Suspected Problem with Mylan Pharmaceuticals' Estradiol Dosage
(poor instructions and syringe markings)

This document contains information regarding potentially incorrect application instructions provided with Mylan Pharmaceuticals, Inc.'s ("Mylan") prescription medication "Estradiol." Upon the advice of my wife's primary care doctor, an initial prescription of Estradiol cream and subsequently one refill was purchased from Sam's Club pharmacy. The package included a metal tube of medicine, a plastic applicator, and printed instructions.

Mylan appears, per my claim, to have admitted an error in dosage cause by their written instructions; however, they will not provide information regarding the potential medical implications of having administered an improper dosage.

After approximately two thirds (2/3) of the Estradiol had been used, it became apparent that the full number of indicated doses would not be available. Great care was used in filling the applicator plunger using the graduated marks on the applicator. The refill package was identical, and again the amount of medicine provided seemed insufficient to produce the number of doses indicated.

The 42.5-gram tube (as labeled) should have provided for 21, 2-gram doses per the applicator graduation marks. In fact, only approximately 15, 2-gram doses were available. That means either 42.5 grams were not included in the tube, or the applicator was inaccurately marked.

If the former was the case, then we did not receive the advertised amount of Estradiol, and thus the full regimen of treatment was not available. If the later was the case, then more than 2 grams was applied with each dose, resulting in a series of overdoses. The instruction sheet contains dire warnings of potential side effects of usage.

Very cordial and helpful information (Exhibit A) was provided to Mylan in order for them to determine the veracity of our claim. Mylan's final response (Exhibit D) seems to indicate a problem was in fact identified, but no details were provided. The Mylan representative we spoke to on the telephone stated no further information would be forthcoming regarding (a) whether a shortage of medicine was provided or whether the applicator was mismarked thereby resulting in improper dosages, and (b) what the implication of either finding in (a) is regarding my wife's future health.

Included hereafter are copies of communications regarding this issue (November 15, 2020 – January 11, 2021).

• Exhibit A - Original written submission to Mylan (via USPS).
• Exhibit B – Initial telephone conversation with Mylan representative following Exhibit A letter.
• Exhibit C – Letter to Mylan following initial Exhibit B telephone conversation.
• Exhibit D – E-Mail received from Mylan acknowledging problem in need of correction, but providing no detail concerning findings.
• Exhibit E – E-Mail sent to Mylan in response to Exhibit D e-mail from Mylan.
• Exhibit F –Exhibit F is phone call to Mylan seeking further explanation.

Exhibit A - Original written submission to Mylan Pharmaceuticals, Inc. (via USPS).

November 15, 2020

Mylan Pharmaceuticals, Inc.

Robert J. Coury Global Center 1000

Mylan Blvd. Canonsburg, PA 15317

Case# PQC-2020-22xxx

To Whom It May Concern:

I am reporting what I believe is a dosage measurement error involving Estradiol as supplied in the 1.5 oz (42.5 g) tube. As shown on the following pages, using the included plastic applicator with its graduated markings appears to be causing more than the prescribed 2 gram (2 g) dose of cream to be administered if the tube actually contains 42.5 g. A 42.5 g tube can be expected to deliver 21.25, 2 g doses within some reasonable error. After carefully administering two (2) complete 42.5 g tubes of Estradiol using the provided applicator, each tube resulted in only 15, 2 g doses being administered.

My conclusion is that either the applicator graduations are incorrectly spaced, or the Estradiol tubes did not each contain 42.5 g of cream as marked.

If the latter is true, then a correction must be made to the Estradiol tube label regarding content amount and restitution made to customers. If the former is true, then it seems users are overdosing Estradiol with each application (42.5 g per 15 doses = 2.8 g per dose rather than 2 g), which is a potentially harmful situation given the extreme precautions listed on the included information documentation regarding cardiovascular, dementia, cancer, and other possible serious side effects.

My wife, ______, began using Estradiol on May 28, 2020, as prescribed by her primary care physician, Dr. _____ ______. An initial prescription filling and one refill were purchased and self-administered. With using the two tubes and provided applicators, a total of only 30, 2 g doses could be administered, whereas 42 doses were expected (21 from each tube). Following are photographs and an explanation of my after-the-fact measurements.

Thank you for your attention to this matter.

Sincerely,

Kirt Blattenberger

Estradiol Measurements as performed by Kirt Blattenberger

These photographs and measurements show (1) the empty volume that is filled before the plunger begins to move upward resulting in additional Estradiol (cream) being added to the dose, and (2) the volume of cream with each measured 2 g dose per applicator markings. Since I do not know the density of the Estradiol cream, I am not able to convert the calculated volumes to equivalent weight units of ounces or grams as labeled on the metal tube. Mylan should have that density figure and/or know the volume of the filled tube so that measurements can be compared.

Note that the included instructions do not provide visual aids for determining proper referencing of the graduated plunger markings with respect to the outer tube. It only says in Step 5, "As cream is squeezed out, plunger will rise to indicate amount of grams." The top edge of the outer tube appears to be the proper reference, and is what was used. I have a video of my pharmacist wondering about it as well when I asked him for advice.

1. Figure 1 shows the unused Estradiol tube and the provided applicator. A weight and ruler are included for reference. Larger versions of all images are available if needed.
2. Figure 2 shows the completely emptied Estradiol tubes.
3. Figure 3 shows applicator attached to the cream tube, where the threaded neck of the tube has pushed the plunger up into the applicator body. Note there is empty volume from the top of the threaded neck to the full-diameter bottom of the plunger (5.96 mm), between the small diameter end of the plunger (7.89 mm) and the inside diameter of the applicator tube (11.03 mm), as indicated by the yellow lines.
4. Figure 4 shows dimensions of a 1 g volume as indicated by the plunger markings. Calculations indicate a volume of approximately 1064.0 mm³ (1.064 cm³) per 1 g of cream.

   Volume = π x radius² x length

               = π x (11.03/2)² x 11.14 mm³

               = 1064 mm3 (1.064 cm³)

   Accordingly, a 42.5 g tube therefore should represent a volume of 42.5 x ,064 mm³ = 45,220 mm³ (45.22 cm³), whereas the actual dispensed amount of 15, 2 g doses, with a tiny amount remaining in the tube, represents a volume of 30 x 1,064 mm³ = 31,920 mm3 (31.92 cm³). A full tube volume measurement of the metal Estradiol tube was not made prior to emptying them.

As a side note, cleaning the provided applicator after use is very difficult given the cream’s properties, particularly the inner wall of the outer tube. Over-the-counter (OTC) products like Monostat 7™ provide individual, disposable applicators for each dose, thereby eliminating the possibility of introducing contaminants with subsequent applications.

Exhibit B – Initial telephone conversation with Mylan representative following Exhibit A letter.

November 30, 2020

Received a telephone call from Mylan representative Amanda regarding my initial letter dated November 15, 2020 (Exhibit A). She stated that the company was investigating my situation and requested that I ship the two Estradiol tubes to them for examination, which I did immediately. Mylan provided a shipping label (see Exhibit C).

Case # PQC-2020-22xxx was assigned.

Exhibit C – Letter to Mylan following initial Exhibit B telephone conversation.

November 30, 2020

Mylan Pharmaceuticals, Inc.

Robert J. Coury Global Center 1000

Mylan Blvd. Canonsburg, PA 15317

Case# PQC-2020-22xxx

To Whom It May Concern:

Per the instruction of Amanda during our telephone conversation today, please find enclosed two (2) sets of the following Estradiol prescription:

• Cardboard packaging
• Empty 42.5 g metal tube
• Plastic applicator tube

In addition to the information provided in our letter dated November 15, 2020, we have photographs of physical measurements made with a digital caliper of the applicator tube filling of the prescribed 2-gram dose.

You will probably wonder why one of the metal tubes is inflated. An attempt was made to measure the volume of the tube to be able to compare it with the volume contained by a 2-gram plastic applicator dose. After the metal tube had been fully emptied through prescribed use, it was inflated with air and then filled with water, then the volume of water was to be measured. However, the tube shape is not a good approximation of the original shape, so the effort was abandoned. In retrospect, the Archimedes method should have been employed before the metal tube was opened whereby it would have been submersed in a beaker of water and the volume displacement noted. Oh well, maybe next time ;-)

We look forward to learning of your finding on this issue.

Sincerely,

Kirt Blattenberger

Exhibit D – E-Mail received from Mylan acknowledging problem in need of correction, but providing no detail concerning findings.

January 8, 2021

Thank you for contacting Mylan and communicating your experience. Please refer to the attached response letter. This email message and any attachments are for the exclusive use of the intended addressee(s). This message may contain confidential, privileged and/or proprietary information, and unauthorized review, use or distribution by persons other than the intended addressee(s) is strictly prohibited and may be unlawful. Unintended transmission does not waive any privilege including attorney-client, attorney work product or claims to confidentiality. If you received this email in error or it was forwarded from recipients who received it in error, please contact me by return message and immediately destroy all electronic, paper and other versions of this message. Thank you.

The document to the right was included in PDF format as an e-mail attachment. Note the following statement: “An evaluation was performed and corrective action was taken as appropriate."

Exhibit E – E-Mail sent to Mylan in response to Exhibit D e-mail from Mylan.

January 8, 2021

Greetings:

Thank you for the feedback, but I need to know what the corrective action is.

I provided very valuable information to you that could potentially lead to lawsuits based on the overdosing issue due to incorrect instructions.

I need to know whether the incorrect usage instructions along with the erroneously indicating applicator is a health threat to my wife. The information sheet warns severely of possible cancer and other implications as the result of using your product.

If you do not respond with the requested information, I will seek legal counsel.

Sincerely,

Kirt Blattenberger

Exhibit F – Phone call to Mylan seeking further explanation.

January 11, 2021 (or thereabouts)

A phone call was placed to Mylan at the phone number included in their letter seeking information about exactly what was discovered regarding the assumed improper dosing instruction, and what the medical implication might be as a result. The representative (did not write down her name) told me the company would not divulge the information, and I responded saying I would seek legal means if necessary to find out. At that point she stated that because I made a reference to legal representation, she could not provide any further data.

We were hoping Mylan would follow up with more information; however, no communications has been received since that phone call.

Posted May 15, 2021