THE PCCA BLOG

Clinical Services Spotlight - Bruce Biundo

Fri, 28 Feb 2020 18:36:44 GMT

By Seth Humble, Digital Content Specialist

Bruce Biundo, one of PCCA’s clinical compounding pharmacists, is a man given over to a tranquil demeanor. He carries about him a venerable gentility. His eloquence is moderated by a vocabulary that runs deep and straight. Bruce, in other words, is a man who says what he means and looks you in the eye authoritatively while saying it, but without any kind of hubris. The word to describe him is — genuine.

“I was born in Independence, Louisiana. It’s a small town with a population of about 1,800 people, close to New Orleans. When I grew up, there was no interstate, so there was just highway running through town.”

“What was it like for you there?” I ask.

“It was a time when small towns did pretty well. It was largely a strawberry-farming community, so people did all of their shopping locally. My father was a pharmacist, and my mother worked in the pharmacy, too. They owned the pharmacy after working seven days a week for years. It was an enormous part of our lives. We lived above the pharmacy, which people might find hard to believe now. One of my first jobs, after my dad installed a soda fountain, was as a Soda Jerk. I have many fond memories of it.”

There is a passing whimsy that tugs at the line of Bruce’s mouth, a smile threaded to a memory.

“How have those memories shaped you in adulthood?” I ask.

Bruce lets out a low, slow breath as he considers. “It’s about answering one question at a time to ensure that a person gets the exact answer they need — one pharmacy at a time.”

Bruce mentions that whenever he goes on vacation or a road trip, he likes to stop inside small community pharmacies along his path, just to check in and see how they are doing. He expresses a deep and abiding commitment to maintaining those relationships. He would never say it himself, but this commitment is likely one of the many reasons Bruce was named the Texas Pharmacy Association’s Pharmacist of the Year in 2013, among his many other accolades. This is an award that recognizes a pharmacist who possesses a record of unquestionable integrity, outstanding service to the local or state association, and a personal record of exemplary service to the pharmacy community. And if there is one particular branch of pharmacy compounding that Bruce is renowned for assisting with, it is hormone replacement therapy (HRT). After having read his recent article on how to establish yourself as a men's health consultant onThe PCCA Blog, I wanted to ask Bruce about his thoughts on the prevalence of HRT.

“HRT has exploded in the last 20 years. How did that happen?” I ask.

“I’m not sure there is any one thing. It was beginning to happen a few years before that. It was beginning to become interesting because we knew, as pharmacists, that it would provide a unique opportunity to begin educating people about it. So we started hormone education events. I don’t remember exactly what we said at those early events, but I do remember everyone who was there.”

That statement about remembering the specific people gets a smile out of me, but Bruce is in the zone; he’s educating me now, seemingly unaware of the wonderful statement he just made.

I remember everyone who was there.

Bruce continues, naming the important folks who worked with him. “Then, not too long after, I realized that our information was heavily focused on women’s HRT, so I began looking for clinical data on what HRT could do for men. I read every book I could find, investigated the research. I first presented on men’s HRT at International Seminar in April of 1999 — 21 years ago. Over the years, more clinical data continued to come out. And now, with bioidentical hormones …”

What happens next is something that is wonderful and only possible when in the hands of a true expert. Bruce Biundo summarizes the history of HRT and the nuances between traditional hormones and bioidentical hormones. He describes how those two things shaped the development of HRT as both a medical necessity and as a commercial opportunity that contributed to the prevalent anti-aging culture in America. He provides a detailed explanation as to why the delivery vehicle for testosterone matters and why patients see different results when using those varying bases. He calls these things the basics, the simple foundational pieces to understanding modern HRT.

He summarizes all this in three minutes.

Concise. Never belittling, always intentional. He does this thing, this practiced, almost magical thing, and when he stops talking, I catch myself hoping he will go on. Bruce has done what only the consummate teacher can do: remind you how much, as humans, we love to learn.

“So what would you say has made the most meaningful impact on you during your time at PCCA?” I ask.

For the first time since we started speaking, Bruce’s eyes fall away from mine after a question. His index finger curls around the cleft of his chin, and he thinks for what seems a long measure of time.

“There is something about being at PCCA that is analogous to being a small community pharmacist,” he eventually replies. “You see the same people over a long period of time — develop relationships, trust. Over 21 years ago, I gave my first presentation on HRT, and I still talk with people who were there.”

He shifts in his chair, straightening up.

“When people ask me what I do at PCCA, I tell them, ‘I talk to my friends on the phone, and I try to help them.’ That’s what it means to me — to be able to help your friends.”

This is Bruce Biundo — a man who grew up among the strawberry fields of Independence, Louisiana, as the son of a pharmacist who knew from a time when he was very young that he wanted to help people through pharmacy care. He is a kind man, though fiercely knowledgeable. And he embodies PCCA’s spirit that seeks to empower compounding pharmacies and ensure they get the very best information for the challenges they face.

How to Establish Yourself as a Men’s Health Consultant

Wed, 22 Jan 2020 18:52:35 GMT

By Bruce Biundo, RPh, FACA, PCCA Clinical Compounding Pharmacist

Where do your male patients get their information about testosterone? About prostate health? About supplements that may help them? From my own observations, many are hearing about these things from ads running on sports talk shows, the internet or other non-medical sources. Listening to and reading some of these advertisements, I see how many men can form unrealistic notions of what “natural testosterone boosters” can do for them, or even what the appropriate and expected benefits of testosterone itself would be. And how about your physicians? While many of them are interested in helping these male patients, they may find it difficult to keep up with what you, the pharmacist, can offer them in terms of treatment options, such as who is a good candidate for testosterone, who is not and what kinds of dosing options you can provide.

Very importantly, you are likely interested in how you can initiate or increase these services to help your pharmacy improve profitability in these challenging times. As a former independent pharmacy owner myself, and longtime community pharmacist, I am very interested in helping you help your bottom line by becoming more established as a men’s health consultant. So let’s take a look at what is involved.

Have Men’s Health Information Readily Available
There are numerous sources of useful information that can help your male patients become more knowledgeable about men’s health issues. A couple books that can be very helpful are Testosterone for Life, by Abraham Morgentaler, MD, and Saving Your Sex Life, by John P. Mulhall, MD. These can be great references for you and your patients. I also find the monthly magazine Men’s Health often provides useful, up-to-date news that both you and your patients can find beneficial. With either the books or the magazine, your male patients will likely become better informed and more interested in what your pharmacy provides.

Offer Private Patient Consultation
Well-established by many pharmacists over the past 20+ years, a private consultation can be a key component in your practice. You should have an appropriate setting for this, preferably a private room, which enhances the patient’s comfort level. You should also charge appropriate professional fees for this service — for example, $60–$100 for a 20–30 minute session, more for consults lasting up to an hour. It is not uncommon for consultation fees of $175–$200 for those of sufficient skills. If you do this on a regular basis and become proficient at it, private consultations can become a lucrative part of your practice.

A typical session could include a brief discussion on testosterone, a review of the patient’s laboratory values and then a walk-through of the patient’s screening form, which he would have previously filled out. During this time, the patient will be free to ask questions on the topic, and in this environment, you, the pharmacist, can satisfy the concerns expressed. The consultation concludes with you making a therapeutic recommendation to the patient’s physician and, often, a specific recommendation to the patient for nutritional supplements. These supplements, of course, are items that your pharmacy could offer, so the patient would be able to get exactly what you recommend.

Offer Nutritional Supplements
There are many excellent products out there that are very helpful, but I want to mention three specific nutrients that appear to be particularly useful relative to male hypogonadism, or low testosterone: magnesium, vitamin D and zinc. A study showed that magnesium supplementation increased free and total testosterone, with even higher increases in men who supplemented magnesium and exercised regularly.¹ Another study showed an association between vitamin D levels and testosterone levels (i.e., men who had low vitamin D levels frequently also had low levels of testosterone).² Other articles have shown the same association. And lastly, researchers have correlated zinc status with testosterone levels; specifically, low zinc levels correlated with low testosterone levels, and restoration of the zinc deficiencies restored testosterone levels.³

Wellness Works offers professional-quality nutritional supplements for pharmacies to offer their customers, including magnesium chelate tablets, magnesium glycinate powder, vitamin D softgels, zinc monomethionine tablets and zinc lozenges.

Keep up with Testosterone Supplementation Updates
The use of testosterone by injection has been long studied; what is newer is the interest in subcutaneous injections of testosterone. An article by Kaminetsky, Jaffe and Swerdloff revealed that patients obtained consistently high levels of testosterone with 100 mg subcutaneously, as contrasted with the bi-weekly intramuscular (IM) dose of 200 mg. They cited patient comfort and convenience as advantages over the more conventional IM dosing.⁴ Subcutaneous dosing has become much more common in recent years, and may be an excellent alternative to IM injections.

At PCCA, we get many calls on sublingual dosing of testosterone as well, and it seems to be increasing in preference compared with the past use. Sublingual dosing has unique characteristics. Because of the rapid absorption and relatively short half-life of testosterone, it is best done several times a day at doses of 15–25 mg, as opposed to high doses once a day. The difference can be readily seen in measured hormone levels: high doses produce very high testosterone levels, but for relatively short periods of time. Better to do a lower dose several times a day, as that will be more like the body’s usual production than the high, once-a-day dose. PCCA members can see our recommended dosing-range chart for various dosage forms.

However, do you give testosterone to all men who are clearly symptomatic and low on measured levels? No. Consider the age of the patient, and inquire as to his desire to maintain fertility. Testosterone supplementation can definitely suppress spermatogenesis, resulting in decreased fertility. Consider clomiphene for those men who are low in testosterone but want to maintain fertility.⁵ Another useful agent is anastrozole, widely used as an aromatase inhibitor, which can block the production of estrogen. Given the strong influence that estradiol has in the production/suppression of the messenger hormone responsible for testosterone production, anastrozole has also shown to be somewhat useful in increasing the production of testosterone in many men.⁶ It may be considered as an alternative to clomiphene in that regard.

PCCA members with Clinical Services access can view related testosterone formulas in our database, including some in Atrevis Hydrogel®.

Develop Collegial Relationships with Physicians
This is probably the most important part of establishing yourself as a men’s health consultant: forming and maintaining professional, mutually beneficial relationships with physicians and other health care providers who are interested in working with you in caring for patients. Fortunately, doctors want your knowledge, your skills and your ability to offer useful solutions to their patients’ needs. And we help PCCA members by offering treatment options, treatment documents and up-to-date information, all of which they can share with practitioners. PCCA members can see our concise yet wide-ranging Male Hypogonadism Packet for discussion of what is involved in treating male patients with low testosterone.

I advise PCCA members to also look at our newly revised Men’s Health Reference Guide, which meticulously indexes and provides links to abstracts for over seven hundred clinical articles. I think they will find it a valuable resource for their toolkits.

Finally, always remember that we are just one call away for PCCA members with Clinical Services access. For questions, they can contact our team of clinical compounding pharmacists at 800.331.2498.

Bruce Biundo, RPh, FACA, PCCA Clinical Compounding Pharmacist, joined the PCCA staff in 1997 after many years as a community pharmacist. In 1998, as PCCA was beginning to develop educational seminars, he realized that there wasn't much focus on men and testosterone issues, and began research on the subject. In April 1999, Bruce presented what is likely the first educational event on low testosterone in men at the PCCA International Seminar. Over the years, he has made presentations at dozens of hormone seminars to physician groups locally and internationally, and has many articles published, mostly dealing with men’s health. In addition, he was a contributor to Remington: The Science and Practice of Pharmacy, 22nd edition, and is the co-author of the nutrition chapter in Aging Men's Health.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

Cinar, V., Polat, Y., Baltaci, A. K., & Moqulkoc, R. (2011). Effects of magnesium supplementation on testosterone levels of athletes and sedentary subjects at rest and after exhaustion. Biological Trace Elements Research, 140(1), 18–23. https://doi.org/10.1007/s12011-010-8676-3
Lee, D. M., Tajar, A., Pye, S. R., Boonen, S., Vanderschueren, D., Bouillon, R., … Wu, F. C. (2012). Association of hypogonadism with vitamin D status: the European Male Ageing Study. European Journal of Endocrinology, 166(1), 77–85. https://doi.org/10.1530/EJE-11-0743
Prasad, A. S., Mantzoros, C. S., Beck, F. W., Hess, J. W., & Brewer, G. J. (1996). Zinc status and serum testosterone levels of healthy adults. Nutrition, 12(5), 344–348.
Kaminetsky, J., Jaffe, J. S., & Swerdloff, R. S. (2015). Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: A phase II study. Sexual Medicine, 3(4), 269–279. https://doi.org/10.1002/sm2.80
Moskovic, D. J., Katz, D. J., Akhavan, A., Park, K., & Mulhall, J. P. (2012). Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU International, 110(10), 1524–1528. https://doi.org/10.1111/j.1464-410X.2012.10968.x
Leder, B. Z., Rohrer, J. L., Rubin, S. D., Gallo, J., & Longcope, C. (2004). Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. The Journal of Clinical Endocrinology & Metabolism, 89(3), 1174–1180. https://doi.org/10.1210/jc.2003-031467

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

The Top 5 Blog Posts of 2019

Wed, 11 Dec 2019 16:29:00 GMT

By PCCA

And just like that, The PCCA Blog is closing its first full calendar year in the world. Between January and November of 2019, we published 71 blog posts and attracted tens of thousands of readers just like you, many of whom have subscribed as well. Thank you to all of our readers and subscribers for making it a wonderful year. We’re grateful to be able to produce content that professionals in the pharmacy compounding industry find valuable. Below are some of our top-performing posts of the year, reflecting some of the biggest changes that our area of health care is experiencing along with the ever-present need for research-based clinical information.

1. Notable Changes in the New USP <795>
Even though implementation of the new USP General Chapter <795> has been delayed due to appeals, it is still crucial to have a full and nuanced understanding of it. In this post, PCCA Clinical Compounding Pharmacist Matt Martin, PharmD, addresses notable changes to the new USP guidelines and provides some considerations for implementation.

2. An Innovative Option for Hirsutism: Topical Metformin
Clinically, hirsutism “refers to women with excess growth of stiff, pigmented hair (known as ‘terminal hair’) in a male pattern,” explains PCCA Clinical Compounding Pharmacist Sara Hover, RPh, FAARM. But she has exciting news about a potential option for women with hirsutism as well.

3. Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk
Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Colleagues and patients alike come to experts like Pamela Smith, Nat Jones and Sara Hover for guidance. In this two-part post, they cover this all-too-important topic in the BHRT conversation, showing what current literature says about the usage of oral vs. topical estrogen.

4. Upcoming Changes to PCCA Formulas per the New USP <795>, <797> and <800>
The new and revised USP chapters affect many aspects of compounding, including formulas. In this post, PCCA Director of Formulation Development Melissa Merrell Rhoads, PharmD, details the updates we’re planning to make to our formulas based on the new USP guidelines. Pro tip: Look at the types of updates we’re going to make to our formulas as a guide for changes you should consider in your own.

5. Notable Changes in the New USP <797>
The new USP General Chapter <797> implementation is delayed because of appeals just like USP <795>, and that gives compounders more time to become familiar with it. Let Dylan Herr, RA/QA Development Manager at Eagle, help with that. She understands that this version makes significant revisions to the old one, and in this post, she provides you with an overview of those changes and strategies for implementing them.

We’re hard at work planning more content for 2020 that we hope will help you serve patients and grow your business, so keep an eye on The PCCA Blog. If you like what you see, consider subscribing. We’ll send you email notifications when we publish new posts. And if you’re already a subscriber, sit back and relax. We’ll be in touch.

Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk (Part Two)

Wed, 13 Nov 2019 14:48:00 GMT

By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

In the first part of this article, we introduced some new information that is important to consider for patients who need bioidentical hormone replacement therapy (BHRT). Recent medical literature is shedding more light on the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. Specifically, we reviewed what the literature is showing and discussed compounded sublingual and buccal estrogen. Here, we will continue the discussion further with compounded topical estrogen.

Compounded Topical Estrogen
In addition to sublingual and buccal estrogen, another common route for compounded hormone replacement is topical. Many times, the terms “topical” and “transdermal” are used interchangeably. Strictly speaking, topical refers to the delivery of a drug into the skin to treat a dermal disorder, with the skin as the target tissue. In contrast, transdermal, or percutaneous, absorption refers to the delivery of a drug through the skin for systemic effect. However, we often refer to BHRT compounds as topical because they are topically applied. So when we talk about topical BHRT here, these compounds are intended for hormone delivery through the skin.

There are many factors to consider with absorption through the skin: physical and chemical properties of the drug, molecular weight, solubility, partition coefficient and dissociation constant, the nature of the carrier vehicle, and the condition of the skin. With hormones, the most important factors are the molecular weight and the vehicle or base.

The low molecular weight of hormones definitely lends them to topical delivery as an excellent option. However, we also have to consider the size of the drug particle. When a drug is reduced to a number of smaller particles, or micronized, the total surface area is greater, which results in an increased rate of dissolution. As Allen and Ansel point out, “Due to the different rates and degrees of absorption obtainable from drugs of various particle size, it is conceivable that products of the same drug substance prepared by two or more reliable pharmaceutical manufacturers may result in different degrees of therapeutic response in the same individual.”¹ In other words, the particle size of a hormone can make a clinical difference, so it’s an important consideration in compounding for BHRT.

The base of the compounded preparation is also critical. The type of base and permeation enhancers used can affect absorption of hormones, and the delivery system must be able to release the drug in a reproducible way. As we mentioned in part one, hormones are lipophilic, and a good base will enhance their diffusion through the stratum corneum.¹ In-depth discussion of the importance of a proper base is outside the scope of this article, but we mention this aspect of hormone absorption to stimulate thought.

The main advantage of topical administration is bypassing the first-pass effect.² Estrogen that is absorbed orally passes through the portal vein into the liver, where it is heavily conjugated before being released into the systemic circulation, which may account for the negative effects we listed in the first part of this article. Since this is only seen with oral administration, it is reasonable to hypothesize that this is related to first-pass hepatic metabolism.

One of the disadvantages of topical delivery is the potential for transference to family members and pets. Therefore, compounders should counsel their patients to be aware of contact with others and identify areas to apply creams that will minimize exposure to others. Another perceived disadvantage to topical hormone delivery relates to the limitations of different types of lab testing. The gold standard is serum testing, for example, but topical hormone application does not typically show up in blood serum results. It shows in the saliva. We could write an entire book explaining and debating the differences between serum testing and saliva testing. Each type of testing is looking at a specific compartment of the body and provides different information. We will leave this topic for a future article. Despite the disadvantages of transference or the debate over testing, topical delivery of estrogen is a practical, proven compounding option, and as we have seen in this article, it is safer than oral delivery for postmenopausal women.

The risk of VTE is a very important consideration for choosing the route of estradiol administration, and being cognizant of the possibility of oral absorption from other dosage forms, such as troches, is an important factor to be aware of as well. While a certain type of compound may be popular, the risk of potential harm must take precedence over convenience when making a dosage form recommendation. Consequently, after review of the medical literature, topically applied estrogen is the only form of estrogen replacement that we recommend for a postmenopausal woman.

Pamela W. Smith, MD, MPH, MS, spent 20 years as an emergency room physician with the Detroit Medical Center and then 24 years as an anti-aging/functional medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of metabolic, anti-aging and personalized medicine. She has been featured on CNN, PBS and many other television networks; has been interviewed in numerous consumer magazines; and has hosted two of her own radio shows. She is currently the Director of the Center for Personalized Medicine and the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine. Dr. Smith is also the co-director of the Master’s Program in Metabolic and Nutritional Medicine at the Morsani College of Medicine, University of South Florida. Additionally, she is the Director of Medical Education for the American Academy of Anti-Aging Medicine. She is the author of the best-selling books HRT: The Answers, What You Must Know about Women’s Hormones, and many others.

Nat Jones, RPh, FIACP, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.

Sara Hover, RPh, FAARM, has been a compounding pharmacist for over 20 years and joined the PCCA Clinical Services team in June 2013. Before joining the PCCA staff, she was the owner and pharmacist of Creative Compounds in Prosper, Texas, an independent, compounding-only pharmacy that focused on women’s health and nutrition. In addition to her expertise in hormone replacement therapy, Sara possesses a vast knowledge of homeopathics as well as herbal and vitamin supplements. Sara obtained her Bachelor of Science degree from the University of Texas at Austin in 1994. She is a lifetime member of the University of Texas College of Pharmacy Alumni Association.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References
1. Allen, L. V., Jr., & Ansel, H. C. (2013). Ansel's pharmaceutical dosage forms and drug delivery systems (10th ed.). Baltimore, MD: Lippincott Williams & Wilkins.
2. Goodman, M. P. (2012). Are all estrogens created equal? A review of oral vs. transdermal therapy. Journal of Women’s Health, 21(2), 161–169. https://doi.org/10.1089/jwh.2011.2839

Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk (Part One)

Mon, 11 Nov 2019 17:06:00 GMT

By Pamela W. Smith, MD, MPH, MS; Nat Jones, RPh, FIACP, PCCA Clinical Compounding Pharmacist; and Sara Hover, RPh, FAARM, PCCA Clinical Compounding Pharmacist

Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Colleagues and patients alike come to us for guidance about this, and our recommendations should be based in part on knowledge about the available delivery options and their impact on safety. In the area of BHRT, some new information has come to light in medical literature that is important to consider for patients. Therefore, we would like to review the risk of venous thromboembolism (VTE) associated with estrogen and how the route of administration can affect its likelihood. In the first part of this article, we will review what the literature is showing and discuss compounded sublingual and buccal estrogen. In the second part of this article we will discuss compounded topical estrogen.

VTE is a general term for a blood clot that forms in a vein. This can manifest as a deep vein thrombosis, where the clot forms in a deep vein of the leg, pelvis or arm.¹ VTE also encompasses pulmonary embolism, which is when a blood clot reaches the lungs.² According to the Centers for Disease Control and Prevention, these “are often underdiagnosed and serious, but preventable medical conditions” that can result in “serious illness, disability, and in some cases, death.”¹ Symptoms of deep vein thrombosis include redness of the skin in the affected area as well as swelling, pain and tenderness to the touch. Pulmonary embolism symptoms include low blood pressure, lightheadedness, fainting, difficulty breathing, fast or irregular heartbeat, chest pain, or even coughing blood. Both conditions are treatable through immediate medical care.¹ There are many risk factors for VTE, including recent surgery, long periods of immobilization and family history, among others.²

What the Literature Says
In recent years, there has been an enormous amount of discussion in the medical literature about estrogen and its route of administration for hormone replacement therapy. The overwhelming evidence has shown that oral estrogen replacement increases the risk of VTE in postmenopausal women with no previous thromboembolic events. Comparatively, non-oral estrogen use did not significantly affect their risk.

In the medical literature examining the relationship between VTE and hormone replacement in menopausal women, the route of administration has been primarily oral. However, studies have revealed that oral estrogen therapy may exert a prothrombotic effect through hepatic induction.^3,4 This is conceivably related to high concentrations of estrogen in the liver due to the liver’s “first-pass” effect. Likewise, a recent study revealed that compared with no hormone therapy, use of oral estradiol was associated with excess risk of VTE. In contrast, use of transdermal estradiol (most commonly used as a patch) was not associated with excess risk of VTE. In addition, the study authors concluded that “transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.”⁵

Furthermore, in addition to an increase in prothrombotic effects, studies have shown that oral estrogen use is related to other possible side effects^6–16:

Increase in blood pressure
Increase in triglycerides
Increase in estrone
Increase in occurrence of gallstones
Increase in liver enzymes
Increase in sex hormone binding globulin, which lowers available testosterone for the body to use
Interruption of tryptophan metabolism and consequently serotonin metabolism
Lower growth hormone levels
Increase in C-creative protein
Increase in carbohydrate cravings

Other medical trials that have compared oral and transdermal estrogen replacement also discovered that transdermally administered estrogen has little or no effect in increasing prothrombotic substances. Furthermore, transdermal estrogen may have beneficial effects on proinflammatory markers (such as C-reactive protein and prothrombin activation peptide) as well as antithrombin activity. It may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity in contrast to oral estrogen as well, which would also be beneficial in many cases.^4,14,17–20

Other study authors also examined the risk of transdermal estrogen use compared to patients that did not use hormone replacement therapy and showed that there was no increased risk compared to nonusers.^21–25 Some research also suggested that transdermal estrogens may substantially improve the benefit/risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.²¹ In fact, other studies revealed that women who were overweight⁸ and women who had prothrombotic mutations also had no increased risk of thrombosis with transdermal estrogen replacement therapy.²⁶

Lastly, researchers have also investigated whether patients with a previous thromboembolism, family history of thromboembolism or prothrombotic mutation could take estrogen replacement therapy. The studies revealed that the above were a strong contraindication to oral hormone replacement therapy, but transdermal estrogen could be considered after careful individual evaluation of the benefits and risks. Furthermore, these studies suggested that transdermal estrogen should also be the first choice for overweight and obese women requiring hormone replacement therapy.^27,28

Compounded Sublingual and Buccal Estrogen
When considering compounded estrogen delivery, there are several choices. The list includes multiple dosage forms, and two of the most common provide sublingual or buccal delivery and topical delivery (with or without permeation enhancement). While vaginal/labial applications, injections and pellets are also treatment options, we are going to focus on the more common ones.

Sublingual and buccal delivery are similar and often used in medicine for patients who either can’t swallow a solid dosage form or for specific medical reasons, such as hyperemesis (severe nausea and vomiting). Sublingual administration involves placing medication under the tongue to absorb through the mucosa into the bloodstream. Buccal administration involves placing a medication between the gum and the cheek, where it absorbs through the mucosa and into the bloodstream. Absorption is generally considered rapid and efficient, and these routes avoid first-pass metabolism, though many dosage forms that are intended for sublingual or buccal delivery commonly also allow oral intake through normal salivary action. Sublingual absorption occurs in part through the ventral surface of the tongue or the floor of the mouth into the reticulated vein. The main mechanism for the absorption of a drug into oral mucosa is via passive diffusion into the lipoidal membrane.

The sublingual area is more permeable than the buccal area, which is more permeable than the palatal area (top of the mouth). These differences are generally related to the relative thickness, blood supply and degree of keratinization of these membranes. For a drug to be absorbed completely through the sublingual route, it must have slightly higher lipid solubility for passive permeation, and luckily, estrogens are lipophilic (fat soluble).²⁹Notably, sublingual BHRT seems to be effective in reducing vasomotor, mood and quality-of-life symptoms experienced in postmenopausal women.³⁰

While compounders have prepared sublingual hormone drop formulas for years,³¹ troches are the most popular sublingual and buccal dosage form for BHRT. There is a lot of older pharmacokinetic data published on sublingual use from manufactured oral estradiol tablets.^32–34 This data clearly shows sublingual administration resulted in rapid absorption with significantly higher estradiol levels than did comparable oral dosing, and these increased levels fell rapidly over the first six hours, indicating the need for multiple daily doses considering the half-life of oral estradiol is approximately one to two hours at steady state. There are no similar pharmacokinetic studies for comparable compounded dosage forms (rapid dissolve tablets or tablet triturates), but assuming extremely close dissolution times, one could expect similar outcomes.

Even though sublingual and buccal absorption of estrogen is relatively rapid, troches dissolve more slowly than tablets (from 20 minutes to an hour depending on the formulation). Additionally, more than 50% of the troche is swallowed by the normal mechanism of saliva formation, and the remainder is absorbed transmucosally.³⁵ Because over half of the troche is swallowed, prescribers and compounders must be aware that estrogens given in this manner may have a similar risk of VTE as oral administration, and we therefore do not recommend estrogen troches for postmenopausal women.

Pamela Wartian Smith, MD, MPH, MS, spent 20 years as an emergency room physician with the Detroit Medical Center and then 24 years as an anti-aging/functional medicine specialist. She is a diplomat of the Board of the American Academy of Anti-Aging Physicians and is an internationally known speaker and author on the subject of metabolic, anti-aging and personalized medicine. She has been featured on CNN, PBS and many other television networks; has been interviewed in numerous consumer magazines; and has hosted two of her own radio shows. She is currently the Director of the Center for Personalized Medicine and the founder of The Fellowship in Anti-Aging, Regenerative, and Functional Medicine. Dr. Smith is also the co-director of the Master’s Program in Metabolic and Nutritional Medicine at the Morsani College of Medicine, University of South Florida. Additionally, she is the Director of Medical Education for the American Academy of Anti-Aging Medicine. She is the author of the best-selling books HRT: The Answers, What You Must Know about Women’s Hormones, and many others.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References
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2.   National Heart, Lung, and Blood Institute. (n.d.). Venous thromboembolism. Retrieved from https://www.nhlbi.nih.gov/health-topics/venous-thromboembolism
3.   Nabulsi, A. A., Folsom, A. R., White, A., Patsch, W., Heiss, G., Wu, K. K., & Szklo, M. (1993). Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The New England Journal of Medicine, 328(15), 1069–1075. https://doi.org/10.1056/NEJM199304153281501
4.   Lowe, G. D., Upton, M. N., Rumley, A., McConnachie, A., O’Reilly, D. S., & Watt, G. C. (2001). Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein — A cross-sectional population survey. Thrombosis and Haemostasis, 86(2), 550–556.
5.   Vinogradova, Y., Coupland, C., & Hippisley-Cox, J. (2019). Use of hormone replacement therapy and risk of venous thromboembolism: Nested case-control studies using the QResearch and CPRD databases. The BMJ, 364.https://doi.org/10.1136/bmj.k4810
6.   Smith, P. (2010). What you must know about women’s hormones. Garden City Park, NY: Square One Publishing, 2010.
7.   Ballagh, S. A. (2005). Vaginal hormone therapy for urogenital and menopausal symptoms. Seminars in Reproductive Medicine, 23(2), 126–140. https://doi.org/10.1055/s-2005-869480
8.   Canonico, M., Oger, E., Conard, J., Meyer, G., Lévesque, H., Trillot, N., … Scarabin, P. Y. (2006). Obesity and risk of venous thromboembolism among postmenopausal women: Differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. Journal of Thrombosis and Haemostasis, 4(6), 1259–1265. https://doi.org/10.1111/j.1538-7836.2006.01933.x
9.   Chetkowski, R. J., Meldrum, D. R., Steingold, K. A., Randle, D., Lu, J. K., Eggena, P., … Judd, H. L. (1986). Biologic effects of transdermal estradiol. The New England Journal of Medicine, 314(25), 1615–1620. https://doi.org/10.1056/NEJM198606193142505
10.   Pansini, F., Bergamini, C. M., Bonaccorsi, G., Breveglieri, P., Calisesi, M., Valpondi, V., … Mollica, G. (1990). Control of carbohydrate metabolism in menopausal women receiving transdermal estrogen therapy. Annals of the New York Academy of Sciences, 592(1), 460–462. https://doi.org/10.1111/j.1749-6632.1990.tb30374.x
11.   Scarabin, P. Y., Alhenc-Gelas, M., Plu-Bureau, G., Taisne, P., Agher, R., & Aiach, M. (1997). Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(11), 3071–3078. https://doi.org/10.1161/01.atv.17.11.3071
12.   Vehkavaara, S., Silveira, A., Hakala-Ala-Pietilä, T., Virkamäki, A., Hovatta, O., Hamsten, A. … Yki-Järvinen, H. (2001). Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thrombosis and Haemostasis, 85(4), 619–625.
13.   Vongpatanasin, W., Tuncel, M., Mansour, Y., Arbique, D., & Victor, R. G. (2001). Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation, 103(24), 2903–2908. https://doi.org/10.1161/01.cir.103.24.2903
14.   Folsom, A. R., Lutsey, P. L., Astor, B. C., & Cushman, M. (2009). C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thrombosis and Haemostasis, 102(4), 615–619. https://doi.org/10.1160/TH09-04-0274
15.   Rovinski, D., Ramos, R. B., Fighera, T. M., Casanova, G. K., & Spritzer, P. M. (2018). Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis. Thrombosis Research, 168, 83–95. https://doi.org/10.1016/j.thromres.2018.06.014
16.   Lissett, C. A., & Shalet, S. M. (2003). The impact of dose and route of estrogen administration on the somatotropic axis in normal women. The Journal of Clinical Endocrinology & Metabolism, 88(10), 4668–4672. https://doi.org/10.1210/jc.2003-022036
17.   Post, M. S., Christella, M., Thomassen, L. G., van der Mooren, M. J., van Baal, W. M., Rosing, J., … Stehouwer, C. D. (2003). Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: A randomized, placebo-controlled study in postmenopausal women. Arteriosclerosis, Thrombosis, Vascular Biology, 23(6), 1116–1121. https://doi.org/10.1161/01.ATV.0000074146.36646.C8
18.   Margarido, P. F., Bagnoli, V. R., Maggio da Fonseca, A., Maciel, G. A., Soares, J. M., Jr., D’Amico, E. A., & Baracat, E. C. (2011). Transdermal estrogen therapy effects on fibrinogen levels in women with a past history of venous thromboembolism: A pilot study. Clinical and Experimental Obstetrics & Gynecology, 38(3), 232–235.
19.   Oger, E., Alhenc-Gelas, M., Lacut, K. Blouch, M. T., Roudaut, N., Kerlan, V., … Mottier, D. (2003). Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: A randomized trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(9), 1671–1676. https://doi.org/10.1161/01.ATV.0000087141.05044.1F
20.   Eilertsen, A. L., Høibraaten, E., Os, I., Andersen, T. O., Sandvik, L., & Sandset, P. M. (2005). The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis. Maturitas, 52(2), 111–118.https://doi.org/10.1016/j.maturitas.2005.01.004
21.   Olié, V., Canonico, M., & Scarabin, P. Y. (2010). Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Current Opinion in Hematology, 17(5), 457–463. https://doi.org/10.1097/MOH.0b013e32833c07bc
22.   Minkin, M. J. (2004). Considerations in the choice of oral vs. transdermal hormone therapy: A review. The Journal of Reproductive Medicine, 49(4), 311–320.
23.   Laliberté, F., Dea, K., Duh, M. S., Kahler, K. H., Rolli, M., & Lefebvre, P. (2011). Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause, 18(10), 1052–1059. https://doi.org/10.1097/gme.0b013e3182175e5c
24.   Renoux, C., Dell’aniello, S., Garbe, E., & Suissa, S. (2010). Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. The BMJ, 340.https://doi.org/10.1136/bmj.c2519
25.   Scarabin, P. Y., Oger, E., & Plu-Bureau, G. (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. The Lancet, 362(9382), 428–432. https://doi.org/10.1016/S0140-6736(03)14066-4
26.   Straczek, C., Oger, E., Yon de Jonage-Canonico, M. B., Plu-Bureau, G., Conard, J., Meyer, G., … Scarabin, P. Y. (2005). Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation, 112(22), 3495–3500. https://doi.org/10.1161/CIRCULATIONAHA.105.565556
27.   Pavičić Baldani, D., Skrgatić, L., Simunić, V., Elvedi Gasporavić, V., & Geršak, B. (2015). Hormonsko nadomjesno liječenje i venske tromboemolije [Hormone replacement therapy and venous thromboembolism]. Liječnički Vjesnik: Glasiol Hrvatskoga Lijenčničkog Zbora/Medical Journal: The Journal of the Croatian Medical Association, 137(1–2), 34–40.
28.   Tremollieres, F., Brincat, M., Erel, C. T., Gambacciani, M., Lambrinoudaki, I., Moen, M. H., … Rees, M. (2011). EMAS position statement: Managing menopausal women with a personal or family history of VTE. Maturitas, 69(2), 195–198. https://doi.org/10.1016/j.maturitas.2011.03.011
29.   Narang, N., & Sharma, J. (2011). Sublingual mucosa as a route for systemic drug delivery. International Journal of Pharmacy and Pharmaceutical Sciences, 3(Suppl. 2), 18–22.
30.   Ruiz, A. D., & Daniels, K. R. (2014). The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: An observational cohort study. International Journal of Pharmaceutical Compounding, 18(1), 70–77.
31.   Allen, L. V., Jr. (2015). Estriol 2 mg and estradiol 0.5 mg per 0.1 mL sublingual drops. U.S. Pharmacist, 40(9), 50–51.
32.   Casper R. F., & Yen, S. S. (1981). Rapid absorption of micronized estradiol-17 beta following sublingual administration. Obstetrics & Gynecology, 57(1), 62–64.
33.   Burnier, A. M., Martin, P. L., Yen, S. S., & Brooks, P. (1981). Sublingual absorption of micronized 17β-estradiol. American Journal of Obstetrics & Gynecology, 140(2), 146–150. https://doi.org/10.1016/0002-9378(81)90101-0
34.   Price, T. M., Blauer, K. L., Hansen, M., Stanczyk, F., Lobo, R., & Bates, G. W. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol. Obstetrics & Gynecology, 89(3), 340–345. https://doi.org/10.1016/S0029-7844(96)00513-3
35.   Drisko, J. A. (2000). “Natural” isomolecular hormone replacement: An evidence-based medicine approach. International Journal of Pharmaceutical Compounding, 4(6), 414–420.

New Data on PCCA Bases You Won’t Want to Miss

Wed, 30 Oct 2019 19:37:00 GMT

By Yi Liu, PharmD, PhD, PCCA Research Pharmacist

If you visited the PCCA Science booth during International Seminar 2019, you probably felt the breadth and depth of research going on at PCCA — case studies, dissecting rules and regulations, comprehensive formula analysis, new product testing, and much more. One example is an interesting case study about treating burn wounds in an immunocompromised adult conducted by Harbin Pharmacy in Birmingham, Alabama, one of PCCA’s member pharmacies. Beyond PCCA, independent researchers recently used Lipoderm^® in a study on improving wrinkles and skin texture in combination with laser treatment. We have recently added links to these resources to the PCCA Science webpage.

Among the other items listed on the PCCA Science page, you don’t want to miss one important category: technical reports. This is especially true after the launch of a new base. Do you want to know how well our newest innovation, VersaBase^® Anhydrous HRT, delivers female hormones before your patients put it on their skin? Do you want to know if it is safe to switch your patients from another topical base to VersaBase Anhydrous HRT? You will be able to find the answers in our technical reports. These resources provide you quick access to the most recent data generated by PCCA’s Research and Development team. The studies are always conducted to present scientific evidence on the most important properties of PCCA products. The data is publication grade, scientifically designed and reproducible, ready for you to show to your prescribers and patients. Here are some newly released technical reports:

What are the other properties of PCCA bases you think are important to know? What data about the bases are you and your physicians eager to see? Go to our webpage and look for it under the Technical Reports tab. If your answer is not there, an easy thing to do is to email PCCAScience@pccarx.com, then let us to help you address those data concerns. We’re happy to hear about the needs of your pharmacy, practitioners and patients. The whole Research and Development team is driven by this and works diligently to development new products and techniques to provide you solutions. Talk with us to make sure your needs are being heard. Maybe next year at International Seminar, the unveiled new product will be exactly what you’ve been waiting for.

Finally, here’s a sneak peek of the next PCCA Science update: Several manuscripts authored by PCCA have recently been accepted for publication in peer-reviewed journals, covering everything from clinical to regulatory topics. We will present these in the next PCCA Science post here on the blog. Stay tuned, and see you soon!

Yi Liu, PharmD, PhD, is a research pharmacist in the Research and Development department at PCCA. She joined PCCA as a clinical pharmacy researcher in the Clinical Services department in 2018 and started her current role in 2019. Yi graduated from Ohio University with a PhD in molecular and cellular biology in 2012. She also worked as a postdoctoral research fellow in the Houston Methodist Research Institute for three years prior to starting pharmacy school. Yi received her PharmD from the University of Houston College of Pharmacy in 2019.

A New Anhydrous Base for Female Hormone Delivery

Fri, 11 Oct 2019 13:52:00 GMT

By PCCA

This morning at International Seminar 2019, attendees packed into the ballroom to hear our Chief Scientific Officer Gus Bassani, PharmD, deliver his PCCA Innovation presentation. This is where Gus reveals the much-anticipated new PCCA products every year. This time, he introduced the audience to VersaBase® Anhydrous HRT, the pharmacy compounding industry’s first proprietary anhydrous base developed specifically to deliver female bioidentical hormones through the skin, such as estriol, estradiol and progesterone.

PCCA Chief Scientific Officer Gus Bassani introduces
International Seminar attendees to VersaBase Anhydrous HRT.

This new base is the latest addition to the VersaBase family of vehicles, and it uses a patent-pending delivery system that improves both the solubility of hormones and their permeation into and through the skin. This is typically difficult to achieve with an anhydrous base, but our Director of Research and Development Daniel Banov, MS, RPh, and his team have spent their careers inventing products that surpass what most consider possible. This one is no exception. VersaBase Anhydrous HRT performed comparably to VersaBase Cream (the industry standard for women’s topical HRT) during in vitro testing that demonstrated it delivering our Special Micronized Progesterone into and through human skin tissue.

VersaBase Anhydrous HRT also complements our newer anhydrous bases that we first released in 2018 to address changing needs in the compounding industry. Like PermE8™ Anhydrous Gel and W06™ Anhydrous Topical Gel, this newest base has water activity lower than 0.6 (Aw < 0.6), which qualifies it as anhydrous according to the standards in the latest version of USP General Chapter <795>. Therefore, formulations in these bases have longer default beyond-use dates (BUDs), which the chapter allows for nonaqueous dosage forms. This can save compounders thousands of dollars per formulation because the medications do not have to be stability tested in order to have the longer BUD. It also makes compounds more convenient for patients, since they won’t have to return to the pharmacy as often for prescription refills. To increase efficiency further, most of the VersaBase Anhydrous HRT formulas that we have tested and published in the PCCA formula database do not require the use of an ointment mill, which reduces both compounding time and cleanup time.

Also on The PCCA Blog: Why Water Activity Matters in Pharmacy Compounding

PCCA members with Clinical Services access can visit our formula database to see the numerous VersaBase Anhydrous HRT formulas that we have already developed to help eet the needs of patients. If they have questions about compounding with this base, they can contact our clinical compounding pharmacists at 800.331.2498.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Micronized or Wettable: Which Type of Progesterone Should You Compound With?

Tue, 06 Aug 2019 14:05:46 GMT

by PCCA

In numerous discussions with compounders recently, the experts on our Clinical Services team have found that there is confusion around some of the different types of progesterone, specifically when to use a micronized progesterone powder and when to use a wettable progesterone powder. To help you determine the best choice, here are some considerations for choosing which progesterone to use.

Micronized or Wettable Progesterone?
For most compounded medications, our Clinical Services and Formulation Development teams recommend that compounders use a micronized progesterone. They specifically prefer our exclusive, USP-grade Special Micronized Progesterone, which has a particle size of 90% less than 5 μm and 100% less than 10 μm to promote better bioavailability. The USP monograph for progesterone does not specify micronization standards,¹ but ours meets or exceeds the monograph criteria and leads the industry in particle size, going beyond what is required.

However, we also offer a USP-grade wettable progesterone for certain situations. To further clarify when compounders should use which type of progesterone, we asked Melissa Merrell Rhoads, PharmD, Director of Formulation Development at PCCA. “Our Special Micronized Progesterone is versatile and can be used in almost any dosage form, from topical creams, oral capsules and troches to rapid dissolve tablets, suppositories and more,” she said. “We typically only recommend the use of wettable progesterone when a troche or suppository is needed at concentrations above 200 mg.” This is because wettable progesterone incorporates more easily into melted bases at these higher concentrations. “However, progesterone troches with concentrations above 100 mg are very bitter, so palatability and patient compliance could be an issue,” Melissa said. “There are really very few reasons not to use our Special Micronized Progesterone — it’s very high quality and less expensive than our wettable version.”

Some compounders have also shared with us that they believed wettable progesterone is less bitter than micronized progesterone, which is a consideration for troches and other dosage forms in which the patient’s taste is a factor. However, our clinical and formulations experts maintain that there is no difference in the bitterness of micronized and wettable progesterone powders. As Melissa indicated above, it is the amount of progesterone, regardless of the type, that will affect the bitterness of a compounded medication.

What Makes It Wettable?
If you do need to use a wettable progesterone, it’s also important to consider what makes it wettable. There are various options available in the compounding industry, but not all of them are USP grade. Even some that are labeled as USP grade contain additives, such as surfactants like sodium lauryl sulfate, that make them wettable. These are often listed on the chemical’s certificate of analysis or safety data sheet. Some USP drug substance monographs explicitly allow additives, and some do not. Thyroid USP’s monograph, for instance, states that “it may contain a suitable diluent such as lactose, sodium chloride, starch, sucrose, or dextrose.”² On the other hand, the USP monograph for progesterone does not explicitly mention an additive.¹ This calls into question whether progesterone powders with additives can, in fact, be USP grade.

Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist, finds this concerning. He points out two sections in the General Notices and Requirements of the United States Pharmacopeia and National Formulary: Section 3.20, Indicating Conformance, and Section 5.20, Added Substances, Excipients, and Ingredients.

Section 3.20 states that “when a drug product, drug substance, compounded preparation, or excipient fails to comply with the identity prescribed in USP or NF or contains an added substance that interferes with the prescribed tests and procedures, the article shall be designated by a name that is clearly distinguishing and differentiating from any name recognized in USP or NF.”³ When considering this passage in relation to wettable progesterone, Matt wonders, “How does a chemical comply with the identity of the USP monograph when it has another chemical that is not discussed in the monograph?”

Section 5.20 states, “Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or they interfere with the assays and tests prescribed for determining compliance with the compendial standards (see section 3.20 Indicating Conformance).”³ Even though this doesn’t rule out additives unless they impair bioavailability, therapeutic efficacy or safety, or they interfere with determining compendial compliance, Matt again raises questions. “How can a company supplying the progesterone with an additive prove that the additive does not create any of these issues?” he says. “Do they have data that can prove this?”

Fortunately, our USP-grade wettable progesterone does not contain additives, but instead is rendered wettable through its manufacturing process. PCCA customers will not find any additives listed on our wettable progesterone certificates of analysis or safety data sheets for this reason.

Soy Source? Not to Worry
Aside from questions about using micronized or wettable progesterone, compounders have also voiced concerns about the fact that some bioidentical hormones — our wettable progesterone included — are derived from soy sources. They are rightly concerned because some patients have allergies or sensitivities to soy. However, even though we list the soy origin of some of our bioidentical hormones, they do not actually contain soy allergen. This is due to the chemical manufacturing process. While the manufacturers may use soy as the starting material to begin chemical synthesis of the bioidentical hormones, the processing steps involved mean that the end product is far removed from the starting material, so much so that they have no detectible soy content.

To prove this, we submitted some of our hormones to an independent lab for allergy testing. (You can see which ones here.) The lab tested specifically for soy content, and the controlled tests found no soy-based allergens with a limit of detection of 2.5 parts per million, or 0.00025%. This means that it would be incredibly unlikely for one of these hormones to cause an issue for a patient with a soy allergy.

Gus Bassani, PharmD, PCCA’s Chief Scientific Officer, wasn’t surprised with the results. “With the pure, pharmaceutical-grade drug substances that we carry, the expectation was that there would not be any soy-based impurity present, despite the fact that soy sterols were used as the starting material to begin chemical synthesis to the bioidentical sex hormones,” he said.

The Bottom Line
With so many choices for chemicals in the pharmacy compounding industry, many of which claim to be of the highest quality, it can be difficult at times to determine which ones are the best choice for your patients. When it comes to progesterone, our experts recommend a USP-grade, micronized progesterone in most cases — specifically Special Micronized Progesterone because of its unparalleled particle size, and because it, like all of our active pharmaceutical ingredients, goes above and beyond minimum requirements and meets The PCCA Standard™. If you need to compound with a wettable progesterone, such as when incorporating it into a melted base at a high concentration, we recommend using one that is USP grade and that does not contain additives. And even if we indicate that one of our bioidentical hormones has a soy source, it is very unlikely that a patient with a soy allergy or sensitivity will have issues with it.

As always, if PCCA members with Clinical Services access have questions about compounding with progesterone, they can contact our clinical compounding pharmacists at 800.331.2498.

References
1.   United States Pharmacopeial Convention. (2019). Progesterone. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
2.   United States Pharmacopeial Convention. (2019). Thyroid. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
3.   United States Pharmacopeial Convention. (2019). General notices and requirements. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Why VersaBase Cream Is Your Best Choice for Women’s HRT

Wed, 17 Apr 2019 18:08:16 GMT

VersaBase Cream is a stable, pharmaceutically elegant base that can accommodate a broad range of active ingredients for customized, patient-specific medications. Compounding pharmacies have been using it for many applications over the years, but where it stands out is in topical and vaginal hormone replacement therapy (HRT). Our Clinical Services, R&D and Formulation Development departments continually research, test and formulate with VersaBase Cream, and independent researchers have worked with it as well. This makes it one of the most studied bases in the pharmacy compounding industry with a substantial portfolio of supporting data and materials, giving compounders incredible support in using it to help their patients.

VersaBase by the Numbers

5 publications to support its use in compounded medications

230+ formulas, offering a plethora of potential treatment options

20 formulas with extended beyond-use dates (BUDs)

13 bracketed formulas with extended BUDs to expand the possibilities for pharmacy and patient

7 related marketing resources to help in discussions with prescribers]

It’s Been Studied
Both PCCA and independent researchers have been studying VersaBase Cream for over a decade, giving compounders support when they recommend it in compounded medications. It has been included in the Journal of Women’s Health Care, where a peer-reviewed, in vitro study showed that it delivered our Special Micronized Progesterone into and through human skin. An independent, peer-reviewed study published in Gynecologic and Obstetric Investigation evaluated the absorption of estriol, estradiol, progesterone, DHEA and testosterone in VersaBase Cream, among other experimental factors. The International Journal of Pharmaceutical Compounding recently published an independent case study showing transdermal delivery of testosterone in this base, and another study evaluating the chemical stability of a range of estriol concentrations in a VersaBase vaginal cream. U.S. Pharmacist has also published an independently developed compounding formulation of progesterone in this base.

It’s Backed by Numerous Formulas
Not only is VersaBase Cream well studied, but we have also supported it with numerous formulations as well, offering compounders, practitioners and patients a host of potential treatment options. We have developed over 230 formulas in total that use VersaBase Cream. Of those, 20 have gone through our FormulaPlus™ program, so they have extended BUDs supported by stability-indicating assays. This can save compounders thousands of dollars in stability testing, it makes compounds more convenient for patients because they won’t need to refill prescriptions as often. We provide the data behind each BUD study as well. Of those formulas, 13 are bracketed, meaning that they offer the compounder a range of active ingredient concentrations with the same extended BUD, substantially expanding their value for the pharmacy and the patient. PCCA members can easily access all of these under the formula tab of the VersaBase Cream page on the Members-Only Website.

It Has Marketing Support
We have also developed various marketing materials to help pharmacies that compound topical and vaginal HRT with VersaBase Cream. PCCA members have access to the product information sheet, customizable top formula cards, a customizable PowerPoint presentation and much more. They can find all of them on the Marketing Resources page of the Members-Only Website.

If PCCA members have questions about compounding with VersaBase Cream, they can contact our Clinical Services department at 800.331.2498.

What happens in Vegas, Stays in Vegas? Not When It Comes to HRT Education

Fri, 05 Apr 2019 18:10:33 GMT

By Ranel Larsen, PharmD, RPh, PCCA Clinical Compounding Pharmacist

This is the saying that comes to mind of when we think about Las Vegas. But, in the case of PCCA’s HRT Symposium, what happens in Vegas does not, in fact, stay there.

“HRT Vegas,” as we often call it, happens each year in February and focuses on hormone replacement therapy (HRT). It is the compounding industry’s biggest hormone replacement event, and this year was no exception. The same can be said of all PCCA Education. At each event, we ask for feedback on suggested topics, speakers and ideas to make the next event bigger and better. This year, HRT Vegas was exceptional, with engaging topics and an incredible line-up of speakers tailored to the needs of our attendees. One of the advantages of compounded HRT is being able to customize the therapy for each patient’s specific needs because, as we know, one size does not fit all. HRT is also a complex topic and should not be considered without a thorough understanding of how all the body’s hormones interact with each other. This is what attendees learn at HRT Vegas, plus much more. Let’s look at some highlights.

HRT and Safety
When we talk about hormones, one of the first things that is usually brought up is safety. Estradiol may improve cognition¹and lower the risk of Alzheimer’s disease,^2,3cardiovascular disease, osteoporosis and other comorbidities in postmenopausal women. With heart disease being the number one cause of death in women, why are more not using HRT? There are two reasons: A poor understanding of the science by physicians and the general public, and a fear of breast cancer. Let’s take a minute to look at a few key studies.

We will start with the Women’s Health Initiative (WHI) study. It is important to have a thorough understanding of this study, as it contains valuable information, and it had and still has a huge impact on the use of hormones. If you look at the estrogen-only arm involving conjugated equine estrogen (CEE), the results showed a decreased risk of breast cancer, coronary heart disease, colorectal cancer and death.⁴ In addition, the WHI 18-year follow-up data showed a significant reduction in breast cancer incidence with CEE alone, and a significant increase in breast cancer incidence with CEE plus medroxyprogesterone.⁵ So it seems that medroxyprogesterone is likely the suspect here.

The Journal of the American College of Cardiology published a study that concluded that natural progesterone, not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.⁶ This suggests that there is a major difference between progesterone and medroxyprogesterone. Just take a look at the chemical structure of each, and you can see how truly different they are. Then, compare the structures of estradiol and testosterone. Look at how a small change can drastically change the chemical. It’s not too surprising that progesterone and medroxyprogesterone have such different actions.

And finally, one of the most substantial pieces of evidence that hormones are safe is the North American Menopause Society (NAMS) Hormone Therapy Position Statement, 2017. It concluded that hormone therapy is the most effective treatment for vasomotor symptoms and genitourinary symptom management and has been shown to prevent bone loss and fracture. In addition, they state, “The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.”⁷

The Route Is Important
The Kronos Early Estrogen Prevention Study (KEEPS), which involved more than 700 women, looked at transdermal estradiol and oral progesterone and found no increase in breast cancer risk. It also concluded that the therapy relieved many of the symptoms of menopause, improved mood and improved several markers of cardiovascular risk.⁸ Another study showed that oral but not transdermal estrogen replacement therapy is associated with risk of venous thromboembolism in postmenopausal women, suggesting that transdermal therapy might be safer than oral therapy with respect to thrombotic risk.⁹ A recent study also highlighted that the transdermal route avoids the hepatic first‐pass metabolism, resulting in fewer adverse effects on coagulation markers compared to oral estrogens and does not increase risk of deep vein thrombosis.¹⁰

It’s a Symphony
PCCA’s HRT Symposium has evolved to a more functional medicine approach over the years, looking at the body as a whole and working to treat the cause instead of simply treating the symptoms. So not only did we learn about estrogen, progesterone and testosterone, but also about thyroid, adrenals and the gut, and how it is all connected.

Why Patients Need a Compounding Pharmacy
Compounders have something that is not offered anywhere else. We have the ability to customize and to use estriol and testosterone, which are not commercially available. We can make different strengths and dosage forms of estrogen and progesterone, and we can make it easy for patients by combining multiple active pharmaceutical ingredients into one dosage form. And most of the time, this means increased compliance and affordability, which means happy patients. “Happy wives equal happy lives,” right? Well I say that happy menopausal patients make for happy pharmacists and practitioners!

This is just a small sampling of what HRT Vegas provided. In addition, our speakers presented many formulas, compounding tips and tricks, and updates on public affairs and regulatory issues. The event brings together pharmacists, marketers and practitioners from all over the U.S. and Canada, building lasting professional relationships and empowering each other. HRT Vegas brings us together, helps us make connections and increases our knowledge to better serve our patients. When you come to PCCA’s HRT Symposium in Las Vegas, what happens in Vegas does not stay in Vegas!

Can’t wait until next year? PCCA members can join us for our Nashville HRT Symposium from August 8–10, 2019. They can also earn their HRT Specialist designation by taking our C4 HRT Online Course, which starts May 13, 2019, and attending the Nashville HRT Symposium.

Ranel A. Larsen, PharmD, RPh, PCCA Clinical Compounding Pharmacist, is a graduate of the Roseman University School of Pharmacy, where she obtained her Doctor of Pharmacy degree in 2006. After working in retail pharmacy for three years, she transitioned to a compounding-only pharmacy, where she worked for over four years. Ranel joined the PCCA staff in April 2014. Her areas of interest include hormone replacement therapy for men and women, veterinary medicine, pain management and dermatology.

References
1.   Hogervorst, E., Williams, J., Budge, M., Riedel, W., & Jolles, J. (2000). The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: A meta-analysis. Neuroscience, 101(3), 485–512.
2.   Nilsen, J., Irwin, R. W., Gallaher, T. K., & Brinton, R. D. (2007). Estradiol in vivo regulation of brain mitochondrial proteome. Journal of Neuroscience, 27(51), 14069–14077. https://doi.org/10.1523/JNEUROSCI.4391-07.2007
3.   Wharton, W., Gleason, C. E., Lorenze, K. R., Markgraf, T. S., Ries, M. L., Carlsson, C. M., & Asthana, S. (2009). Potential role of estrogen in the pathobiology and prevention of Alzheimer's disease. American Journal of Translational Research, 1(2), 131–147.
4.   Anderson, G. L., Limacher, M., Assaf, A. R., Bassford, T., Beresford, S. A., Black, H., … Wassertheil-Smoller, S. (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA, 291(14), 1701–1712. https://doi.org/10.1001/jama.291.14.1701
5.   Manson, J. E., Aragaki, A. K., Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., … Wactawski-Wende, J. (2017). Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women's Health Initiative randomized trials. JAMA, 318(10), 927–938. https://doi.org/10.1001/jama.2017.11217
6.   Rosano, G. M., Webb, C. M., Chierchia, S., Morgani, G. L., Gabraele, M., Sarrel, P. M., … Collins, P. (2000). Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. Journal of the American College of Cardiology, 36(7), 2154–2159.
7.   The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. (2017). The 2017 hormone therapy position statement of The North American Menopause Society. Menopause, 24(7), 728–753. https://doi.org/10.1097/GME.0000000000000921
8.   Cobin, R. H., & Goodman, N. F. (2017). American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause–2017 update. Endocrine Practice, 23(7), 869–880. https://doi.org/10.4158/EP171828.PS
9.   Scarabin, P. Y., Oger, E., & Plu-Bureau, G. (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet, 362(9382), 428–432. https://doi.org/10.1016/S0140-6736(03)14066-4
10.   Mikkola, T. S., Savolainen-Peltonen, H., Venetkoski, M., & Ylikorkala, O. (2017). New evidence for cardiac benefit of postmenopausal hormone therapy. Climacteric, 20(1), 5–10. https://doi.org/10.1080/13697137.2016.1262839

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

New Videos Added to PCCA PLAY

Wed, 16 Jan 2019 17:22:47 GMT

PCCA Play: January's New Releases

PCCA Play is our member-exclusive, educational media library. It offers tens of thousands of dollars’ worth of free educational content available on desktop, tablet or smartphone. PCCA members can also access premium content through a subscription or a la carte rental.

Our library includes everything from mainstage presentations at live PCCA events to our recorded webinars, bringing PCCA members the information they need, when and where they need it.

Hormones and the Skin and GI Health and Its Effects on the Skin
With Pamela W. Smith, MD, MPH, MS, and Ranel Larsen, PharmD, RPh

Chemical Peels and Resurfacing [Available January 24, 2019]
With Valcinir Bedin, MD, PhD, and Daniel Banov, RPh, MS

PCCA Science: Leading Research in Pharmacy Compounding

Mon, 10 Dec 2018 17:31:00 GMT

PCCA Science: Leading Research in Pharmacy Compounding

By Maria Carvalho

At PCCA, we conduct extensive studies on the quality and safety of our proprietary products. We also collaborate with PCCA member pharmacies to conduct case studies that evaluate the efficacy of their compounded medications. We have been generating scientific evidence on pharmacy compounding for decades, and we want to share it publicly whenever possible. That’s why we created PCCA Science, a division within our Research & Development (R&D) department dedicated to writing our studies for publication.

To date, we have over 130 scientific publications, including peer-reviewed journal articles, conference abstracts and posters, technical reports, and case studies. These publications cover a broad range of therapeutic categories, such as aging, dermatology, gastroenterology, hormone replacement therapy, oncology, pain management, veterinary medicine, women’s health and wound therapy, among others. So that everyone can access our research related to pharmacy compounding and our proprietary products, we collected all of our studies on the PCCA Science webpage.

We have also attracted the interest of researchers and professionals worldwide who occasionally publish studies including our proprietary products. We regularly check scientific databases to search for these studies, and when we find them, we provide links to the corresponding journal articles on the PCCA Science webpage. As such, this page includes not only our R&D studies, but also those conducted by independent researchers.

Every month, we have new and exciting publications to share with the compounding community. We will periodically post updates about them on The PCCA Blog so that you don’t miss anything that could potentially be very useful for you, your patients or the health care practitioners you work with.

Below are our latest publications and research posters. Stay tuned for more PCCA Science updates.

Journal Articles

• Budesonide 1-mg/10-mL and 2-mg/10-mL Mucolox Oral Suspensions
A formulation published in the July/August 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

• Basics of Sterile Compounding: Criteria for Determining Beyond-Use Dating
An article published in the July/August 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

• Quality Assurance and Quality Control: Being Prepared for U.S. Food and Drug Administration Inspections and Staying in Compliance with United States Pharmacopeia Chapter <797>: Part 1
An article published in the September/October 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

• Quality Assurance and Quality Control: Being Prepared for U.S. Food and Drug Administration Inspections and Staying in Compliance with United States Pharmacopeia Chapter <797>: Part 2
An article published in the November/December 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

• Case Study: Absorption of Testosterone Cream via Scrotal Delivery
A case study published in the November/December 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

• Physical and Chemical Stability of Estriol 0.025% to 1% Vaginal Creams (VersaBase)
A stability study published in the November/December 2018 issue of the International Journal of Pharmaceutical Compounding. Read the abstract here

Conference Posters

• Physicochemical stability of omeprazole 2 mg/mL and 10 mg/mL oral suspensions in SuspendIt
Presented at the 10th EuPFI Conference in London, United Kingdom, 12–13 September, 2018. Access the poster here
• Physicochemical stability of lansoprazole 3 mg/mL and 10 mg/mL oral suspensions in SuspendIt
Presented at the 10th EuPFI Conference in London, United Kingdom, 12–13 September, 2018. Access the poster here

Case Study

Disease-Related Drooling Saliva in the Elderly (PCCA Sorbitol Lollipop)
Published by PCCA Science. Access it here

Maria Carvalho, PharmD, MRPharmS, PhD, is the Manager of PCCA Science.