Compounding Bio-identical Hormonal Replacement

Transcription

1 Pharmacy Technician Education for Association Members Pharmacy te mseries Compounding Bio-identical Hormonal Replacement By: Wesley Nuffer, PharmD, BCPS,CDE Assistant Professor, Assistant Director of Experiential Programs University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences Dr. Nuffer is an assistant professor with the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences. His clinical work is done at the University of Colorado Hospital in the Endocrinology, Metabolism and Diabetes Practice clinic. His specialty areas include diabetes, obesity, women s health, and experiential education. Dr. Nuffer previously consulted with menopausal women, compounding and holding BHRT group classes at an independent pharmacy in Denver for several years. Dr. Nuffer reports no actual or potential conflicts of interest in relation to this continuing pharmacy education activity and reports off-label use will not be discussed. CPE Information: Universal Activity Number: H01-T CPE/Hours: 1 contact hours (0.1 CEUs) Target Audience: Pharmacy Technicians Activity Type: Knowledge-based Initial release date: 1/1/2013 Planned expiration date: 12/31/2014 The Collaborative Education Institute is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Therapy Menopause is a natural process in every woman s life, generally occurring between the ages of 49-54, where a woman s menstrual cycle ceases, signifying the end of normal ovarian function. During this change, there are marked fluctuations in a woman s hormone production, as the ovaries transition to stop producing her primary estrogen (estradiol) and a new, less potent source of estrogen is produced (estrone) at significantly lower levels. Progesterone levels also decrease substantially during this time. 1 The transition into menopause is often accompanied by fluctuations in women s menstrual cycles, which may last shorter or longer, may be lighter or heavier in volume, and no longer come regularly on a monthly pattern. The hormone fluctuations also produce a number of uncomfortable symptoms, with the most common symptoms reported being hot flashes or flushes, night sweats, insomnia, mood swings, a foggy memory, and both skin and vagi- Activity Goal: To familiarize the pharmacy technician with the field of bio-identical hormone therapy, focusing on the two major hormones, and to highlight several key concepts regarding the compounding of hormones. Learning Objectives: Upon successful completion of this knowledge-based CPE activity, pharmacy technicians should be able to: 1. Distinguish between bio-identical hormone replacement therapies (BHRT) that are available commercially and those that must be prepared by compounding the product 2. Define the basics of which women s hormones are compounded and potential benefits of each 3. Recognize a particular compounded formulation (cream, troche, tablet, etc.) to best meet an individual woman s needs 4. Recognize how different BHRT products are compounded and estimate the advantages and disadvantages of different formulations 5. Discuss the current evidence surrounding the use of compounded BHRT products This activity has been developed specifically for pharmacy technicians and is one of 10 activities in the TEAM series.

2 nal dryness. The incidence and severity of these symptoms are very individual; some women describe them as merely bothersome or hardly notice the change, while others experience very severe symptoms that greatly impact their overall quality of life. 2 In the past, it was thought that with the decline in estradiol, a woman s risk for heart disease and her risk of bone loss increased. The standard of care was to prescribe hormone replacement therapy (HRT) to avoid these risks. This approach changed drastically, however, after the results of the Women s Health Initiative trial, which demonstrated that the most prevalent hormone combination of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) may actually carry substantial health risks which outweigh any protective benefits these hormones produced. 3 Following this trial, there was a tremendous paradigm shift in the management of menopause, with guidelines recommending HRT only for symptomatic relief, and only for a short period of time. It also left huge numbers of women looking for alternative solutions for their menopause symptoms. page 2 WHI Trial The Women s Health Initiative was a huge, multi-center research project that, in its entirety, studied more than 160,000 post-menopausal women aged over 15 years. While there were actually four different randomized interventions within the project, the trial that received the most attention was a comparison between conjugated estrogen alone or conjugated estrogen plus progestin compared against placebo in post-menopausal women, evaluating treatment effects on coronary heart disease and invasive breast cancer. The study design is as follows: The treatment group showed a higher incidence of heart attacks, strokes, breast cancer and blood clots when compared to placebo. To put the numbers in perspective, for every 10,000 women who received the treatment of CEE plus MPA, there would be an additional seven heart attacks, eight cases of breast cancer, nine cases of stroke and eighteen blood clots due to treatment. While there were positive results regarding hip fractures and colon cancer, these benefits were assessed not to outweigh the risks. The estrogen-only arm of the trial continued on until 2004, where it, too, was stopped early, due to an identified increased risk of stroke in the treatment group. Of note, the substantial heart disease and breast cancer risks were not seen in this group. 4 Practice Points: The entire approach to managing a woman who has reached menopause changed after the WHI trial, due to the conventional hormones treatment demonstrating a significant risk with use. This shows just over 10,500 women receiving CEE treatment or placebo with approximately 16,600 women receiving the combination of CEE and MPA or placebo. Women who had received a hysterectomy were given estrogen alone, as they would not be at risk for endometrial cancer, which MPA is given to prevent. The trial was designed to follow these patients over approximately 8.5 years. In 2002, however, the National Institute of Health made the determination to stop the combined CEE + MPA treatment arm early, after an average of 5.2 years of follow-up, due to the assessment that the health risks exceeded benefits of treatment. 3 The results from this combined arm are depicted here: Questions regarding the WHI Trial Results While experts agree that the WHI trial design and sample size were strong and clearly demonstrate a risk in the women studied who were using conventional hormone replacement, there have been some criticisms about the trial s design. One observation pointed out the wide diversity in the ages of the women studied, extending all the way out to the age of 79, which is well beyond the start of menopause. Many experts feel that the benefits of hormone therapy are most pronounced at the start of menopause, in women aged 50-59, and that those women may respond differently than women over 60. In fact, further analysis of the WHI trial data examining women taking estrogen alone indicates that the identified risks from this trial were not present in the younger cohort of patients who fell into the age group. 5 Another criticism is of universally applying the results to all estrogen and progestin treatments

3 since the study focused on only one particular formulation of each; the conjugated equine estrogen and medroxyprogesterone acetate. Some experts questioned whether other estrogen and progestin formulations, which have some documented different physiologic effects in the body, may carry the same risk as these two products. Change in HRT Approach Following the publication of this major trial, the entire medical approach towards menopause management shifted. The American Colleges of Obstetrics and Gynecology (ACOG) and the North American Menopause Society both released updated guidelines, stating that estrogen replacement or estrogen and progestin replacement should not be used for treatment of any chronic condition. 6,7 The only remaining indication for HRT was for symptomatic relief, and guidelines clearly stated that women should be on the lowest possible dose of hormones for the shortest amount of time. Women currently on hormones were encouraged to taper their treatment off and discontinue it, and many women were told by their physicians to simply stop their hormones, which in several cases led to the resurgence of significantly uncomfortable menopausal symptoms. New lower dose formulations of conjugated equine estrogen were developed and produced to better meet these new guidelines. Other medications were also explored for managing these symptoms, such as antidepressants like fluoxetine and venlafaxine, or the anti-hypertensive clonidine. While these agents do demonstrate some effectiveness in controlling hot flashes, they do not demonstrate the same effectiveness shown by supplementing estrogen. Also, many women did not like the idea of taking an antidepressant for several years to control menopausal symptoms. Finally, a different approach to hormone replacement rapidly began to gain popularity: the use of bio-identical hormones. The success that bio-identical hormone therapy showed led to a revised statement by ACOG in 2012 to endorse its use for shortterm treatment of menopausal symptoms. 8 Bio-identical hormone replacement The term bio-identical in regards to hormones is used to describe molecules that are an exact copy of what a woman would naturally produce in her body. There are three different estrogens which naturally occur in a woman s body: estrone (E1), estradiol (E2), and estriol (E3). This can be easily remembered by their names: estrone= E1, estradiol = E2, and estriol = E3. Of these, estradiol is the most potent, and is the focus of many of the available prescription estrogen products. While any of the estradiol prescription products are, by definition, bio-identical, bio-identical hormone replacement therapy (BHRT) generally refers to products specially compounded in compounding pharmacies, utilizing the source hormone powders to formulate hormones in a variety of dosage forms and vehicles. Bio-identical hormones also include progesterone, which is available by prescription under the trade name Prometrium, and is also widely compounded into different formulations. Other compounded hormones that are also used for women include testosterone, dihydroepiandosterone (DHEA), and pregnenolone, which are beyond the scope of this monograph. page 3 BHRT therapy has continued to grow in popularity among women of menopausal age. Many of these women feel that conventional medicine has not provided them adequate solutions to controlling severe menopause symptoms, and some are willing to face potential risks of therapy in order to improve their quality of life, which has been significantly impacted. In the search for alternative treatments, bio-identical hormone replacement began to be marketed as a safer alternative for women, based on the idea that the body already recognizes these molecules and knows how to handle them. Several physicians began to publish books promoting both bio-identical (natural) progesterone and estrogens, and some key famous spokespersons (Suzanne Somers, Oprah Winfrey) continued to publicize successes seen with using these bio-identical products. Compounding pharmacies correctly identified this as a unique opportunity and began their own marketing to promote an alternative to conventional hormone replacement by using bio-identical hormones. With the increased use of the internet, a multitude of internet sites were established marketing bio-identical hormones. Unfortunately, with this marketing came a general feeling of mistrust of the medical establishment, propagated by book titles such as What Your Doctor May Not Tell You about Menopause. 9 Providers began to recognize the need to better understand these products, so that they could carry on an informed discussion with the women they are treating, who inevitably come in armed with questions and information based largely from popular media. Practice Points: The term bio-identical refers to molecules that are an exact copy of what is naturally produced in the body. There are bio-identical hormones available by prescription (estradiol, progesterone) and also compounded. Compounded BHRT products By far, the most popular of the bio-identical hormones formulated for women are progesterone and estrogen products. The late Dr. John Lee was a pioneer in what he coined natural progesterone therapy, citing an abundance of his personal successes in managing women utilizing bio-identical progesterone. While it was quite apparent that he had some tremendous success working with women, it was difficult to determine how much impact the progesterone supplementation had, as he also implemented some pretty rigorous dietary and vitamin/nutrient interventions with the women he worked with. 9 After the WHI trial, BHRT advocates began to highlight that the CEE used for the study actually came from the urine of pregnant horses, easily pointing out that women would benefit more from a product that is naturally found in their body than one that comes from a horse. The fact that there is very little scientific evidence to support BHRT estrogen s perceived better safety and tolerability did little to impact the rising momentum this therapy was gaining. One major advantage that is often highlighted by compounded pharmacies is the ability to customize medications for the individual. As such, there are a variety of different hormone products that can be developed and produced to help manage a woman s menopausal symptoms. Delivering a drug orally (by swallowing a tablet, capsule, or liquid) results in drug absorption that travels first to the liver before it enters systemic

4 circulation. This is significant because the liver can metabolize the drug partially or completely before the drug ever exerts its intended systemic effects. This is called the first-pass effect. Administering a drug by a different route, such as a topical administration across the skin (using a cream or patch) or placing a drug in the cheek or under the tongue (called buccal administration) avoids this first-pass effect, stopping the liver from metabolizing the drug until after it reaches systemic circulation. In regards to hormone administration, these different deliveries can have a significant impact on the effects of the compounded medication. One example is with progesterone, which is very highly metabolized (>90%) by the liver. Progesterone administered orally will form a number of different metabolites, some which are active and have effects in the body, others which are not active. One particular metabolite of progesterone is extremely sedating, accounting for the major drowsiness side effect seen when taking oral progesterone. Administering progesterone topically avoids this liver metabolism, allowing the compounding pharmacy to provide a much lower dose of the drug, which will still reach systemic circulation but will not have nearly the same sedation effects seen with the oral pill. By understanding these different pharmacokinetic and pharmacodynamics properties of the hormones, compounding pharmacists can customize the type of product an individual patient may need. A woman complaining of insomnia, for instance, may benefit from an oral progesterone capsule, which will cause sedation and may help her sleep. A different woman may not want marked sedation with her hormone replacement, and may elect to receive a progesterone cream instead. When considering which delivery system to utilize for a specific hormone product, it is important to consider the overall dose that will be delivered. One popular dosage form for estrogens is a troche (pronounced tro-key), which is a lozenge designed to dissolve under the tongue. While this is also possible with progesterone, the larger overall dose needed creates a troche that is substantially larger in size, which requires the woman to have the product placed in her mouth for several minutes while it dissolves. Even with customized flavoring, many women tire of this prolonged dissolving time, and the longer the product sits in the mouth, the more likely some of it gets swallowed, leading to a different absorption path that is not optimal. Similarly, creams need to be formulated so that a very small volume (approximately 0.5cc) holds the therapeutic dose. Cream doses that exceed ~1mL in volume require such a large surface area of the body to rub the product in that absorption begins to become compromised, or the woman feels like she is bathing in the product. Generally, women are instructed to administer the cream to the inside of the forearm or thigh(roughly the size of a pea) and to thoroughly rub the cream into that area for approximately 20 seconds. These areas have good blood perfusion, and the prolonged rubbing facilitates complete absorption and minimizes risks of exposing others (such as the husband or family pet) to hormones by having cream remain on the skin. Finally, local administration is also an important consideration. A woman suffering only from vaginal dryness may benefit from a vaginal estrogen cream or suppository, which can be administered locally at a lower dose, resulting in a lower overall blood level of the drug, page 4 minimizing systemic effects. With all of these available options for delivering hormones, there have been significant advances in technology available to the compounding pharmacist. New cream bases, such as PLO gels (pluronic lecithin organogel) optimize how the drug penetrates the skin and absorbs into the bloodstream. There are different agents, such as methylcellulose, which create a sustained-release property, allowing the drug to absorb more slowly and be dosed once a day, improving patient adherence. Diligent compounding pharmacies also frequently send their formulated products out to an independent lab for analysis to verify that the product contains the correct drug at the correct potency. There have also been a number of improvements to the dosing devices used to deliver these products; creams are typically dispensed in syringes with caps that can be utilized to provide an exact amount of drug, as opposed to scoops or spoons, which are estimates at best and can result in varied doses delivered. Several patented devices are available for use in order to facilitate exact dosing. Practice Points: Different dosage forms allow pharmacists to change the side effect profile and concentration of the hormone given by taking advantage of the body s physiological processes. Combination products Due to the fact that compounding pharmacies start with powder sources of these hormones (usually originating from yam or soy sources to generate diosgenin, which is then chemically converted into hormones) it is also possible to combine several medications into one formulation. Many compounding pharmacists work closely with a woman s provider to make recommendations for different combination products. It is not uncommon for a woman to receive a hormone replacement cream that could contain estrogens, progesterone, and testosterone, all at varying concentrations. The benefit to this type of approach is improving adherence by providing multiple drugs in one formulation. One disadvantage is if the dose of one hormone needs to be adjusted, a woman cannot simply vary the volume of cream applied, as it would affect the dose of the other active hormones as well. While there is a certain amount of variability between different compounding pharmacies, depending on the providers they work with and the specific pharmacy preferences, there are some general standardized products used when compounding hormones. As an example, Pharmacy Compounding Centers of America, or PCCA, is one of the leading organizations in the nation in providing compounding chemicals, recipes, education and support for compounding pharmacies. 10 While not forgetting about individual variability, these are recognized compounded products:

5 Tri-est: Tri-est is a combination of all three bio-identical estrogens: estriol, estradiol, and estrone. These are provided at a fixed ratio, usually at 80:10:10 (80% estriol, 10% estradiol, and 10% estrone). Bi-est: Bi-est combines estriol and estradiol, usually in an 80:20 mix (80% estriol, 20% estradiol). While there is no exact conversion between different hormone products, this chart gives an approximate equivalence in dose between available estrogen products: Since estradiol is the most potent of the three estrogens, the amount of Bi-est or Tri-est is usually based on the equivalent amount of estradiol. For the 0.5mg estradiol example, the dose of Bi-est would be calculated as follows: page 5 BHRT - What s the Evidence? The major criticism regarding bio-identical hormones is the lack of scientific evidence to support claims made about their safety and effectiveness. With aggressive marketing and promotion of these products, this issue became worse as pharmacies and internet sites began to make claims that were well beyond what could be substantiated by the existing evidence. Some data points to benefits that bio-identical hormones may have compared to the CEE/MPA combination. However, making claims that go beyond this evidence damages the bioidentical hormone replacement practice and makes it an easy target for criticism. This section will briefly summarize existing evidence regarding these hormones. Estradiol dose = 20% of total Bi-est dose (or 1/5th of the total Bi-est dose) 0.5mg estradiol= 0.5/0.2 (or 0.5 * 5) = 2.5mg Bi-est (Conversions provided by consultation with experts at PCCA) Measuring Hormone Levels One controversial area regarding hormone replacement therapy is whether or not levels should be drawn to guide therapy. Several compounding pharmacies endorse saliva hormone levels for directing patient treatment. Measuring saliva levels of hormones, a practice done since the 1980s, has largely been criticized for the high level of variability saliva samples can yield. Proponents of saliva testing believe that the saliva is similar to blood ultrafiltrate, and so hormone concentrations in saliva should represent the bioavailable (free/unbound) hormones found in serum. 11 Opponents to saliva testing cite evidence that demonstrate saliva levels to have poor reproducibility, lack data on the stability of the saliva sample during storage and handling, and demonstrate wide interassay variability (running the same sample two different times may yield two quite different levels). 11 Many of these opponents feel that blood levels are more standardized and are superior to saliva tests. Further confounding this issue is the fact that national guidelines on hormone replacement do not support basing therapy on hormone levels of any type. Instead, they cite that hormone replacement should be based on the woman s specific symptoms, utilizing the lowest possible dose that will adequately control these, and re-evaluating therapy every few years. 6 Practice Points: The idea of basing hormone replacement therapy on blood or saliva levels is controversial and not supported by the leading Women s Health guidelines at this time. One benefit of the virtual explosion of bio-identical hormone interest is that the literature is now abound with commentaries, opinions, and articles discussing the use and claims of BHRT. There were two major review articles published over the last five years that summarized the available evidence regarding the use of BHRT and are an excellent starting-point for practitioners. 11,12 Dr. Cirigliano published a highly critical article in 2007, citing a number of different articles and studies that demonstrated little or no efficacy with using BHRT. He concludes that no biologically active estrogen should be considered without risk at this time and that the majority of the claims regarding BHRT therapy are driven by the media and by women s fears in conventional hormone therapy. He also expresses concern over using topical progesterone creams (which may not provide adequate serum levels) in women who have an intact endometrial lining, as the traditional use of any progestin is to protect against endometrial cancer. The article is well-written and well-referenced and provides a compelling argument against the use of BHRT. 11 On the other side of this controversy, Dr. Kent Holtorf published an article in 2009 citing a number of smaller randomized studies, cross-sectional surveys, retrospective analyses, and animal models that supported the idea that bio-identical hormones, specifically estriol and progesterone, possess unique qualities that differentiate them from conjugated equine estrogen and medroxyprogesterone acetate. Of particular interest was the documented differences in how the progesterone performed physiologically compared with medroxyprogesterone; Dr. Holtorf makes a compelling, eloquent argument for supplementing progesterone for a variety of reasons. 12 The truth about BHRT treatment is that further large, welldesigned randomized placebo-controlled trials need to be performed. The existing evidence can neither verify nor disprove

6 the safety and efficacy that these hormones have in managing women s menopausal symptoms. Unfortunately, there is no ability to patent a bio-identical hormone, so these trials, which are so often sponsored by industry in order to produce a new product, have little financial support. Until a government-led initiative or other large group takes on this unique challenge, clinicians will have to base their decisions on clinical experience and on the existing evidence. Practice Points: The evidence regarding bio-identical hormones is controversial, and further large, well-designed studies need to be done to determine what role BHRT will hold for women in the future. Role for Pharmacy Technicians Bio-identical hormone replacement therapy continues to be a topic of extreme interest, particularly to women in or approaching menopausal age. Understanding the basics of this form of pharmacy practice, and understanding the controversies regarding it are critical for understanding the discussions with interested patients. While there are still many questions to be answered regarding the use of BHRT, many women have benefited from the individualized approach taken by quality compounding pharmacies. Being able to recognize realistic expectations of what BHRT can and cannot do will help legitimize the practice and may help curb some of the criticisms this area has received. page 6 References: 1. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14: Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ 1993;307: Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women s Health Initiative randomized controlled trial. JAMA 2002;288: Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized controlled trial. JAMA 2004;291: Update on the Women s Health Initiative Estrogen-Alone Trial (Accessed , at 6. ACOG Today. American Congress of Obstetricians and Gynecologists (Accessed 10/5/12, at Today/acogToday1004.pdf?dmc=1&ts= T ) 7. North American Menopause Society Position Statement (Accessed 10/5/12, at hhttp:// 8. The American Congress of Obstetricians and Gynecologists Committee Opinion- Compounded Bioidentical Menopause Hormone Therapy. (Accessed , at Compounded_Bioidentical_Menopausal_Hormone_Therapy.) 9. Lee RJ. What your doctor may not tell you about premenopause and what your doctor may not tell you about menopause. 1st Omnibus ed. New York, NY: Warner Books; Professional Compounding Centers of America. (Accessed 10/5/12, at Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health (Larchmt) 2007;16: Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med 2009;121:73-85.

7 Assessment Questions 1) Which of the following products would be considered a bioidentical hormone that needs to be compounded? A) Medroxyprogesterone acetate B) Tri-est C) Conjugated equine estrogen D) Fluoxetine 2) What was one major impact of the WHI trial? A) It was determined that CEE + MPA does not protect against heart disease B) Women should only be on CEE + MPA if they have high risk of GI bleeding C) Hormones were found to be superior to placebo in preventing breast cancer D) Testosterone should be used in conjunction with CEE + MPA 3) In a woman who is suffering from insomnia, which formulation of progesterone would be the most helpful? A) Drops, as they absorb the most quickly B) Topical cream, as topical administration bypasses liver s clearance C) Troche, so that she falls asleep trying to dissolve the large lozenge D) Oral capsule, so that the sedating metabolites generated can help her sleep 4) What is one of the major advantages to combining several hormones in one cream? A) Cost- combining products is cheaper for the patient B) Portability- it s easier to carry around in the patient s purse C) Adherence- including several hormones in one preparation makes it easier to adhere to recommended therapy D) Effectiveness- mixing hormones generates benefits beyond what they individually offer 5) What is one advantage of using a compounding pharmacy to create hormone products A) Compounding pharmacies are generally cheaper than retail stores B) Only compounding pharmacies have access to bio-identical hormones C) Compounding pharmacies have superior purity in their products D) These pharmacies have the ability to formulate several hormones into one product, such as a cream 6) What are the two most prevalent compounded hormones? A) Estrogens (bi-est or tri-est) and progesterone B) Testosterone and estrogen C) DHEA and pregnenolone D) CEE and MPA 7) Estradiol is classified as: A) Progesterone B) E2 C) E1 D) E3 8) Regarding the evidence, which of the following are true regarding BHRT? A) The evidence clearly states NOT to use these products B) There is some evidence supporting the use of BHRT, but larger, randomized trials are needed C) There is clear evidence that BHRT outperforms traditional hormone treatment D) No one should consider evidence when considering treatment options 9) Which statement is correct regarding the use of saliva hormone testing? A) This practice is analogous to selling snake oil and should never be used B)This should only be done for women taking multiple hormones C) While there are some proponents of this practice, it is currently highly debated as to its accuracy and clinical use D) Saliva testing is documented clearly superior to blood level testing 10) What concentration of Tri-est would be equivalent to 1mg of estradiol? A) 1mg B) 2mg C) 10mg D) 5mg CPE Instructions: Pharmacy technicians must read this activity and successfully complete the exam (70% pass rate) and evaluation prior to December 31, 2014 using the following instructions: Login to MY PORTFOLIO on On the right of the title of this article, click on GO TO EXAM Upon successful completion of the exam, you will see a page with explanations to the exam questions. After reading through this feedback, scroll to the bottom of the page and click GO TO EVALUATION Complete the evaluation and click SUBMIT You can obtain your CPE Statement of Credit at within 45 days If you have any questions about this process, please contact Cindy Smith, csmith@gotocei.org,