spoonie77

Hey, thanks so much for that tip PeachyMom. Uber helpful! Before I head in to see my MO to figure out Plan C, I'll look into that microdosing for Lupron. Had no idea that existed and hopefully you're right that I'll have more luck finding info out that way as I go forward.

Thanks again!

Spoonie

Spoonie77

....posting for new members....