IJPC 13 4 Hormone Replacement Therapy
IJPC 13 4 Hormone Replacement Therapy
IJPC 13 4 Hormone Replacement Therapy
march/april 2009
IIN
NTTEERRN
NAATTIIO
ONNAALL JJO
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PHARMACEUTICAL
HARMACEUTICAL
COMPOUNDING
COMPOUNDING
hormone replacement
Sterile therapy
compounding
270
94 Compliance
The Physiologic Role and Use of Estriol
by Hospitals and Healthcare
290 Contract
106 Preventing nonmicrobiologic Airborne
Sterilization
Contamination in theand Validation
Compounding
276 Facilities
Hormonewith the Revised
Treatment United
Options
Pharmacopeia Chapter <797>
StatesWhat
for Males: Companies
Compounded
offer newa options
Pharmacy: Ensuring
Compounders,
for Sterile for
Safe Environment
Preparations
Staff, and Clients
to Do for Men with Low Testosterone
100
280 Renovation
Tips forTests,
Saliva Cleanroom
Part 1: Construction and
Clinical Use, Elements 120
300 Treating methicillin-Resistant
Preparing nonsterile and Sterile Hazardous
of Testing, and Guidelines for Posttreatment Staphylococcus Aureus Infections with
Compounds in an Institutional Setting
Interpretation Compounded Vancomycin Preparations
VOLUME 13
Volume 13 no.2
nO. 4
IJPC
July|August|2009
Volume 13 Number 4
IN THIS ISSUE...
270 Features
270 The Physiologic Role and Use of Estriol
JIM E. PAOLETTI, RPH, FAARFM
Business of Compounding
312 Marketing
Optimizing Your Website: Search Engine Optimization, Pay Per Click, Email
Marketing
PATRICIA L. STOREY, RPH, FACA
Report: ( ADVERTI SI NG )
Safety of Maternal Testosterone 342 Quality of DIRECTOR OF ADVERTISING
Lauren Bernick, BA
Therapy During Breast Feeding Progesterone TEL: (direct) 405-513-4236 or (toll free) 800-757-4572 ext. 4
FAX: 877-781-5107
REBECCA L. GLASER, MD, FACS; MARK
NEWMAN, MS; MELANIE PARSONS, Suppositories EMAIL: [email protected]
TRUST
When I was a child, my dad would often cluding compounding. Mistakes are very rare,
place me on a ledge or tree limb and say “jump but they do occur, and being “upfront” with
and I’ll catch you!” I trusted him, jumped, and the patients is important. Addressing the issues
he caught me. Trust is defined as “Confidence with facts can help to maintain that trust.
in the integrity, ability, character, and truth When falsehoods, distortions of the truth,
of a person or thing.” (The American Heritage and half-truths are the “standard of the day,”
Dictionary, 2nd College Edition. Boston, MA: whether in our personal lives, our professional
Houghton Mifflin Co; 1982.) practice, or in politics, we eventually get to
For years, pharmacists have been ranked the place where we cannot depend upon what
as among the most trusted professionals in a we hear. Truth and trust obviously start at
community; however, it seems that the trust is home, in our practice, our community, etc. and
slowly waning. This may be due to a number continues all the way up to the highest offices
of factors; some of which we can control, some of our land.
we can’t. We hear statements from many sources that
Compounding pharmacists depend upon are not true. Consequently, our trust in those
the trust of physicians and other healthcare individuals and entities is shattered. The sad
professionals, and upon the trust of patients. thing is that decisions are being made daily on
However, when a pharmacist changes a physi- false information. These decisions may involve
cian’s prescription from a branded product to reliance on information from the drug compa-
a generic product, the change of which was nies, the U.S. Food and Drug Administration,
mandated by a third-party payer, an insurance research studies, etc., and the information may
company, or the government, and the physi- be incorrect.
cian learns of the change but is not aware that Our political leaders certainly are not ex-
the loss was not the pharmacist’s fault, how perts in all fields, but they tend to act as if they
long will it take before physicians lose trust in are. They are making decisions that will have
compounding pharmacy? We must let physicians great impact on our nation and expect us to
know about the situations under which we practice! trust them! However, how many of these deci-
A similar situation sometimes occurs with sions are made from incorrect data, opinions,
patients. They may be accustomed to a small and falsehoods? Decisions made on the basis of
orange tablet but on their next refill they inaccurate information will affect our lives and
receive a medium white tablet. The drug the practice of pharmacy in the future. When
may be exactly as prescribed, but a generic is working with others, trust (based on truth) is
required to be dispensed by the payer. Patients vital. How long will it take for “trust” to be a
then become wary of the medications they thing of the past?
receive, and there is a slight loss of trust in the
pharmacist at that point. We must let the patients
know about these situations when they occur!
The news media fosters this loss of trust
whenever there is a mistake that occurs con- Loyd V. Allen, Jr., PhD, RPh
cerning drugs or the practice of pharmacy, in- Editor-in-Chief
p hy s io log ic rol e
e
th & use of estri
ol
Abstract
Obtaining estrogen balance with a physiologic estriol and estradiol ratio is an
The treatment of normalizing hormone balance is generally important aspect of physiologic bioidentical hormone restoration therapy. Risks,
referred to as hormone “replacement” therapy. The author including that of breast cancer, should be minimized while attempting to obtain
of this article prefers the term hormone “restoration” the protective benefits and symptom management with therapy. Estriol plays a
therapy, as he feels that the term better represents the goal of central role in protecting against breast cancer and should be considered an
hormone therapy. integral part of therapy for any patient with lower than normal physiologic levels.
S afety and efficacy with the use of estriol (E3) for treat-
ing symptoms of menopause has been established
and extensively reviewed.1-35 Studies go back 30
years, and there are no reports of cancer or adverse
effects, other than caution about slight potential
endometrial proliferation requiring monitoring of
therapy. E3 has demonstrated favorable effects on
parameters such as blood lipids, bone loss, menopausal
symptoms, and especially vaginal and urogenital disorders. Even the
North American Menopause Society founder Wolf Utian has authored
a 1980 review in which he states that E3 shows similar benefit to alter-
native estrogens with a potential for reduced risk.32
In addition to treatment of menopausal disorders, E3 plays an
important physiological role in the normal balance of estrogens and,
therefore, needs to be considered as an integral part of hormone
Tamoxifen, an estrogenic substance that is promoted as an anti-
estrogen, works by the same mechanism as E3, and can be viewed as
a synthetic substitute for E3. E3 prevented the development of breast
cancer in rats after administration of carcinogens, the same as tamox-
ifen.37,75 Progesterone (in rats) has also been shown to have the same
short-term reduction of breast cancer risk as tamoxifen.76 Tamoxifen,
however, possesses dangerous long-term side effects,77-82 including an in-
crease in the risk of return of breast cancer after five years of continuous
use. Considering the proven effectiveness for reducing breast cancer risk
with physiological E3 and progesterone, it is easy to understand why in
Europe the use of E3 and progesterone for protection in breast cancer
survivors is preferred over the use of tamoxifen.
Endogenous E3 modulates activity of endogenous E1 and E2, and the
literature indicates exogenous administration can have the same activity.
E3, therefore, has a beneficial role in the protection of over-proliferation
restoration therapy. An important, often overlooked role of E3 is its pro- and prevention of breast cancer. Considering that E3 has been proven to
tective activity against the proliferation induced by the much stronger be both safe and beneficial for the treatment of menopausal symptoms
estrogens estrone (E1) and estradiol (E2). E3 possesses a unique ability and protective against breast cancer with no reported safety issues, any
to act as both an estrogen and anti-estrogen.33 An estrogen that acts as U.S. Food and Drug Administration restriction to the use of E3 or any of
an anti-estrogen with E1 and E2, E3 competitively inhibits E1 and E2 their efforts to make it difficult to obtain E3 should be considered creat-
binding. E3 also inhibits activated receptor binding to estrogen response ing a less-safe situation for patients and could be considered criminal.
elements, limiting transcription.36 A comparison of the binding of the
three major estrogens in the human body elucidates one of the major
mechanisms for decreased proliferation of breast tissue by E3. The
three estrogens bind with different affinity to the two different estrogen
receptor subtypes, ERα and ERβ. While ERα promotes breast cell
How Much Estriol?
For years, the prevailing assumption among proponents of natural
proliferation, ERβ inhibits proliferation and prevents breast cancer or bioidentical therapy was that E3 was present at 80% of the total of
development via G2 cell cycle arrest.37-43 E2 equally activates ERα and the three major estrogens found in the human body. This was based on
ERβ, while E1 selectively binds to ERα at a 5:1 ratio, therefore having information from the book Natural Hormones for Women Over 45, in which
significant increased breast cell proliferation in comparison. E3 selec- Jonathan Wright shared that urinary measurements of the estrogens and
tively binds to ERβ at a 3:1 ratio thus possessing significant potential for estrogen metabolites showed this to be true. More recent work, includ-
breast cancer protection.44,45 ing the study by Xu et al,83 has shown the actual amount of E3 present
Numerous studies have associated high endogenous levels of E3 is about 34% of the total estrogens. What clinical difference does this
during pregnancy with a significantly reduced risk of breast cancer.46-55 make in estrogen restorative therapy? Since E3 modulates the activity of
All but one study56 looking at urinary E3 levels have demonstrated an the stronger estrogens, E1 and E2, the amount of E3 used in a formula-
inverse correlation between urinary E3 levels and the risk of breast tion containing a mixture of these estrogens influences the activity of
cancer.35,57-63 the other estrogens.
E3 is significantly less likely than E1, E2, and conjugated equine Two estrogen receptors bound to estrogen molecules form a dimer
estrogens to induce proliferation in breast tissues.46-55,57-60 Administra- receptor complex which is responsible for the genomic actions of
tion of E3 has been shown to be associated with a significant reduction estrogens. Thus, two estrogen molecules are required to form the dimer
in the risk of breast cancer compared to any other estrogen. In a 1999 receptor complex and initiate translation. The strength of an estrogen is
population-based case-controlled study of 3345 Swedish women 50 to primarily determined by the binding affinity or how tightly the estrogen
74 years of age with invasive breast cancer and 3,454 controls, E3 use molecule is bound to the receptor. The stronger the binding, the longer
showed no appreciable difference in risk compared to nonusers.64 In a the estrogen molecule remains bound to the estrogen receptor before it
large 2004 Cohort study of 31,451 postmenopausal women aged 45 to dissociates and the message for the genomic response ends.
64, Bakken et al showed that the use of an E3-containing preparation As an example, the genomic response to the estrogen receptors
was not associated with risk of breast cancer seen with other estrogen producing proliferation of the uterus is exactly the same for E1 and
preparations (RR = 1.0).65 In contrast, the larger, longer term studies E2. The difference in the amount of proliferation produced by the two
have shown that any estrogen-only therapy other than E3 has been as- different estrogens results from the E3 molecule disassociating much
sociated with a significant increase in breast cancer rate.66-74 Although more quickly from the receptor, and the proliferative effect from E3 is
large-scale randomized control trials are needed to quantify the effects not maintained. Theoretically, if enough E3 was present and maintained
of E3 on breast cancer, applying the principles of evidence-based medi- in the uterus, the proliferative effects seen would be identical to the
cine with the present knowledge from the literature requires a strong stronger E2.
consideration of the use of E3 in physiologic hormone balancing to For an explanatory scenario, assume that E2 is the much stronger
provide protection from breast cancer. estrogen for the genomic response desired. Although both estrogens
14. Takahashi K, Okada M, Ozaki T et al. Safety and The role of oestriol in the prevention of mammary
Conclusion
Obtaining estrogen balance with a physi-
efficacy of oestriol for symptoms of natural or surgi-
cally induced menopause. Hum Reprod 2000; 15(5):
1028–1036.
15. Hayashi T, Ito I, Kano H et al. Estriol (E3) replace-
34.
carcinoma. Acta Endocrinol Suppl (Copenh) 1980; 233:
17–27.
Tzingounis VA, Aksu MF, Greenblatt RB. Estriol
in the management of the menopause. JAMA 1978;
ologic E3 and E2 ratio is an important aspect ment improves endothelial function and bone mineral 239(16): 1638–1641.
of physiologic bioidentical hormone restora- density in very elderly women. J Gerontol A Biol Sci 35. Lemon HM. Estriol prevention of mammary carci-
Med Sci 2000; 55(4): B183–B190. noma induced by 7,12-dimethylbenzanthracene and
tion therapy. Risks, including that of breast procarbazine. Cancer Res 1975; 35(5): 1341–1353.
16. Takahashi K, Manabe A, Okada M et al. Efficacy and
cancer, should be minimized while attempting safety of oral estriol for managing postmenopausal 36. Melamed M, Castaño E, Notides AC et al. Molecular
to obtain the protective benefits and symp- symptoms. Maturitas 2000; 34(2): 169–177. and kinetic basis for the mixed agonist/antago-
tom management with therapy. E3 plays a 17. Head KA. Estriol: Safety and Efficacy. Altern Med Rev nist activity of estriol. Mol Endocrinol 1997; 11(12):
1998; 3(2): 101–113. 1868–1878.
central role in protecting against breast cancer 37. Isaksson E, Wang H, Sahlin L et al. Expression of
18. Nishibe A, Morimoto S, Hirota K et al. Effect of
and should be considered an integral part of estriol and bone mineral density of lumbar vertebrae estrogen receptors (alpha, beta) and insulin-like
therapy for any patient with lower than normal growth factor-1 in breast tissue from surgically
in elderly and postmenopausal women. Nippon Ronen
postmenopausal cynomolgus macaques after long-
physiologic levels. Igakkai Zasshi 1996; 33(5): 353–359.
term treatment with HRT and tamoxifen. Breast 2002;
19. Barentsen R, van de Weijer PH, Schram JH. Continu-
11(4): 295–300.
ous low dose estradiol released from a vaginal ring
References
1. Terauchi M, Obayashi S, Aso T. Estriol, conjugated
equine estrogens, and alendronate therapy for osteo-
versus estriol vaginal cream for urogenital atrophy.
Eur J Obstet Gynecol Reprod Biol 1997; 71(1): 73–80.
20. Minaguchi H, Uemura T, Shirasu K et al. Effect of
estriol on bone loss in postmenopausal Japanese
38. Paruthiyil S, Parmar H, Kerekatte V et al. Estrogen
receptor beta inhibits human breast cancer cell pro-
liferation and tumor formation by causing a G2 cell
cycle arrest. Cancer Res 2004; 64(1): 423–428.
39. Helguero LA, Faulds MH, Gustafsson JA et al.
porosis. Int J Gynaecol Obstet 2006; 92(2): 141–142. women: A multicenter prospective open study. J Estrogen receptors alfa (ERalpha) and beta (ERbeta)
2. Zullo MA, Plotti F, Calcagno M et al. Vaginal Obstet Gynaecol Res 1996; 22(3): 259–265. differentially regulate proliferation and apoptosis
estrogen therapy and overactive bladder symptoms in 21. Nozaki M, Hashimoto K, Inoue Y et al. Usefulness of of the normal murine mammary epithelial cell line
postmenopausal patients after a tension-free vaginal estriol for the treatment of bone loss in postmeno- HC11. Oncogene 2005; 24(44): 6605–6616.
tape procedure: A randomized clinical trial. Meno- pausal women. Nippon Sanka Fujinka Gakkai Zasshi 40. Bardin A, Boulle N, Lazennec G et al. Loss of ERbeta
pause 2005; 12(4): 421–427. 1996; 48(2): 83–88. expression as a common step in estrogen-dependent
3. Ozkinay E, Terek MC, Yayci M et al. The effective- 22. Bottiglione F, Volpe A, Esposito G et al. Transvaginal tumor progression. Endocr Relat Cancer 2004; 11(3):
ness of live lactobacilli in combination with low dose estriol administration in postmenopausal women: 537–551.
oestriol (Gynoflor) to restore the vaginal flora after A double blind comparative study of two different 41. Weatherman RV, Clegg NJ, Scanlan TS. Differential
treatment of vaginal infections. BJOG 2005; 112(2): doses. Maturitas 1995; 22(3): 227–232. SERM activation of the estrogen receptors (ERalpha
234–240. 23. Vooijs GP, Geurts TB. Review of the endometrial and ERbeta) at AP-1 sites. Chem Biol 2001; 8(5):
4. Palacios S, Castelo-Branco C, Cancelo MJ et al. safety during intravaginal treatment with estriol. Eur 427–436.
Low-dose, vaginally administered estrogens may J Obstet Gynecol Reprod Biol 1995; 62(1): 101–106. 42. Pettersson K, Delaunay F, Gustafsson JA. Estrogen
enhance local benefits of systemic therapy in the 24. Yang TS, Tsan SH, Chang SP et al. Efficacy and receptor beta acts as a dominant regulator of estrogen
treatment of urogenital atrophy in postmenopausal safety of estriol replacement therapy for climacteric signaling. Oncogene 2000; 19(43): 4970–4978.
women on hormone therapy. Maturitas 2005; 50(2): women. Zhonghua Yi Xue Za Zhi (Taipei) 1995; 55(5): 43. Saji S, Jensen EV, Nilsson S et al. Estrogen receptors
98–104. 386–391. alpha and beta in the rodent mammary gland. Proc
5. Hejlová P, Zivný J. Effect of vaginal estriol on uro- 25. Raz R, Stamm WE. A controlled trial of intravaginal Natl Acad Sci U S A 2000; 97(1): 337–342.
genital symptoms in postmenopausal women. Ceska estriol in postmenopausal women with recurrent 44. Zhu BT, Han GZ, Shim JY et al. Quantitative
Gynekol 2004; 69(4): 329–335. urinary tract infections. N Engl J Med 1993; 329(11): structure-activity relationship of various endogenous
6. Dessole S, Rubattu G, Ambrosini G et al. Efficacy 753–756. estrogen metabolites for human estrogen receptor
of low-dose intravaginal estriol on urogenital aging 26. Iosif CS. Effects of protracted administration of alpha and beta subtypes: Insights into the structural
in postmenopausal women. Menopause 2004; 11(1): estriol on the lower genito urinary tract in post- determinants favoring a differential subtype binding.
49–56. menopausal women. Arch Gynecol Obstet 1992; 251(3): Endocrinology 2006; 147(9): 4132–4150.
7. D’iakov VV, Godunov BN, Gvozdev MIu. Long- 115–120. 45. Rich RL, Hoth LR, Geoghegan KF et al. Kinetic
27. Blum M. Benefits of vaginal estriol cream combined analysis of estrogen receptor/ligand interactions. Proc
term use of ovestin by postmenopausal women with
with clonidine HCL for menopausal syndrome treat- Natl Acad Sci U S A 2002; 99(13): 8562–8567.
urinary incontinence. Urologiia 2003; (1): 43–46.
ment. Clin Exp Obstet Gynecol 1985; 12(1–2): 1–2. 46. Campagnoli C, Abba C, Ambroggio S et al. Preg-
8. Dew JE, Wren BG, Eden JA. A cohort study of topical
28. Trevoux R, van der Velden WH, Popoviñ D. Ovestin nancy, progesterone and progestins in relation to
vaginal estrogen therapy in women previously treated
breast cancer risk. J Steroid Biochem Mol Biol 2005;
for breast cancer. Climacteric 2003; 6(1): 45–52. vaginal cream and suppositories for the treatment of
97(5): 441–450.
9. Granberg S, Eurenius K, Lindgren R et al. The effects menopausal vaginal atrophy. Reproduction 1982; 6(2):
47. Innes KE, Byers TE. First pregnancy characteristics
of oral estriol on the endometrium in postmenopausal 101–106.
and subsequent breast cancer risk among young
women. Maturitas 2002; 42(2): 149–156. 29. Haspels AA, Luisi M, Kicovic PM. Endocrinological
women. Int J Cancer 2004; 112(2): 306–311.
10. Hayashi T, Kano H, Sumi D et al. The long-term and clinical investigations in post-menopausal women
48. Troisi R, Weiss HA, Hoover RN et al. Pregnancy
effect of estriol on endothelial function and bone following administration of vaginal cream containing characteristics and maternal risk of breast cancer.
mineral density in octogenarian women. J Am Geriatr oestriol. Maturitas 1981; 3(3–4): 321–327. Epidemiology 1998; 9(6): 641–647.
Soc 2002; 50(4): 777–778. 30. Keller PJ, Riedmann R, Fischer M et al. Oestrogens, 49. Vatten LJ, Romundstad PR, Trichopoulos D et al.
11. Manonai J, Theppisai U. Effect of oral estriol on gonadotropins and prolactin after intra-vaginal ad- Pre-eclampsia in pregnancy and subsequent risk for
urogenital symptoms, vaginal cytology, and plasma ministration of oestriol in post-menopausal women. breast cancer. Br J Cancer 2002; 87(9): 971–973.
hormone level in postmenopausal women. J Med Maturitas 1981; 3(1): 47–53. 50. Speroff L. The breast as an endocrine target organ.
Assoc Thai 2001; 84(4): 539–544. 31. Kicovic PM, Cortes-Prieto J, Milojeviñ et al. The Contemp Obstet Gynec 1977; 9: 69–72.
12. Ushiroyama T, Sakai M, Higashiyama T et al. treatment of postmenopausal vaginal atrophy with 51. Rosner B, Colditz, GA, Willett WC. Reproductive
Estrogen replacement therapy in postmenopausal Ovestin vaginal cream or suppositories: Clinical, risk factors in a prospective study of breast cancer:
women: A study of the efficacy of estriol and changes endocrinological and safety aspects Maturitas 1980; The Nurses’ Health Study. Am J Epidemiol 1994;
in plasma gonadotropin levels. Gynecol Endocrinol 2001; 2(4): 275–282. 139(8): 819–835.
15(1): 74–80. 32. Utian WH. The place of oestriol therapy after 52. Russo J, Tay LK, Russo IH. Differentiation of the
13. Lose G, Englev E. Oestradiol-releasing vaginal ring menopause. Acta Endocrinol Suppl (Copenh) 1980; 233: mammary gland and susceptibility to carcinogenesis.
versus oestriol vaginal pessaries in the treatment of 51–56. Breast Cancer Res Treat 1982; 2(1): 5–73.
bothersome lower urinary tract symptoms. BJOG 33. Lemon HM. Pathophysiologic considerations in the 53. Pasqualini JR. The fetus, pregnancy, and breast
2000; 107(8): 1029–1034. treatment of menopausal patients with oestrogens; cancer. In: Pasqualini JR, ed. Breast Cancer: Prognosis,
Treatment, and Prevention. New York, NY: Marcel 73. Fournier A, Berrino F, Riboli E et al. Breast cancer 81. Cuzick J, Forbes J, Edwards R et al. First results from
Dekker Inc.; 2002:19–71. risk in relation to different types of hormone replace- the International Breast Cancer Intervention Study
54. Vatten LJ, Romundstad PR, Trichopoulos D ET AL. ment therapy in the E3N-EPIC cohort. Int J Cancer (IBIS-I): A randomised prevention trial. Lancet 2002;
Pregnancy related protection against breast cancer 2005; 114(3): 448–454. 360(9336): 817–824.
depends on length of gestation. Br J Cancer 2002; 74. Bergkvist L, Adami HO, Persson I et al. The risk of 82. Wilkinson E. Experts question benefits of tamoxifen.
87(3): 289–290. breast cancer after estrogen and estrogen-progestin Lancet Oncol 2006; 7(9): 714.
55. Ekbom A, Hsieh CC, Lipworth L et al. Intrauterine replacement. N Engl J Med 1989; 321(5): 293–297. 83. Xu X, Duncan AM, Merz-Demlow BE et al. Men-
environment and breast cancer risk in women: A 75. Lemon HM, Kumar PF, Peterson C et al. Inhibition strual cycle effects on urinary estrogen metabolites. J
population-based study. J Natl Cancer Inst 1997; 89(1): of radiogenic mammary carcinoma in rats by estriol Clin Endocrinol Metab 1999; 84(11): 3914–3918.
71–76. or tamoxifen. Cancer 1989; 63(9): 1685–1692. 84. Gaikwad NW, Yang L, Muti P et al. The molecular
56. Marmorston J, Crowley LG, Myers SM et al. II. 76. Inoh A, Kamiya K, Fujii Y et al. Protective effects etiology of breast cancer: Evidence from biomarkers
Urinary excretion of estrone, estradiol, and estriol by of progesterone and tamoxifen in estrogen-induced of risk. Int J Cancer 2008; 122(9): 1949–1957.
patients with breast cancer and benign breast disease. mammary carcinogenesis in ovariectomized W/Fu 85. Cavalieri EL, Rogan EG, Chakravarti D. Initiation of
Am J Obstet Gynecol 1965; 92: 460–467. rats. Jpn J Cancer Res 1985; 76(8): 699–704. cancer and other diseases by catechol ortho-quinones:
57. MacMahon B, Cole P, Brown JB et al. Oestrogen 77. Bergman L, Beelen ML, Gallee MP et al. Risk and A unifying mechanism. Cell Mol Life Sci 2002; 59(4):
profiles of Asian and North American women. Lancet prognosis of endometrial cancer after tamoxifen 665–681.
1971; 2(7730): 900–902. for breast cancer. Comprehensive Cancer Centres’ 86. Cavalieri EL, Li KM, Balu N et al. Catechol
58. Gross J, Modan B, Bertini B et al. Relationship
ALERT Group. Assessment of liver and endome- ortho-quinones: The electrophilic compounds that
between steroid excretion patterns and breast cancer
trial cancer risk following tamoxifen. Lancet 2000; form depurinating DNA adducts and could initiate
incidence in Israeli women of various origins. J Natl
356(9233): 881–887. cancer and other diseases. Carcinogenesis 2002; 23(6):
Cancer Inst 1997; 59(1): 7–11.
78. Powles T, Eeles R, Ashley S et al. Interim analysis of 1071–1077.
59. Cole P, MacMahon B. Oestrogen fractions during
the incidence of breast cancer in the Royal Marsden 87. Cavalieri EL, Rogan EG. A unified mechanism in
early reproductive life in the aetiology of breast
Hospital tamoxifen randomised chemoprevention the initiation of cancer. Ann N Y Acad Sci 2002; 959:
cancer. Lancet 1969; 1(7595): 604–606.
60. Dickinson LE, MacMahon B, Cole P et al. Estrogen trial. Lancet 1998; 352(9122): 98–101. 341–354.
profiles of Oriental and Caucasian women in Hawaii. 79. Saphner T, Tormey DC, Gray R. Venous and arterial
N Engl J Med 1974; 291(23): 1211–1213. thrombosis in patients who received adjuvant therapy Address correspondence to Jim E. Paoletti, RPh,
61. Ursin G, Wilson M, Henderson BE et al. Do urinary for breast cancer. J Clin Oncol 1991; 9(2): 286–294.
80. van Leeuwen FE, Benraadt J, Coebergh JW et al. Risk
FAARFM, ZRT Laboratory, 8605 SW Creekside
estrogen metabolites reflect the differences in breast
cancer risk between Singapore Chinese and United of endometrial cancer after tamoxifen treatment of Drive, Beaverton, OR 97008. E-mail: jepaoletti@
States African-American and white women? Cancer breast cancer. Lancet 1994; 343(8895): 448–452. zrtlab.com
Res 2001; 61(8): 3326–3329.
62. Lemon HM. Genetic predisposition to carcinoma of
the breast: Multiple human genotypes for estrogen 16
alpha hydroxylase activity in Caucasians. J Surg Oncol
63.
1972; 4(3): 255–273.
Lemon HM, Wotiz HH, Parsons L et al. Reduced es- Frustrated trying to get physicians to
triol excretion in patients with breast cancer prior to
64.
endocrine therapy. JAMA 1966; 196(13): 1128–1136.
Magnusson C, Baron JA, Correia N et al. Breast-
understand the benefits of compounding?
cancer risk following long-term oestrogen- and
oestrogen-progestin-replacement therapy. Int J Cancer
1999; 81(3): 339–344.
If you have knocked on physicians doors to no avail,
65. Bakken K, Alsaker E, Eggen AE et al. Hormone
replacement therapy and incidence of hormone-
let’s rethink the problems:
dependent cancers in the Norwegian Women and
Cancer study. Int J Cancer 2004; 112(1): 130–134. Problem 1: You are tainted as a messenger because M.D.’s might
66. Fournier A, Berrino F, Clavel-Chapelon F. Unequal
risks for breast cancer associated with different
believe that you are promoting compounding out of self interest.
hormone replacement therapies: Results from the
E3N cohort study. Breast Cancer Res Treat 2008; 107(1):
103–111.
Problem 2: Physicians are likely to think “what’s in it for me?”
67. Mueck AO, Seeger H, Wallwiener D. Comparison
of proliferative effects of estradiol and conjugated
equine estrogens on human breast cancer cells and Problem 3: Physicians are taught by mentoring. Unless they
impact of continuous combined progestogen addition. can see a fellow M.D. successfully using compounding,
Climacteric 2003; 6(3): 221–227.
68. Chen WY, Manson JE, Hankinson SE et al. Unop- especially for hormones, they are not going to start trying
posed estrogen therapy and the risk of invasive breast
cancer. Arch Intern Med 2006; 166(9): 1027–1032. what BIG PHARMA tells them is “untested, unscientific
69. Beral V; Million Women Study Collaborators. Breast
cancer and hormone-replacement therapy in the Mil-
experimentation" on their patients.
lion Women Study. Lancet 2003; 362(9382): 419–427.
70. Ribot C, Trémollieres F. Hormone replacement ther-
apy in postmenopausal women: All the treatments are
Solution: Bring them to a two day seminar where an
71.
not the same. Gynecol Obstet Fertil 2007; 35(5): 388–397.
Mueck AO, Seeger H, Wallwiener D. Comparison of
M.D. teaches them the benefits of hormone testing,
the proliferative effects of estradiol and conjugated
equine estrogens on human breast cancer cells and
BHRT, and how to add $150,000 to their bottom line.
impact of continuous combined progestogen addition.
72.
Climacteric 2003; 6(3): 221–227.
Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer
Fast Track Your Marketing and Call 201-871-3199
risk in postmenopausal women using estrogen-only
therapy. Obstet Gynecol 2006; 108(6): 1354–1360. or visit: www.CompoundingPharmacyMarketer.com
What to Do for
Men with
Low Testosterone Bruce Biundo, BS, RPh
Professional Compounding Centers of America
Houston, Texas
Abstract
Male hypogonadism is a condition that is receiving increasing medical scrutiny,
resulting in research producing results favorable to the consideration of maintaining
physiological levels of testosterone. As healthcare professionals interested in the health
and welfare of a significant portion of the population, surely compounding pharmacists
are interested in what can be done for men with this condition to help these patients
improve their quality of life and long-term health. This article discusses the various ways
that men’s testosterone levels can be raised and provides insight into the importance of
androgen-estrogen balance.
Testosterone deficiency in aging men, also often referred to as bined their clinical practices with vital research, which has resulted in an
andropause, partial androgen deficiency in the aging male, or late-onset emerging view that testosterone needs to be re-examined as it relates to
hypogodonadism, has been linked to erectile dysfunction, low libido, prostate cancer and benign prostatic hyperplasia.8-10 So, there are many
depressed mood, declining muscle tone, osteoporosis, and associations research articles and books available for pharmacists, physicians, and
with many other conditions such as Type II diabetes and cardiovascular other healthcare professionals to review.
disease.1-4 These claims are substantiated in the large number of pub- From the substantial amount of published solid clinical information,
lished articles on this subject, and include newly published articles that it seems that we are suddenly realizing how important this hormone is
discuss how low testosterone levels predict incident stroke and transient to men…and it’s about time! As a pharmacist with a long-standing, deep
ischemic attacks in older men5 and that testosterone deficiency may interest in this subject, I have been very pleased to see the positive thrust
have a significant relationship to Peyronie’s disease.6 Furthermore, Dr. of research in the past two to three years relating to the results and
Malcolm Carruthers from the Centre for Men’s Health, London, United treatment of low testosterone in men. As healthcare professionals inter-
Kingdom, one of the true pioneers in this field, has a newly published ested in the health and welfare of a significant portion of the population,
article about the need for international action on treating testosterone surely compounding pharmacists are interested in what can be done for
deficiency.7 Dr. Abraham Morgentaler (Harvard Medical School) and Dr. men with this condition to help these patients improve their quality of
John Mulhall (Sloan-Ketting Cancer Institute in New York) have com- life and long-term health. This article discusses the various ways that
men’s testosterone levels can be raised and provides insight into the Human Chorionic Gonadotropin
importance of androgen/estrogen balance. LH activity can be mimicked by using the action of HCG. The use
The subject of estradiol as it relates to men’s health has been an area of this agent can be helpful in some men to increase testicular output of
of interest for many (including myself) for a long time. While we want testosterone.18 Subcutaneous injections are the usual method of admin-
to maintain adequate levels of estradiol (at the very least, as a protection istration of HCG, and several protocols have been used. For example,
against osteoporosis), new research suggests we should be aware of de- a protocol of 500 U three times per week has been dosed, up to the
clining androgen/estrogen ratios,11-13 and that it is prudent to measure dose used by Dr. Mulhall in his practice, 1000 U to 1500 U three times
estradiol in men on a continuing basis just as we do testosterone. a week.8 For some men, this may be a useful treatment in lieu of actual
testosterone supplementation. It should be noted that this kind of treat-
ment would not be useful in a man diagnosed with primary testicular
Who Should be Treated? failure, in which the testes are unable to produce testosterone. For those
Men who have been properly diagnosed with hypogonadism by way patients who cringe at the sight of a needle, an injection is perhaps not
of laboratory values as well as the evaluation of the patient’s symptoms the agent of choice, but, for many, it is a viable option.
should receive treatment, and this article is written for those patients
who have been properly diagnosed (i.e., the lab values and symptoms
tend to correlate with one another, and the patient has been carefully Lifestyle Changes
screened). Also of importance and worth mentioning is that in many men
lifestyle modifications could boost testosterone production and keep the
androgen/estradiol relationship healthy. Sedentary lifestyles, central
Treatment Options adiposity, unhealthy habits (e.g., smoking, excessive alcohol use) work
This article offers two broad categories of treatment: (1) those that against healthy testosterone levels. Whenever and to whatever extent
do not involve testosterone supplementation and (2) those that involve possible, we should recommend an active exercise program, particularly
testosterone supplementation. We will first discuss the treatments that involving weight-resistant activities, and healthy eating that promote
do not involve testosterone supplementation by looking at the role of loss of excess weight and fat. Many men who follow these tenets of
Luteinizing hormone (LH), human chorionic gonadotropin (HCG), healthy eating, dieting, and exercise will find that their hormone levels
estradiol, aromatase inhibitors or estrogen blockers, and lifestyle modi- correlate with their healthy lifestyles.
fications.
Parenteral Administration
Current experiences suggest that testosterone gel may be the most
Parenteral administration has been established for many years, using
physiological and well-tolerated transdermal testosterone-delivery
one of the ester forms, cypionate or enanthate, and can be effective.1
system yet. Application of the gel is simple, practical for the patient
A big drawback has always been the erratic release of these injections,
and replaces painful intramuscular injections. Owing to the short
which, while suggested to be dosed at 200 mg every 2 to 3 weeks, often
action of testosterone gel, application can be ceased in case of the
have their major effect in the first 7 to 9 days. In fact, many of the side
appearance of side effects, such as an excessive increase in he-
effects associated with testosterone supplementation, such as high con-
matocrit, prostate-specific antigen or an abnormal digital rectal
version to estradiol, are primarily associated with traditional schedules
examination.27
of parenteral administration. A way to overcome this is to dose at a
somewhat lower level, 75 mg to 100 mg on a weekly basis.19 Vehicles other than gels may also prove to be effective. Of all
healthcare professionals, compounding pharmacists are especially
well-positioned to understand the unique qualities of delivery systems
Sublingual/Buccal Administration and to make recommendations based on proven efficacy, aesthetic ap-
Testosterone can be administered via sublingual or buccal tablet
peal, patient acceptance, and ease of use. An excellent discussion on
triturates, troches, or drops. In this manner, there is a rapid and high
these and other pertinent issues is found in the publication titled Ansel’s
rate of absorption. Two concerns in dosing this way are (1) masking
Pharmaceutical Dosage Forms and Drug Delivery Systems.28 Concerns have
the bitter taste of testosterone and (2), more importantly, erratic blood
occasionally arisen that topical administration will result in dispropor-
levels. Peak levels may be reached in 30 to 45 minutes but will remain
tionately high conversions to estradiol, but, in studies that measured
elevated for a relatively short time, 2 to 5 hours. An ideal dose has not
that effect, it has not proven to be valid.19,23 On the other hand, because
been realized yet, but, if the goal is to maintain levels throughout the
of the presence of 5-alpha reductase in skin, topical application may
day, a suggested dose would be 10 mg to 25 mg 3 times daily. Sublingual result in a slightly disproportionate increase in dihydrotestosterone
dosing may be very useful for a male who is already supplementing (DHT).19,23 This is not necessarily a bad thing but it is noteworthy, as
testosterone but needs an extra boost to enhance sexual function. there may be times when the patient being treated for hypgodonadism
is also being treated with a 5-alpha reductase blocker.
Interestingly, one study showed that the use of the 5-alpha reductase
Topical Application blocker, dutasteride, not only blocked the conversion of testosterone to
This is the most physiologic route of administration, affording
DHT, but also increased the levels of testosterone.29
continual, steady-state release of testosterone. From the first patches
to later commercial gels, topical administration has proven to be safe,
effective, and offers ease in adjusting dosage. And, there is abundant
clinical data available to support its use. Furthermore, from the years of
Sex Hormone-Binding Globulin
Sex hormone-binding globulin (SHBG) increases with age and can
use, the many studies conducted, the results, both in terms of laborato-
be a factor in limiting the amount of free testosterone as a percent of
ry values and, more importantly, patient outcomes, we have established
total. Testosterone itself can lower SHBG, therefore, successful topical
dosage ranges with topical gels: 50 mg to 100 mg. These are doses that application can result in both increased total and free testosterone.
have been used consistently and proven safe and beneficial over the past When that does not prove to be effective and high SHBG remains a
ten years.1,20-23 A problem that occurs in many men is the negative- concern, danazol has been used in doses of 50 mg to 100 mg daily.30
feedback loop, or suppression of endogenous testosterone, which results
in disappointing levels of testosterone with supplementation. This
result can occur from even low doses, and to overcome that effect, doses
of 100 mg are often needed. The mechanism is decreased production of
Conclusion
Male hypogonadism is a condition that is receiving increasing
LH; the very same mechanism also results in depressed follicle-stim- medical scrutiny, resulting in research favorable to the consideration
ulating hormone activity, lowering sperm production. It is this activity of maintaining physiological levels of testosterone. The Professional
which has aroused interest in testosterone as a male contraceptive.24 Compounding Centers of America’s professional resource contains over
We know that commercial gel products were introduced in early 2000, 600 full-text articles on the subject of men’s health. For those of you
and an absorption rate of approximately 10% has been established.25 interested in finding the science, be assured that it is available. Remem-
Therefore, with 10% absorption, 50 mg of a gel will deliver approxi- ber that you, the knowledgeable compounding pharmacist, are in an
mately 5 mg net testosterone, and 100 mg of a gel will deliver 10 mg excellent position to help educate physicians, nurse practitioners, and
net testosterone. For comparison with a patch, 50 mg of a gel equates to patients on the benefits of testosterone and hormonal balance in men.
a 5-mg patch. While that may look confusing, it means that the dosing
systems are quite different from one another, and one cannot go from
patch to gel and use the exact same dosing.26 References
Compounding pharmacists can prepare formulations that are effec- 1. Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitu-
tive and more patient-friendly by using higher-concentration prepara- tion. 2nd ed. Heidelberg, Germany: Springer; 1998: 229–258.
tions, requiring smaller dosages. For example, a 5% gel will deliver 2. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testoster-
50 mg in 1 mL rather than the 5 g required to do the same from a 1% one and mortality in older men. J Clin Endocrinol Metab 2008; 93(1):
gel. In a newly published article in Aging Male, Lunenfeld et al states: 68–75.
3. Tung DS, Cunningham GR. Androgen deficiency in men. The Endo- body composition parameters in hypogonadal men. J Clin Endocrinol
crinologist 2007; 17(2): 101–115. Metab 2000; 85(8): 2839–2853.
4. Gould DC, Kirby RS, Amoroso P. Hypoandrogen-metabolic 26. Mazer N, Bell D, Wu J et al. Comparison of the steady-state phar-
syndrome: A potentially common and underdiagnosed condition in macokinetics, metabolism, and variability of a transdermal testos-
men. Int J Clin Pract 2007; 61(2): 341–344. terone patch versus a transdermal testosterone gel in hypogonadal
5. Yeap BB, Hyde Z, Almeida OP et al. Lower testosterone levels men. J Sex Med 2005; 2(2): 213–226.
predict incident stroke and transient ischemic attack in older men. 27. Lunenfeld B, Oettel M. Therapeutic potential of testosterone gels.
J Clin Endocrinol Metab 2009; [In print]. Aging Health 2009; 5(2): 227–245.
6. Moreno S, Morgentaler A. Testosterone deficiency and Peyronie’s 28. Allen LV Jr, Popovich NG, Ansel HC. Ansel’s Pharmaceutical Dosage
disease: Pilot data suggesting a significant relationship. J Sex Med Forms and Drug Delivery System. 9th ed. Baltimore, MD: Lippincott,
Published online: 2009 Mar 30. Williams, & Wilkins; 2005: 298–315.
7. Carruthers M. Time for international action on treating testoster- 29. Amory JK, Bremner WJ. Oral testosterone in oil plus dutasteride in
one deficiency syndrome. Aging Male 2009; 12(1): 21–28. men: A pharmacokinetic study. J Clin Endocrinol Metab 2005; 90(5):
8. Mulhall JP. Saving Your Sex Life: A Guide for Men with Prostate Cancer. 2610–2617.
Munster, IN: Hilton Publishing Company; 2008: 220. 30. Carruthers ME. Use of danazol in the treatment of hypogonadism
9. Morgentaler A. Testosterone for Life. Columbus, OH: McGraw-Hill; in men. European Patent EP1079836. [Free patents online Website.]
2008: 1–195. 1999. Available at: www.freepatentsonline.com/EP107983681.html.
10. Rhoden EL, Morgentaler A. Testosterone replacement therapy in Accessed January 3, 2008.
hypogonadal men at high risk for prostate cancer: Results of 1 year
of treatment in men with prostatic intraepithelial neoplasia. J Urol
2003; 170(6 Pt 1): 2348–2351. Address correspondence to Bruce Biundo, BS, RPh, Professional Compounding
11. Maggio M, Lauretani F et al. Estradiol and metabolic syndrome in Centers of America, 9901 S. Wilcrest, Houston, TX 77099. E-mail: bbiundo@
older Italian men: The InCHIANTI Study. J Androl 2008; [In print]. pccarx.com
12. Bonkhoff H, Berges R. The evolving role of oestrogens and their
receptors in the development and progression of prostate cancer.
Eur Urol 2008; [In print].
13. Orwoll E, Lambert LC et al. Testosterone and estradiol among
older men. J Clin Endocrinol Metab 2006; 91(4): 1336–1344.
14. Burnett-Bowie SA, Roupenian KC, Dere ME et al. Effects of
aromatase inhibition in hypogonadal older men: A randomized, ACCURATE & SAFE
double-blind, placebo-controlled trial. Clin Endocrinol (Oxf) 2008; Containment Solutions for Compounding
[In print].
15. de Boer H, Verschoor L et al. Letrozole normalizes serum testoster-
one in severely obese men with hypogonadotropic hypogonadism.
Diabetes Obes Metab 2005; 7(3): 211–215.
16. Leder BZ, Rohrer JL, Rubin SD et al. Effects of aromatase inhibi-
tion in elderly men with low or borderline-low serum testosterone
levels. J Clin Endocrinol Metab 2004; 89(3): 1174–1180.
17. Ribeiro R, Abucham J. Recovery of persistent hypogonadism by
clomiphene in males with prolactinomas under dopamine agonist
treatment. Eur J Endocrinol 2009; [In print].
18. Tsujimura A, Matsumiya K, Takao T et al. Treatment with human
chorionic gonadotropin for PADAM: A preliminary report. Aging
Male 2005; 8(3–4): 175–179.
19. Cunningham GR. Testosterone replacement therapy for late-onset
hypogonadism. Nat Clin Pract Urol 2006; 3(5): 260–267.
20. Seftel A. Testosterone replacement therapy for male hypogonad-
ism, part III: Pharmacologic and clinical profiles, monitoring, safety Flow Sciences’ team of engineering professionals have been
issues, and potential future agents. Int J Impot Res 2007; 19(1): 2–24. providing containment solutions to compounding, pharmaceutical,
chemical, and biotech industries for over 15 years.
21. Tenover JL. Male hormone replacement therapy including “andro-
pause”. Endocrinol Metab Clin North Am 1998; 27(4): 969–987. Product Features:
*HQWOHQRQWXUEXOHQWDLUÀRZ
22. Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment, SUHYHQWVEDODQFHÀXFWXDWLRQ
and monitoring of late-onset hypogonadism in males: ISA, ISSAM,
and EAU recommendations. J Androl 2006; 27(2): 135–137. Dished resin base provides easy
cleanup and containment spills
23. Srinivas-Shankar U, Wu FC. Drug insight: Testosterone prepara-
tions. Nat Clin Pract Urol 2006; 3(12): 653–665. (UJRQRPLFGHVLJQDOORZVRSHUDWRUWRFRPIRUWDEO\LQWHUDFWZLWKFRPSRXQGV
ABSTRACT
Saliva is an excellent medium for the mea-
surement of the biologically active fraction
of steroid hormones in the bloodstream be-
cause it is a natural ultrafiltrate of blood, and
steroids not bound by carrier proteins in the
blood freely diffuse into saliva. The baseline
measurement of hormone levels in saliva pro-
vides an accurate assessment and can be used
to identify or monitor a number of clinical
conditions, including climacteric changes in
perimenopausal or postmenopausal women,
adrenal disorders such as Addison’s disease or
Cushing’s disease, and androgen deficiency.
In men and women, the age-related decrease
of hormones such as testosterone and dehy-
droepiandrosterone can also be assessed and
monitored. When compared with serum test-
ing, saliva testing offers several advantages.
Saliva collection is simple, noninvasive, stress
free, painless, and safe for the patient and
practitioner. The collection time for saliva test-
ing is more controllable than that for serum
testing. The transport of saliva samples for as-
sessment can be accomplished inexpensively
via the U.S. Postal Service because hormones
are stable in saliva for three weeks at room
temperature, and the cost of that testing is
covered by many insurance plans. In this first
of a two-part series, we discuss the clinical
Collecting saliva for analysis is simple: use and basic elements of saliva testing and
The patient spits directly into a tube provide guidelines for posttreatment interpre-
provided in the saliva test kit. tation by compounding pharmacists.
This article, which is part 1 of a two-part series, discusses the clinical use and basic elements of saliva testing and provides guidelines for posttreatment
interpretation by compounding pharmacists. Part 2 will provide a detailed description of the hormones assessed by saliva testing, describe the pharma-
cokinetics of hormone replacement therapy, and explain the importance of timely testing.
UNSUPPLEMENTED SALIVARY
TABLE. RANGES OF UNBOUND (FREE) HORMONE LEVELS HORMONE RANGES
FOUND IN SALIVA.a Unsupplemented salivary hormone ranges
represent normal physiologic levels for the
ESTRADIOL groups of patients described (e.g., premeno-
Unsupplemented Saliva Range (pg/mL) pausal or postmenopausal women, age-specific
Premenopausal women Follicular 0.5 – 5.0 or sex-specific groups). These ranges do not
Midcycle 3.0 – 8.0 necessarily represent optimal levels for good
Luteal 0.5 – 5.0 health because physiologically normal levels
Men and postmenopausal women <1.5 can be risk factors for pathologic processes in
certain groups (e.g., low levels of estrogen in
Supplemented postmenopausal women are associated with
Oral 2.0 – 20.0 a relatively greater risk for bone fracture as a
Transdermal patch 1.0 – 5.0 result of increased bone turnover).
Cream or gel 10.0 – 50.0
ESTRONE SUPPLEMENTED SALIVARY
Unsupplemented Saliva Range (pg/mL) HORMONE RANGES
Premenopausal women, Supplemented salivary hormone ranges are
postmenopausal women, and men 2.5 – 5.4 derived from groups of patients treated with
a narrow range of standard dosing with vari-
Supplemented ous hormones, including cortisol, estradiol,
Oral 2.0 – 20.0 estrone, estriol, progesterone, and testoster-
Cream or gel 10.0 – 50.0 one. Thus these are expected ranges rather
than optimal ranges as delineated by clinical
ESTRIOL
endpoints. A physiologic effect (e.g., relief of
Unsupplemented Saliva Range (pg/mL)
symptoms, a decrease in the bone turnover
Premenopausal women 4.4 – 8.3
rate) can be expected in most patients whose
Postmenopausal women 3.0 – 11.8
level of a specific hormone is at the lower end
Men 4.7 – 7.1
of the expected supplemental ranges.
Supplemented Hormone levels vary widely among indi-
Oral 20 – 40 viduals. As would be expected, women have
Cream or gel 300 – 500 higher levels of estrogens and progesterone
than do men, and “cycling” women (i.e., those
PROGESTERONE who experience a typical menstrual cycle)
Unsupplemented Saliva Range (ng/mL) have higher levels of those hormones than
Premenopausal women Follicular <0.1 do menopausal women. In general, men have
Luteal 0.1 – 0.5 higher DHEA and testosterone levels than do
Men and postmenopausal women <0.05 women, and in both sexes, the level of each
of those hormones decreases dramatically
Supplemented with age. In healthy individuals, cortisol levels
Oral 0.1 – 0.5 remain relatively constant throughout life,
Cream or gel 1.0 – 10.0 regardless of sex or age.
TESTOSTERONE Specific diagnoses cannot be based on
Supplemented Morning Ranges Saliva Range (pg/mL) laboratory values alone, and the timing of
Women Cream or gel 80 – 250 the collection of specimens for the testing of
Men Cream or gel 100 – 500 diurnally variable hormones or from patients
receiving hormone supplementation is critical.
Female Male Therefore, laboratories should establish ex-
Age (Years) Range (pg/mL) Age (Years) Range (pg/mL) pected ranges that should be calibrated relative
20 – 29 17 – 52 20 – 29 42 – 145 to a specific time of day (e.g., early morning)
30 – 39 15 – 44 30 – 39 53 – 114 and to specific times relative to the dosing of
40 – 49 13 – 37 40 – 49 41 – 104 supplementation (trough levels). It is impor-
50 – 59 12 – 34 50 – 59 36 – 96 tant to remember that normal ranges may not
60 – 69 12 – 35 60 – 69 32 – 86 be valid for different collection regimens (i.e.,
>70 11 – 34 70 – 79 31 – 81 afternoon collections or those that capture
>80 26 – 54 peak levels).
aThese established ranges were determined after patients’ treatments with a transdermal cream or gel, an oral dosage Low hormone levels in saliva can be part of
form, or a transdermal patch. the clinical assessment that suggests the benefit
of supplementation. Causes of hormone levels available from compounding pharmacies, Enzyme immunoassay lacks the sensitivity to
higher than the normal physiologic range at which dosages and dosage forms (tablets, accurately measure the levels of certain hor-
include excessive hormone supplementation creams, gels, injections) tailored to the needs mones circulating in low concentrations.
and disorders such as Cushing's syndrome or of the individual patient can be prepared.
polycystic ovaries. For a detailed discussion Endogenous hormone levels vary according to
of the hormones assessed via saliva testing the the patient’s sex and age, and not all patients SPECIMEN REQUIREMENTS
pharmacokinetics of hormone replacement respond similarly to the same dosage of a sup- A 7-mL sample of saliva, which is required
therapy, and the importance of timely testing, plementary hormone. The following variables for testing, can be shipped under ambient
please see part 2 of this series. must be considered when hormone levels in conditions to a laboratory for analysis. Within
saliva are measured: the hormone or combina- one day of its collection, the saliva sample
tion of hormones administered, the dosage, the should be either frozen or shipped to a testing
INTERPRETING dosage interval, the delivery system, and the laboratory. Saliva is stable at ambient tempera-
ture for at least three weeks, and a specimen
POSTTREATMENT patient’s sex and age. Each of those parameters
is reviewed below. received any time during the first three weeks
RESULTS: GUIDELINES after collection is acceptable for testing.
Methods and procedures have been developed
FOR COMPOUNDING ELEMENTS OF SALIVA to quantitate circulating levels of estradiol,
estriol, estrone, progesterone, testosterone,
PHARMACISTS TESTING DHEA, 5α-dihydrotestosterone, cortisol, and
Highly specific antibodies are used to Hormones in saliva are best assayed by
melatonin.
measure free bioidentical hormone lev- radioimmunoassay, in which the competition
els in saliva. As we stated previously, it has between radioactive and nonradioactive hor-
been well documented in the literature that mones for a fixed number of antibody-binding TIME OF COLLECTION
levels of hormones found in saliva reflect the sites is measured to determine the concen- The time of saliva collection is critically
free fraction of plasma hormone and range tration of hormone present in the specimen. important because of menstrual circadian and
between 1% and 10% of serum or plasma
levels (2,8–10). It is important to measure the
unbound free (i.e., bioavailable) hormone level
because only the free form of the hormone
binds to cells and causes physiologic change.
The goal of HRT is to increase the level
of a single hormone or various hormones
for clinical benefit. Most studies assessing
hormone levels and supplementation have
been performed with conjugated estrogens and
progestins, and far fewer investigations (with
the exception of those involving 17β-estradiol
patches) have assessed the results of BHRT.
Studies of subjects treated with an estradiol
patch have shown that a clinical endpoint, such
as bone protection, can be achieved at the low-
est dose available. One study using low-dose
oral micronized estradiol in combination with
progesterone (Prometrium) demonstrated
bone protection over a three-year period.11
Saliva testing of low-dose patch users usually
reveals hormone levels within the physiologic
range of a cycling woman. Similarly, adminis-
tering oral 17β-estradiol to perimenopausal or
menopausal women produces salivary levels
of that hormone that, when measured 8 to 12
hours after administration, are usually within
the physiologic range of cycling women.
HRT can be supplied as either a synthetic
or a bioidentical hormone that can be prepared
by a compounding pharmacist for administra-
tion as a single agent or in a combination of
hormones. Many prescribed hormone products
are synthetic, but BHRT is now more readily
s Alaska
s Colorado
s Delaware
s Indiana
s Kansas
s Louisiana
s Mississippi
s Minnesota
s Missouri
s Montana
s Nebraska
s New Hampshire
s New Mexico
s Ohio
s Oklahoma
s South Dakota
s Texas
s Utah
s Vermont
s Virginia
s Washington
s Washington DC
s West Virginia
s Wisconsin
pharmacokinetic cycling. Testosterone, DHEA, and cortisol levels vary generating and mailing the test results and a saliva hormone report. The
diurnally, and the levels of those hormones are highest just after the form should be sent to the healthcare provider, and a copy may be sent
patient wakes, so it is extremely important that the time of collection to the patient at the provider’s request.
be indicated. Patients treated with hormone supplementation exhibit a
pharmacokinetic variation in hormone levels relative to the time of dos-
ing. If peak levels are desired, the timing of collection can be adjusted to
SPECIMEN AUTHORIZATION
Most states require the signature of a licensed medical provider as
coincide with peak supplemented hormonal levels.
authorization for the laboratory analysis of body fluids (blood, saliva,
etc.). Excepted from that requirement are tests approved by the U.S.
TURNAROUND TIME Food and Drug Administration for over-the-counter access. None of the
According to the panel requested, laboratories should establish a tests described in this report have been authorized for over-the-counter
timeframe, beginning with the date of receipt of the specimen, for sale. At the time of this writing, 24 states (see the map above) permit a
patient to request testing without supplying a signature from a licensed on the dose and delivery system, most steroid hormones have a short
provider; however, in no case will insurance plans pay for the testing half-life, and levels increase to peak concentrations within 2 to 4 hours
unless the patient supplies an authorized signature and the appropriate after administration and decrease to baseline values 8 to 24 hours after
diagnosis code that defines the purpose of the testing. The Pharmacy administration. To achieve the same effect, the dose of orally admin-
Board of California, for example, explicitly prohibits pharmacists from istered hormones must usually be higher than that of transdermally
requesting most diagnostic tests without a licensed provider’s authoriza- administered hormones, primarily because of the first-pass effect in the
tion. However, many compounding pharmacists across the country work liver, during which a large proportion of an orally delivered hormone is
closely with licensed medical providers to supply that needed authoriza- inactivated. A typical dose for transdermal estrogens delivered by patch
tion. is about one-tenth of the oral dose (i.e., approximately 0.05 to 0.1 mg of
estradiol). Because doses of hormones are often prescribed empirically
to provide symptomatic relief, many clinicians rely on patient feedback
HORMONE OR COMBINATION OF to determine appropriate dosing. This can be extremely misleading
HORMONES ADMINISTERED because a variety of symptoms can be attributed to the effects of various
Consider the following: hormones.
1. Which hormones are included in the treatment?
2. Does the treatment include a synthetic or bioidentical form of the DOSAGE INTERVAL
hormone? Consider the following:
3. Are pretreatment hormone levels expected to increase as a result of
1. What was the reported time of the last dosing?
conversion?
2. Were all replacement hormones taken at the same time?
3. Was the saliva sample collected at a trough interval?
Because of antibody specificity, saliva can be used to measure only the
effects of BHRT, synthetic conversion, or precursor hormones. Estro-
Usually, doses of hormone replacement are taken twice each day (in
gens are produced from the conversion of androgens such as DHEA
the early morning and at bedtime), although the once-daily adminis-
and testosterone. Nonhormone-containing wild yam and soy extracts
do not convert to bioidentical hormones, but dietary supplements and
compounded prescriptions that contain bioidentical hormones produce
a measurable increase in salivary hormone levels. In rare cases, dietary
supplements have been shown to increase hormone levels. An in-house
study showed that a wild-oat extract (TestoPlex; Xymogen Exclusive
Professional Formulas, Orlando, Florida) increased the level of testoster-
one in men who demonstrated low initial levels of that hormone.
Conjugated estrogens such as Premarin, which contains a high
concentration of estrone, require synthetic conversion. The estrone in
Premarin is converted in the human body to 17β-estradiol, which can
be measured in saliva. Saliva testing studies have revealed that a typical
daily dosage of .626 mg of Premarin can produce an estradiol increase
within the physiologic range. In most laboratories, however, the antibod-
ies used in testing do not measure levels of synthetic hormones such as
progestins (e.g., Provera). Because the molecular structure of synthetic
hormones differs so greatly from that of endogenous human hormones,
many synthetic hormones do not react with the testing antibodies.
Precursor hormones often stimulate the increase of secondary hor-
mones. It must be emphasized, however, that this effect does not always
occur and that the response to treatment with precursor hormones varies
among patients and according to sex. Moderate doses of DHEA, for
example, can cause a measurable increase in the levels of testosterone
and DHEA in women but not in men.
DOSAGE
Consider the following:
1. What are the patient’s baseline saliva hormone levels before treat-
ment?
2. Is the prescription an oral or a topical preparation?
3. Is the patient experiencing symptoms?
tration of some hormones may be effective. effect, and others are more rapidly absorbed. hormone at bedtime, it is advisable to measure
Some treatment schedules require intervals Regardless of the delivery system, hormone saliva hormone levels at night just before
of nonhormone use, such as progesterone use levels should be monitored at their troughs. dosing, which is by definition the appropriate
for only 14 days each month. When hormone Because hormone levels increase and decrease interval for testing the trough level.
levels are interpreted in the saliva of patients during the interval between doses, a trough The site of topically applied hormones
treated with a hormone supplement, it is ex- measurement by definition reflects the lowest can also influence the rate of absorption and
tremely important to accurately determine the point on the dosing curve. Thus, a high trough hormone levels. The patient should be advised
interval since the last dose was taken. Salivary level suggests that even higher levels occurred to occasionally rotate the site of hormone ap-
hormone levels can be expected to follow a during the dosing interval; therefore, a reduc- plication to maintain the desired therapeutic
pattern of peak levels 2 to 4 hours and trough tion in dosage would be recommended. A effect. On rare occasions, hormones accumu-
levels 8 to 24 hours after dosing. Ideally, trough trough level that is lower than the physiologic late in body fat, and a temporary buildup of
levels for each therapeutic hormone quantified target range suggests that an increased dose hormone can occur after long-term topical use.
in saliva should fall within either the youthful would be beneficial. Cream and gels should be Patients with an unexpectedly high saliva level
physiologic range (i.e., the levels most often as- prescribed at a strength that is approximately of a specific hormone should be asked whether
sociated with healthy young individuals) or the 10% of a typical oral dose. Usually, creams they apply their hormone-containing cream or
expected supplemented range (i.e., the levels are applied more frequently (and at a lower gel by hand and might inadvertently contami-
statistically determined in large populations dosage) than gels. Doses of longer-acting gels nate their lips or oral cavity with that prepara-
of patients treated with a known amount of a can be higher at the onset of therapy and will tion. Hormone preparations that remain on
specific hormone for a specific period). therefore provide the desired therapeutic the patient’s hand can also contaminate saliva
effect for relatively longer intervals (e.g., 12 to during collection.
24 hours). Topically applied hormones can be inad-
DELIVERY SYSTEM Sublingual hormone measurements should vertently rubbed onto others. Higher-than-
Consider the following: be interpreted cautiously. Sometimes patients expected estradiol levels have been found
1. Was the hormone delivered in a cream or treated with a sublingual hormone prepara- in men as a result of nighttime touch from a
gel base? tion at bedtime retain residual hormone in female partner treated with that hormone, and
2. Was the hormone taken sublingually? their oral cavity. Direct contamination by that in women, higher-than-expected testoster-
3. Did the patient wash his or her hands after residual hormone can produce extremely high one levels have been produced by extended
applying a topical hormone preparation? hormone levels that do not reflect the morning nighttime contact with a male partner who had
serum concentration. In general, a washout
applied topical testosterone.
The base compound used to deliver a medi- period is necessary before saliva levels are
cation can greatly affect the hormone levels measured after sublingual dosing. The washout
achieved after treatment. In general, creams should include typical eating and fluid intake PATIENT’S SEX
are more rapidly absorbed than gels. Some throughout the day before hormone levels are Consider the following:
gels coat the skin to produce a timed-release measured. In patients who take a sublingual
1. In premenopausal patients, how many days
have passed since the first day of the men-
strual flow?
2. At which time of day was the saliva sample
collected?
The compounding
industry’s largest
capsule supplier
Letco Medical is your number one
resource for capsules. We have the
largest selection of sizes and colors
available to compounding pharmacies.
And, our clear innovative packaging
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levels. Letco is also one of the leading
VXSSOLHUVRIÀQHSKDUPDFHXWLFDOLQ-
gredients, pharmacy equipment, and
who menstruate irregularly or are experiencing more intense climac-
teric symptoms, the collection of multiple saliva samples (typically five specialty pharmaceuticals to custom-
collections spread throughout a 28-day cycle) is beneficial. The testing ers throughout the world.
of cycling women treated with hormones can thus be performed at any
time of the month during the dosing interval, again with the recom-
mendation that trough levels be determined. Testosterone, DHEA, and
cortisol exhibit diurnal patterns; levels of those hormones are higher
But that is only half the story. It’s our
in the morning and lower at night. For baseline comparison, it is best personal devotion to you that makes
to measure hormone levels in the early morning at the same time, each
time that testing is performed.
us such a great partner. As a customer,
you are our most important asset and
PATIENT’S AGE how we measure our success.
Consider the following:
What is the age of the patient? Call today and get to know Letco.
Hormone levels decrease with age. A 40-year-old woman has ap- Don’t forget to ask for details on our
proximately 50% of the unsupplemented testosterone that she had in FREE Next Day Air shipping program.
her 20s, and the level of that hormone will continue to decrease gradu-
ally as she ages. The testosterone level begins to decrease in men in their
late 30s and continues to decrease steadily and gradually during each
subsequent decade of life at a rate of 1% to 2% per year, until unsupple-
mented testosterone levels of men in their 80s are similar to those in
women of the same age. Progesterone and testosterone levels begin to
decrease in perimenopausal women who are about 40 years old, and
estradiol levels seem to decrease somewhat later (toward the onset of
menopause, which many women experience in their early 50s). However,
because endogenous hormone levels vary greatly among individuals, the
need to measure a specific hormone level in a specific patient is essential.
Many women experience perimenopausal symptoms and exhibit lower
levels of estradiol and progesterone at a younger-than-typical age. Ten www.letcomedical.com
percent to 15% of menopausal women maintain cycling levels of estra-
were established statistically by measuring Blue Cross, Blue Shield, United Healthcare,
saliva hormone levels in patients treated with a Medicare).
specific dose of a single hormone. In our opin- To understand the ways in which a patient
ion, it is desirable to decrease the hormone responds to a particular hormone dose, the
dose until symptomatic relief occurs while compounding pharmacist must look beyond
saliva trough levels are maintained within the the relief of symptoms to determine the physi-
youthful unsupplemented or supplemented ologic response to a specific preparation. The
range, depending on the route of administra- results of saliva testing define that response.
tion. The essence of pharmaceutical compounding
is customizing, and testing hormone levels in
saliva is a key element in designing an indi-
TIPS FOR SALIVA vidualized therapeutic approach.
TEST RESULT
INTERPRETATION REFERENCES
Results from our laboratory have revealed 1. Wilson DW, Walker RF, Griffiths K. Saliva as
the following: a medium for chronobiological studies: Its
particular potential in steroid endocrinology.
1. Unsupplemented physiologic hormone Ann Ist Super Sanita 1993; 29(4): 607–611.
levels tend to be fairly consistent on a 2. Read GF, Walker RF, Wilson DW et al. Steroid
daily and monthly basis. Unsupplemented analysis in saliva for the assessment of endo-
androgen (e.g., DHEA, testosterone) levels crine function. Ann N Y Acad Sci 1990; 595:
generally track together either high or low. 260–274.
When one level is considerably higher than 3. Lac G, Lac N, Robert A. Steroid assays in
the other (relative to the untreated physi- saliva: A method to detect plasmatic contami-
ologic level), supplementation should be nations. Arch Int Physiol Biochim Biophys 1993;
101(5): 257–262.
suspected.
4. Quissell DO. Steroid hormone analysis in
2. Approximately 15% of postmenopausal human saliva. Ann N Y Acad Sci 1993; 694:
women who are not receiving treatment 143–145.
with HRT will maintain higher-than-base- 5. Al-Ansari AA, Mahmod S, Landon J et al.
diol after menopause, and, interestingly, many line (i.e., .5 pg/mL) estradiol levels. Re: Salivary thyroxine as an estimate of free
of those women have a relatively higher level 3. Hormone levels in the saliva of patients thyroxine. J Nucl Med 1984; 25(4): 538–539.
of androgen. Usually, restoring hormone levels treated with conjugated estrogens and 6. Elson MK, Morley JE, Shafer RB. Salivary
to a value equal to or greater than the youthful estradiol patches are usually within the thyroxine as an estimate of free thyroxine:
physiologic range is considered desirable in physiologic range. However, some patients Concise communication. J Nucl Med 1983;
both men and women. may require a dosage adjustment to achieve 24(8): 700–702.
that range. 7. Kirschbaum C, Hellhammer DH. Salivary
cortisol in psychobiological research: An over-
EXPECTED RANGE 4. Higher dosing and shorter dosing intervals
view. Neuropsychobiology 1989; 22(3): 150–169.
Consider the following: usually result in higher hormone levels in
8. Vining RF, McGinley RA. The measurement
saliva. of hormones in saliva: Possibilities and pitfalls.
1. Which hormone delivery system was used?
2. Do the supplemented saliva hormone J Steroid Biochem 1987; 27(1–3): 81–94.
values fall within the expected range or the CONCLUSION 9. Lipson SF, Ellison PT. Development of
protocols for the application of salivary steroid
youthful physiologic range? Unlike blood or urine, saliva reflects the analyses to field conditions. Am J Hum Biol
biologically active fraction of steroids in the 1989; 1: 249–255.
From 1998 to 2000, the results of in-house bloodstream. Saliva testing is noninvasive, 10. Morley JE, Perry HM 3rd, Patrick P et al.
studies performed at the Aeron LifeCycles simple to perform and undergo, safe for the Validation of salivary testosterone as a screen-
laboratory were used to establish expected patient and practitioner, stress free, painless, ing test for male hypogonadism. Aging Male
ranges for levels of specific hormones (estrone, and both private and convenient for the patient 2006; 9(3): 165–169.
estradiol, estriol, progesterone, testosterone) and his or her physician. The collection time 11. Prestwood KM, Kenny AM, Kleppinger A et
in male and female patients who were either for saliva testing is more controllable than al. Ultralow-dose micronized 17beta-estradiol
treated with HRT (n = approximately 800) that for serum testing. Because hormones are and bone density and bone metabolism in
or who received no HRT (n = approximately stable in saliva at room temperature for at least older women: A randomized controlled trial.
800). Age- and sex-specific levels of those three weeks after collection, the transport of JAMA 2003; 290(8): 1042–1048.
hormones were noted in the study subjects. It saliva samples to a laboratory for analysis can
was found that (1) variations among patients be accomplished via the U.S. Postal Service. Address correspondence to John Kells, CEO and
resulted in a broad overlap of ranges, and (2) a In addition, the cost of saliva testing, which is President, Aeron LifeCycles Clinical Laboratory,
general decrease in hormone levels occurred usually less expensive than that for blood test- 1933 Davis Street, Suite 310, San Leandro, CA
with advancing age. The supplemented ranges ing, is covered by many insurance plans (e.g., 94577. E-mail: [email protected]
2 bottles
per pack means
less waste!
*Regular vial resins may contain zinc stearate which reacts with ethylene oxide, a commonly used sterilizing agent. Through a series of chemical processes involving
components of ophthalmic medication, totally unacceptable particles may form. EPS® INC. eliminates this possibility using and sterilizing only stearate-free resins.
Compounding pharmacists and pharmacy that workers who handle antineoplastic drugs is determined by the toxicity of those drugs
technicians are repeatedly exposed to airborne risk the potential systemic absorption of those and the extent and frequency of exposure.1
nonmicrobiologic contaminants during the agents by inhalation. In response to evidence suggesting that
preparation and dispensing of customized Pharmacy employees who rarely handle exposure to various chemicals used in com-
medications. The safety of individuals who hazardous drugs have a lower risk of exposure pounding causes adverse effects, because the
handle potentially hazardous drugs became to such agents than do workers whose contact pure bulk powders used in compounding can
a published concern when reports of second with potentially toxic agents is frequent. To easily become airborne, and because those
cancers in patients treated with antineoplas- minimize exposure, areas of the pharmacy that powders vary in toxicity, a co-author of this
tic drugs were linked with the discovery of contain hazardous drugs should be restricted report (BM) prioritized the need for air-qual-
mutagenic substances in nurses who handled to staff with required access. Communication ity monitoring (specifically for the hormones
those drugs and treated those patients.1 Since via a pass-through window minimizes traffic compounded most often in his pharmacy) in
that time, exposure to hazardous agents in the flow through those restricted areas.3 the compounding area and throughout his
workplace has been further associated with a The effect of occupational exposure to store, The Compounding Pharmacy. The re-
variety of acute, short-term, and long-term hormones has also been studied.2 Disorders sults of air-monitoring tests conducted by the
adverse effects.1 According to the results of two diagnosed in workers exposed to those sub- industrial hygienist and co-author of this paper
controlled surveys,1 pharmacists, pharmacy stances included abnormal menstruation, pos- (GI) were used to evaluate the air quality in
technicians, and nurses with routine occu- sible testicular dysfunction, the masculiniza- that pharmacy, and the findings of the assess-
pational exposure to hazardous drugs in the tion of female workers, breast development in ment are described below.
workplace experienced a significant increase male workers, an increase in the incidence of
in signs and symptoms that included dizzi-
ness, sore throat, chronic cough, headache, eye
breast cancer (which may have resulted from
the inhalation and skin absorption of estrogen
Industrial Hygiene:
irritation, and infections. Other studies have during work-related tasks), and (possibly) im- A Definition
shown an increased incidence of impaired paired fertility or other types of cancer.2 The Threshold limit values, which are airborne
fertility, fetal abnormalities, and fetal loss risk to personnel who handle hazardous drugs concentrations of substances to which nearly
in healthcare personnel who are frequently
exposed to such agents.1 Information from
the United States Department of Labor Oc-
cupational Safety and Health Administration
(OSHA) indicates that the compounding of
many medications, including the following YOUR QUALITY CONTROL LAB
types of agents, presents a significant risk to
compounders: certain antineoplastic drugs
(e.g., externally applied busulfan), hormone-
containing medications (e.g., estradiol,
progesterone, estriol, testosterone, meth-
yltestosterone), and various antibiotics (e.g.,
penicillin) that can cause an allergic reaction
when compounded.2
Compounding staff can be exposed to haz-
ardous drugs by inhalation, unintentional in-
gestion via hand-to-mouth contact, a “sharps”
injury, accidental injection by a needle-stick,
or skin contact that results in absorption.3
The most likely routes of exposure are by
inhalation or contact.1 Aerosolization, which
is an established phenomenon that cannot be
prevented during routine handling of powders
and liquids, occurs when a needle is withdrawn
from a vial containing a drug, during the con-
nection or disconnection of infusions, when
air is expelled from a syringe, and during the
ne
On-Li ing
trituration of tablets.4 Compounding staff are
also exposed to hazardous airborne drugs dur- rt
ing the operation of a tablet encapsulation ma- Repo ble!
chine, hand manipulation, or while performing Availa
tasks that involve sieving or granulation.2 A When you think quality, think Eagle.
study by deWerk and colleagues5 suggested
%'#%'!$%'#(!%$""
,*** "$"+(!"%#
environmental exposure. Progesterone and 2. A list of hazardous materials used, handled, istrative tasks. Each personal air sample was
testosterone were selected for analysis because stored, or produced in the workplace in obtained via a small pump, which was worn
a high volume of prescriptions containing terms of quantity per unit time, as well as a at waist-level by the monitored employee
those agents is prepared at The Compounding brief description of how the materials were and was connected with ultrasoft vinyl tubing
Pharmacy, and the methodology for determin- used to a collection device (a fiberglass filter in a
ing the environmental level of those substances 3. A list of potential harmful physical hazards polystyrene cassette that was placed within the
has been established. Because overexposure and a description of their sources breathing zone of the monitored employee).
to either of those hormones can be harmful, 4. A brief description of existing controls, As the employee performed his or her routine
the results of their measurement were used such as ventilation, or a list of personal duties, known volumes of air were drawn
to estimate possible environmental levels of protective equipment and an evaluation of through the fiberglass filter. At the conclusion
other similar substances. The first of three its use and effectiveness of the sampling period, the filter from each
air-quality assessments was performed in 5. The number of personnel assigned to the device was sent to a laboratory accredited by
The Compounding Pharmacy in October of workplace in a specific location the American Industrial Hygiene Associa-
2003. The findings from the most recent such tion for analysis, and the amount of hormone
analysis, which was performed in 2006, are trapped on the filter was measured by means
described in this report.
Conducting the of high-performance liquid chromatography
Each air-quality assessment of The Com- Air-quality Assessment with ultraviolet detection. The final report
An industrial hygienist (GI) obtained listed the name of the individual tested, the
pounding Pharmacy began with a baseline sur-
personal air samples (which for analysis are task performed during the testing period, the
vey that included the following information:
preferred to area samples) collected by an duration of testing, the actual concentration
1. A description of operations within the air-sampling device that was worn continu- of the target hormone in milligrams per cubic
work area, including documentation of the ously for a specified duration by each of three meter of air, and the time-weighted average
time required to perform each task and the laboratory employees who were performing exposure level, which may differ from the
sequence in which each task was performed routine encapsulation, blending, or admin- actual concentration.
Abstract
Autism is a complex disorder that
affects children. Children who pre-
sent with symptoms of autism re-
quire a comprehensive evaluation
by a multidisciplinary team includ-
ing a psychologist, neurologist,
psychiatrist, speech therapist, and
other professionals who diagnose
children with autism spectrum dis-
orders. Following the diagnosis, a
treatment plan is developed, which
in most cases involve educational
and behavioral interventions and
medications. The multidisciplinary
team then expands to a team of
professionals to treat the disor-
der, the team of which includes a
pharmacist. Anxiety, depression,
obsessive-compulsive disorder,
behavioral problems, seizures,
impulsivity, and hyperactivity are
the main symptoms of autism that
have in many cases been success-
fully minimized and in some cases
alleviated by proper medication.
The childhood disorder of autism, also called autism disorder (AD), mc-receptor, and has been found in various open label trials to reduce
is a lifelong condition characterized as affecting social, cognitive, and several AD symptoms such as hyperactivity and SIB.9 Other possible
imaginative abilities.1 Clinical symptoms are evident by the time the behavior improvements have been noted for agitation, aggression, ir-
child is three years old; the patient’s symptoms continue throughout life. ritability, temper tantrums, social withdrawal, attention, eye contact,
Children with AD exhibit numerous developmental abnormalities in and repetitive behaviors.10 Occasionally, naltrexone has been reported
areas such as social interaction and communication as well as restricted to mildly promote social tendencies, such as eye contact and social
interests and activities. AD may be associated with regression, feed- solicitation, and attempts to communicate under socially stimulating
ing and eating problems, stereotypy, grand mal seizures, self-injurious circumstances. Naltrexone use for AD has been reported in children as
behavior (SIB), and aggressiveness. young as 2.8 years of age and very few side effects have been observed.
Numerous theories for the causality of AD exist and many treat- Naltrexone use may cause restlessness or difficulty sleeping during the
ment options are being researched. One area of long-term research is first week of use and gastrointestinal upset is a rare side effect that may
the opioid-excess theory of AD. The opioid excess theory hypothesizes last a few days. Improvements with naltrexone therapy in AD have been
that children with AD have an increased production of endogenous seen within as little as 7 hours.10
opioid peptide neurotransmitters (β-endorphins) or that alterations in
the normal activity of the system may exist.2 Clinical evidence sug-
gests that one of the defining characteristics of childhood AD is SIB,
Case Report 1
A case study was reported in 1987 by Bernstein and Hughes about Ms.
which may be mediated and maintained by abnormally high levels of A, a 27-year-old autistic and mentally retarded patient who had been
β-endorphins. Indirect evidence for the opioid excess theory comes institutionalized since she was four years old.11 Her autistic symptoms
from the similarities in symptoms between autistic children and young included noncommunication, unresponsiveness, rocking, and self-abuse
animals treated with low doses of opioids. In 1979, Panksepp noted that that had continued throughout the years without improvement. Ms. A’s
opioid-treated animals displayed similar behavior and clinical character- self-abuse had gotten progressively worse over the years in her residen-
istics of children with autistic behavior.3 Panksepp observed that animals tial facility. She often struck her jaw repeatedly, many times inducing
treated with opiates had a high tolerance to pain, less desire for social bleeding and dislocation of her temporal mandibular joint. Attempts
interaction, and exhibited preoccupation with repetitive behavior. Also, made to control this behavior comprised of therapy that included reward
opiate-treated animals exhibited increased seizure activity and tended
to walk on their toes similar to the behavior of many autistic children.
These early observations provided a theoretical basis that AD may be
due to abnormalities in the endogenous opioid system.
Several studies have demonstrated elevated plasma β-endorphin
levels in some autistic children and adolescents and several theories
exist to how elevated β-endorphin levels may affect the developing
human brain.4 Sahley and Panksepp hypothesized that AD may reflect
the failure to cleave certain enzymes, over-saturating the brain with
β-endorphins, leaving the brain and other developing organs of the
child at earlier stages of development, and preventing the brain from
becoming responsive to sensory and social environment.5 One theory
states that if endogenous opioids are high, then opioid receptors may be
subsensitive and self-injury may raise receptor input to a normal level
to relieve a sense of dysphoria.6 Another hypothesis speculates that
individuals who exhibit SIB become endorphin dependent and chronic
elevation of β-endorphins leads to down-regulation of opioid receptors.
In these patients, SIB is maintained by the need to release endogenous
opiates to attenuate pain. Another theory is that chronically elevated
β-endorphin levels increase the pain threshold resulting in reduced
responsiveness to stimulation.7
Many children with AD appear to have an increased threshold to
pain and may hurt themselves severely without crying.1 People with
autism spectrum disorders (ASD) may demonstrate a variety of activities
that might cause harm to themselves. These activities include poking of
body parts, skin picking, self-biting, punching and slapping of the head
and other parts of the body, head-to-object banging, body-to-object
banging, lip chewing, removal of hair and nails, and teeth banging.8 Also,
it is noteworthy that self-injurious and stereotypic behaviors can occur
when exogenous narcotics are withdrawn from addicted animals.3
Naltrexone hydrochloride is an analog of naloxone and is an orally
effective narcotic antagonist that is U.S. Food and Drug Administra-
tion approved as an adjunct for treating alcohol and opioid dependent
individuals. Naltrexone antagonizes opioid receptors, particularly the
interventions and medications. The multidisciplinary team then expands 5. Sahley TL, Panksepp J. Brain opioids and autism: An updated analysis of possible
to a team of professionals to treat the disorder, the team of which in- linkages. J Autism Dev Disord 1987; 17(2): 201–216.
6. Sandman CA. β-endorphin disregulation in autistic and self-injurious behavior: A
cludes a pharmacist. Anxiety, depression, obsessive-compulsive disorder, neurodevelopmental hypothesis. Synapse 1988; 2(3): 193–199.
behavioral problems, seizures, impulsivity, and hyperactivity are the main 7. Rothenberger A. Psychopharmacological treatment of self-injurious behavior in
symptoms of AD that have in many cases been successfully minimized individuals with autism. Acta Paedopsychiatr 1993; 56(2): 99–104.
and in some cases alleviated by proper medication. The formulation that 8. Hollander E. Autism spectrum disorders. Informa Health Care 2003; 289–290.
was discussed in the case reports within this article was analyzed by an 9. Williams PG, Allard AM, Sears L et al. Brief report: Case reports on naltrexone use
in children with autism: Controlled observations regarding benefits and practical
independent analytical laboratory with results showing 97.22% of active
issues of medication management. J of Autism Dev Disord 2001; 31(1): 103–108.
drug present. Lab potency results can be a vital tool for compounding 10. Elchaar GM, Maisch NM, Augusto LM et al. Efficacy and safety of naltrexone use
pharmacists to ensure their preparations are as accurate as possible. Cur- in pediatric patients with autistic disorder. Ann Pharmacother 2006; 40(6): 1086–1095.
rently, there is no cure for AD; however, compounding pharmacists can 11. Bernstein GA, Hughes JR, Mitchell JE et al. Effects of narcotic antagonists on self-
play a vital role in the treatment of AD, as witnessed by the case reports injurious behavior: A single case study. J Am Acad Child Adolesc Psychiatry 1987; 26(6):
886–889.
provided within this article.
12. Allen LV Jr. The Art, Science and Technology of Pharmaceutical Compounding. 2nd ed.
Washington, DC: American Pharmaceutical Association; 2002: 147–148.
References
1. Sher L. Autistic disorder and the endogenous opioid system. Med Hypotheses 1997;
13. Nind M. Kellett M. Responding to individuals with severe learning difficulties and
stereotyped behaviour: Challenges for an inclusive era. Eur J Spec Needs Educ 2002;
17(3): 265–282.
48(5): 413–414. 14. Edelson SM. Autism Research Institute. Stereotypic (Self-Stimulatory) Behavior.
2. Shattock P, Whiteley P. Biochemical aspects in autism spectrum disorders: Updat- [Autism Research Institute Website.] 1995. Available at: www.autism.com/families/
ing the opioid-excess theory and presenting new opportunities for biochemical problems/stim.htm. Accessed February 27, 2009.
intervention. Expert Opin Ther Targets 2002; 6(2): 175–183.
3. Panksepp J. A neurochemical theory of autism. Trends Neurochem Sci 1979; 2:
174–177.
4. Cazzulo AG, Musetti MC, Musetti L et al. β-endorphin levels in peripheral blood Address correspondence to Tom Wynn RPh, Tri-State Compounding Pharmacy,
mononuclear cells and long-term naltrexone treatment in autistic children. Eur 7715 Beechmont Avenue, Cincinnati, OH 45225. E-mail: twynn_kunkelrx@
Neuropsychopharmacol 1999; 9(4): 361–366. zoomtown.com
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Abstract
All healthcare facilities are different, and there are no comprehen-
sive guidelines or United States Pharmacopeial standards that
will address all of a facility’s needs. All physicians and health-
care professionals at a facility need to work together and rely on
credible published guidelines, state and federal regulations, their
own professional judgment, experience, and common sense to
create their own comprehensive program for handling hazard-
ous drugs and chemicals. Some of the subjects discussed in this
article as they pertain to the preparation of nonsterile and sterile
hazardous compounds in an institutional setting are: personnel
and training; establishing policies and procedures; environmen-
tal issues; decontamination, deactivation, and disinfecting; and
containment and disposal.
Numerous studies on the occupational exposure of hospital personnel to the toxic effects of
antineoplastic agents or hazardous substances have been published over the last three decades.
Exposure to these drugs in the workplace has been associated with acute symptoms or short-term
reactions, such as flu-like symptoms, sore throats, chronic cough, eye and skin irritations, infec-
tions, and headaches.1 Studies have shown an increase in fetal abnormalities, miscarriages, cancer,
and genotoxic or mutagenic effects in healthcare workers who handle hazardous drugs.2-5 Health-
care workers may be exposed to hazardous substances during receipt, compounding, transport,
This is the tenth article published in the Interna- delivery, or administration of the drug, contact with waste, or during equipment maintenance and
tional Journal of Pharmaceutical Compounding and repair. Routes of exposure include accidental injection, dermal absorption, ingestion of contami-
written by Linda F. McElhiney that is dedicated nated food or mouth contact with contaminated hands, or inhalation (See the sidebar titled Routes
to helping hospital pharmacies meet the standards of Exposure.). Although inhalation may be suspected as the primary route of exposure, especially
or guidelines presented by the American Society when compounding with powders or working with volatile substances, studies have shown that
of Health-System Pharmacists, United States an additional consideration as a primary route of exposure is surface contamination and dermal
absorption.6,7
Pharmacopeial Convention, Inc., Joint Commis-
Publications about the risks associated with handling hazardous substances are abundant.
sion on Accreditation of Healthcare Organizations,
Guidelines on handling hazardous substances have been published by the National Institute for
Occupational Safety and Health Administration, and Occupational Safety and Health (NIOSH),8 American Society of Health-System Pharmacists
International Academy of Compounding Pharma- (ASHP),9 International Academy of Compounding Pharmacists (IACP),8 and the United States
cists. This article focuses on the importance of the Pharmacopeial Convention, Inc. (USP).10 However, even with these publications’ warnings of risks
hazardous compounding standards and guidelines as associated with handling hazardous substances, a study conducted by a group of PharmD students
it applies to hospital pharmacy practice. from Ohio Northern University (ONU), presented by Ms. Michelle George at the 2006 ASHP
Medication
Class II BSC
Recommended Required PPE
Handled Properly in
Participating Hospitals
Azathioprine Yes Gloves/goggles/gown No Routes of Exposure
Chloramphenicol No Gloves/goggles/gown Yes
Cidofovir Yes Gloves/goggles/gown No UÊ VV`iÌ>ÊiVÌ
Colchicine No Gloves/goggles/gown Yes UÊ iÀ>Ê>LÃÀ«Ì
Cyclosporine Yes Gloves/goggles/gown No UÊ }iÃÌÊvÊVÌ>>Ìi`Ê
Dutasteride No Gloves/gown Yes food or mouth contact with
Estradiol No Gloves/goggles/gown Yes contaminated hands
Estrogen, No Gloves/goggles/gown Yes UÊ
>>Ì
conjugated
Ganciclovir Yes Gloves/goggles/gown No
Mycophenolate Yes Gloves/goggles/gown No
mofetil
Oxytocin
Pentamidine
No
No
Gloves/goggles/gown
Gloves/goggles/gown
Yes
Yes
isethionate Items to Include in
Podophyllum resin Yes Gloves/goggles/gown No
Progesterone No Gloves/goggles/gown Yes
a Hazard Assessment
Rituxan No Gloves/goggles/gown Yes of a Facility
Tacrolimus Yes Gloves/goggles/gown No UÊ iVÌ>>ÌÊ>`ÊVi>}
Testosterone No Gloves/goggles/gown Yes
UÊ
µÕ«iÌ
Trifluridine No Gloves Yes
UÊ
µÕ«iÌÊ>Ìi>Vi
Zidovudine Yes Gloves/gown No
UÊ *
ÞÃV>Ê>ÞÕÌÊvÊÜÀÊ>Ài>Ã
BSC = biological safety cabinet
PPE = personal protective equipment UÊ *ÌiÌ>ÊiÝ«ÃÕÀiÃÊ`ÕÀ}ÊÜÀ
UÊ ,ÕÌiÊ«iÀ>ÌÃ
annual meeting, reported that several area hos- titled Items to Include in a Hazard Assessment UÊ -«ÊÀiëÃi
pital pharmacies were not preparing selected of a Facility should be included in this evalua- UÊ /Ì>ÊÜÀ}ÊiÛÀiÌ
hazardous agents properly and that their tion. ASHP guidelines state that “both hazard UÊ /Þ«iÃÊvÊ`ÀÕ}ÃÊLi}Ê
>`i`
actions may have resulted in unnecessary risks identification (the qualitative evaluation of UÊ 6Õi]ÊvÀiµÕiVÞ]Ê>`ÊvÀÊvÊ
to hospital workers and patients.11 The area the toxicity of a given drug) and an exposure drug handled
hospitals included in the study were surveyed assessment (the amount of worker contact with UÊ 7>ÃÌiÊ
>`}
about the preparation of 19 non-chemother- the drug) are required to complete a hazard
UÊ 7>ÃÌiÊÃi}Ài}>Ì]ÊVÌ>iÌ]Ê
apeutic medications that were selected from assessment.”11 Since different hazardous drugs
and disposal
the NIOSH list of hazardous medications (see are used at each facility, there is no standard
Table 1). Eight of the 19 medications were not assessment available.
being prepared in a Class II biological safety This article highlights key points in the guidelines, staff should be trained in the strin-
cabinet (BSC) or a compounding aseptic con- NIOSH, ASHP, IACP, and USP guidelines for gent aseptic (for compounding sterile hazard-
tainment isolator (CACI), commonly known compounding hazardous drugs, provides infor- ous drugs) and negative-pressure techniques.9
as a barrier isolator or glove box. Luci Power, mation on protective equipment and devices Once trained, competency must be reassessed
MS, RPh, senior pharmacist and manager for for compounders, and offers recommendations on a regular basis, preferably annually.
Parenteral Support Services at the University for daily compounding operations. None of the published guidelines out-
of California Medical Center in San Francisco, line specific requirements for a hazardous
who is a member of the NIOSH working compounding training program; however,
group on Hazardous Drugs and lead author PERSONNEL AND ASHP does publish a training program, “Safe
of the 2006 ASHP guidelines,9 commented on TRAINING Handling of Hazardous Drugs” by Luci Power
this study and recommended that “Each prac- All compounding personnel should undergo and James Jorgenson, which is compliant with
tice site must look at drugs that are hazardous special training and demonstrate competence the current ASHP and NIOSH guidelines
per NIOSH and ASHP criteria and decide if on handling hazardous substances by an objec- and the new USP and Joint Commission on
the drugs should be labeled as hazardous drugs tive method prior to compounding hazardous Accreditation of Healthcare Organizations
and handled in a special safety program.”12 drugs. Everyone should become thoroughly (JCAHO) standards. The program provides 6
NIOSH recommends that an evaluation familiar with all of the safety procedures used hours of continuing education credit (ACPE
be conducted at the facility to identify and to minimize exposure during compound- Program #204-000-06-093-H04) and includes
assess the hazards before anyone begins work ing, transport, administration, and disposal a workbook and a 90-minute DVD or VHS
with hazardous drugs. The items in the sidebar of hazardous drugs. According to the ASHP tape. Study guides are also available. This pro-
Keypoints of Hazardous Drugs as Compounded Sterile Preparations in
United States Pharmacopeia Chapter <797>
UÊ 1ÃiÊ>««À«À>ÌiÊ«iÀÃ>Ê«ÀÌiVÌÛiÊiµÕ«iÌ°
UÊ 1ÃiÊ>««À«À>ÌiÊ«À>ÀÞÊi}iiÀ}ÊVÌÀÃÊL}V>ÊÃ>viÌÞÊV>LiÌÃÊ>`ÊV«Õ`}Ê>Ãi«ÌVÊVÌ>iÌÊ
isolators).
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>â>À`ÕÃÊ`ÀÕ}ÃÊÃi«>À>ÌiÞÊvÀÊÌ
iÀÊÛiÌÀÞ°
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ÊÜ>ÌiÀÊVÕÊi}>ÌÛiÊ«ÀiÃÃÕÀiÊÊVi>ÀÃÊ
containing compounding aseptic containment isolators or where hazardous compounding and drugs are stored.
UÊ ÌÀÊÀÊ«ÀiÃÃÕÀâ>ÌÊ>`Ê`VÕiÌÊÀiÃÕÌð
UÊ >`iÊ
>â>À`ÕÃÊ`ÀÕ}ÃÊÜÌ
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iÌ
iÀ>«ÞÊ}ÛiÃÊ`ÕÀ}ÊÀiViÛ}]Ê`ÃÌÀLÕÌ]ÊÃÌV}]ÊÛiÌÀÞ}]ÊV«Õ`}]Ê
administration, and disposal.
UÊ *Ài«>ÀiÊÊ>ÊÌiÀ>Ì>Ê"À}>â>ÌÊvÀÊ-Ì>`>À`â>ÌÊ
>ÃÃÊxÊiÛÀiÌÊÜÌ
ÊVÃi`ÃÞÃÌiÊÌÀ>ÃviÀÊ`iÛViÃÊ
and primary engineering controls in place.
UÊ VViÃÃÊÌÊ>Ài>ÊÃ
Õ`ÊLiÊÌi`ÊÌÊÌÀ>i`Ê«iÀÃi°
UÊ VÕiÌÊ«iÀÃiÊÌÀ>}Ê>Õ>Þ°
UÊ i}>ÌÛiÊ«ÀiÃÃÕÀiÊiÛÀiÌÊÌÊÀiµÕÀi`ÊvÀÊÜÛÕiÊV«Õ`}Ê«iÀ>ÌÃÊÜ
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devices are used.
UÊ "LÌ>ÊÜÀÌÌiÊ>VÜi`}iiÌÊvÊ«iÀÃiÊvÊÀi«À`ÕVÌÛiÊV>«>LÌÞÊVViÀ}ÊÀÃÃÊ>ÃÃV>Ìi`ÊÜÌ
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hazardous drugs.
UÊ Ã«Ã>ÊvÊÜ>ÃÌiÊiiÌÃÊ>Ê>««V>LiÊvi`iÀ>Ê>`ÊÃÌ>ÌiÊÀi}Õ>Ìð
UÊ VÕiÌÊÌÌ>ÊiÝ
>ÕÃÌÊvÊ«À>ÀÞÊi}iiÀ}ÊVÌÀð
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ð
pharmacy, nursing, medical staff, housekeep- may be placed in Type B powder containment
ing, transportation, maintenance, employee hoods to minimize airborne contamination
health, industrial hygiene, clinical laboratories, when weighing bulk hazardous powders for
and safety. compounding. If the facility can only accom-
Hospitals are creating positions for safety modate one BSC, the hood must be cleaned
administrators and committees to address and disinfected between compounding a sterile
hazardous drug issues. The safety administra- and a nonsterile hazardous compound.
tors and committees are generally responsible The use of automated systems to pre-
for developing hazardous drug lists within the pare and dispense medications is becoming
facilities and developing or revising policies popular in healthcare facilities. An auto-
and procedures for handling hazardous drugs mated system, IntelliFillChemo , developed by
using the 2004 NIOSH Alert and the 2006 ForHealth Technologies, Inc. and acquired
ASHP guidelines. by Baxa Corporation in March 2009, is a
robotic system that aseptically prepares sterile
hazardous injectable drugs in an ISO Class 5
ENVIRONMENT contained environment. Orders are entered
All hazardous compounding should be done and the materials are loaded into one end of
in a controlled area where access is limited the system. The robot uses barcodes to select
to authorized personnel trained in handling
hazardous drugs. All of the standards and
the appropriate materials and robotic arms to
prepare the compounds. The finished prepara-
SALIVA TESTING
guidelines recommend negative-pressure tions are labeled and overwrapped before
rooms or rooms with attached airlocks or exiting the system for dispensing. Waste is also ACCURATE | RELIABLE | FAST
anterooms. If sterile hazardous compounds self-contained. Finally, IntelliFillChemo has a
are being prepared, the room must also be an built-in chemo hood for manual compounding.
International Organization for Standardization Another automated robotic system, CytoCare,
(ISO) Class 7 environment. All surfaces must is being distributed by a new company, Devon
be smooth, impervious, or capable of being Robotics. This system was originally marketed
readily cleaned and decontaminated. Poured in Europe and is currently installed at over
resin floors and stainless steel or chemical-re- 60 healthcare institutions worldwide, includ-
sistant countertops are great options for these ing some of the top hospitals in the U.S.13 >/@*/66:,3()90?&
rooms. Environmental monitoring devices and CytoCare features software that integrates -HZ[;\YUHYV\UK;PTLZ
testing should be used to ensure that the air with hospital pharmacy systems. Features are
pressure or airflow is within normal limits and -+((WWYV]LK;LZ[PUN
a six-axis robotic arm and an automated waste
that there is no contamination of the area. disposal system, and dose accuracy is checked *VUZ\S[H[PVUZ>P[O
packaging of hazardous drugs. All gloves used at the time of this publication. Sterile surgical
PERSONAL PROTECTIVE
EQUIPMENT
Personnel should follow all recommenda-
tions for personal protective equipment (PPE).
The selection of PPE may be dependent on
the type of hazardous drug that the com-
pounder is handling. PPE includes gloves,
gowns, masks or respirators, face shields or
safety goggles, and coverings.
Both NIOSH and ASHP recommend that
gloves be worn at all times when handling
hazardous drugs, including touching the outer
ing calculations or checking labels, should be completed before entering the BSC or CACI. This
COMPOUNDING practice should eliminate or minimize the need to exit the BSC or CACI before the compounding
STERILE HAZARDOUS is complete. The sidebar titled Tips on Preparing Hazardous Compounded Sterile Preparations
from American Society of Health-System Pharmacists Guidelines provides tips on compounding
DRUGS sterile hazardous compounds. No personnel should be preparing hazardous drugs without proper
Compounding hazardous sterile drugs is training and demonstrated competency.
addressed in the revised USP Chapter <797>.
(See the sidebar titled Keypoints of Hazard-
ous Drugs as Compounded Sterile Prepara- COMPOUNDING NONSTERILE HAZARDOUS
tions in the United States Pharmacopeia Chapter DRUGS
<797>.) Organization is the key to minimizing Although most hazardous drugs are not available in oral liquid dosage forms, they are often
contamination and maximizing productivity. prescribed for children and adults who cannot swallow tablets or capsules. Compounding nonster-
All compounding materials should be gathered ile hazardous drugs does not require an ISO Class 5 environment, but the compounding should be
prior to entering the negative-pressure clean- done in a protected environment and not on an open countertop in the pharmacy. Formulations
room. All activities not requiring a primary for these types of compounds may require that tablets be crushed into a fine powder, capsules are
engineering controls (PEC), such as perform- opened, or bulk hazardous powder is weighed on a balance. Parenteral dosage forms may also be
used to prepare these compounds. Without suspension is prepared. The final suspension is
negative-pressure room, calibrate the final NIOSH alert and material safety data sheets
container by measuring the final volume using (MSDSs). The sidebar titled American Society
water in a graduated cylinder, pour it into of Health-System Pharmacists’ Recommenda-
Occupational the container, and mark the container with tions for Handling and Compounding Hazard-
a washable marker. The mixture in the hood ous Nonsterile Hazardous Drugs summarizes
Safety and Health can be poured into the container, the volume ASHP’s guidelines.
Administration- brought up to the calibrated amount with the
recommended vehicle, and the container capped and shook
DECONTAMINATION,
to mix. After the compounding is complete,
Steps for Immediate the mortar and pestle can be disposed of in the DEACTIVATION, AND
Treatment of hazardous waste container.
Contaminated Worker Another common compounding technique, DISINFECTING
The ASHP guidelines define decontamina-
the syringe method, can be used to prepare
1. Call for help, if needed. tion, deactivation, and disinfecting, all of which
small quantities of certain hazardous com-
have a different meaning.
2. Remove contaminated pounds, such as mercaptopurine suspension or
clothing immediately. azathioprine suspension. The plunger of a
3. Flood affected eye with water 30-mL or 60-mL Luer-Lock syringe is t DEACTIVATION is defined as “treating
or isotonic solution for at least removed, the empty syringe barrel is placed a chemical agent, such as a hazardous drug,
on a balance and tared, and the hazardous with another chemical, heat, ultraviolet
15 minutes.
powder is backloaded into the syringe and light, or another agent to create a less haz-
4. Clean exposed skin with soap ardous agent.”
weighed. A second Luer-Lock syringe of the
and water, rinsing thoroughly. same size is used to measure the vehicle. In a t DECONTAMINATION is defined as
5. Obtain medical attention. BSC or CACI, the syringes are attached with “inactivation, neutralization, or removal of
È°ÊVÕiÌÊiÝ«ÃÕÀiÊÊ a Luer Lock-to-Luer Lock connector and the toxic agents, usually by chemical means.”
employee medical record and contents of each syringe are pushed back and t DISINFECTING is defined as “removal
medical surveillance log. forth between the two syringes until a uniform of a viable organism from surfaces using
sterile 70% alcohol or other appropriate decontaminated at the beginning of each shift doing inventory, or pulling these drugs from
disinfectant prior to compounding sterile and every thirty minutes during continuous storage.19-21
preparations.” compounding.
DELIVERY AND
Deactivating a hazardous substance is
preferred; however, there is no single process
TRANSPORT
Hazardous drugs within an institution
available to deactivate all hazardous drugs. should be transported in zippered plastic bags
Alcohol is not a deactivating agent, and its use or special containers that protect them. These
as a deactivating agent may actually spread the outer coverings or containers also need to be
hazardous contamination rather than clean the properly labeled and identified as hazardous
PEC. It should only be used as a disinfecting substances. Hazardous drugs should be deliv-
agent after deactivation and decontamination ered by pharmacy personnel or picked up by
when appropriate agents are used. hospital staff. They should never be delivered
Compounders should decontaminate PECs via a pneumatic tube system. Spillage in a
per manufacturer recommendations. Since pneumatic tube system could result in wide-
each hazardous substance may have its own spread contamination and a shut-down of the
unique properties, the MSDS should also entire pneumatic tube system until the institu-
be obtained and read for decontamination tion’s hazmat team can decontaminate it.
recommendations. Many hazardous drugs are
deactivated by sodium hypochlorite solution,
which is a strong oxidizing agent. Sodium thio-
ADMINISTRATION
More hospitals are developing procedures
sulfate neutralizes many hazardous substances.
for pharmacy personnel to prime the intrave-
There is a commercially available product, nous tubing prior to delivery of the hazard-
SurfaceSafe (SuperGen) that provides a 2-step ous compound to the unit to minimize risk
wipe system using sodium hypochlorite, deter- of exposure to the person administering the
gent, and thiosulfate. drug and risk of contaminating the patient’s
Preparing mechlorethamine ointment cre- environment. Most manipulation of hazardous
ates a difficult situation for the compounder in drugs, such as crushing or splitting tablets and
decontaminating the PEC. Prior to preparing, LABELING, measuring oral liquids in oral syringes or con-
the compounder must prepare a 5% solution PACKAGING, AND tainers, are also being done in the pharmacy
of sodium thiosulfate solution and a 5% solu- under a protected, controlled environment.
tion of sodium bicarbonate to neutralize the STORAGE Hospitals are also implementing needle-
All hazardous drugs must have distinctive
contaminated devices and equipment. Equal free systems to reduce the risk of spills and
labels identifying those drugs as requiring
volumes of each solution must be added to contamination and prevent accidental needle
special handling instructions. Bins and stor-
all of the mechlorethamine vials and allow to sticks when preparing and administering the
age areas should be clearly labeled too. Each
stand for at least 45 minutes before disposal. drugs. All hospital personnel administering
facility may create different classes or risk
All of the contaminated gloves, syringes, nee- hazardous drugs should wear the appropri-
levels of hazardous drugs which have color-
dles, pad, or any trash or waste must be placed ate PPE based on the hazard risk and type of
coded labels that indicate the PPE required to
in a disposable container or sealable plastic bag dosage form.
handle and administer those drugs. Handling
and equal volumes of each solution is added or administering solid dosage forms may only Extensive nursing guidelines have been
to the bag or container to allow everything to require gloving, while parenteral dosage forms developed by the Oncology Nursing Society22
soak and neutralize in the solutions. The inside may require gloving, gowning, and wearing and ASHP guidelines contain recommenda-
of the PEC should also be wiped down with a mask. All hospital personnel need to be in- tions for reducing exposure to hazardous drugs
the combined solutions and allowed to set for serviced on the meaning of these labels. during administration in all practice settings.
45 minutes before cleaning and disinfecting. Hazardous drugs should be stored in a Detailed information is provided for intrave-
The neutralizing and cleaning instructions are separate area from the rest of the drug inven- nous, intramuscular or subcutaneous, and oral
written in the package insert for Mustargen. tory to minimize the number of staff members administration.
The PEC should be cleaned at least two that are potentially exposed to the danger.
or three times daily and as needed if used These drugs should be stored in an area with SPILL MANAGEMENT
for 24-hour service. If the PEC is only used sufficient exhaust ventilation to dilute and re- Each facility must develop policies and
during one shift daily, it should be cleaned move airborne contamination. The storage bins procedures to prevent spills and to manage
and decontaminated prior to compounding and shelving should have high fronts or guards cleanup of hazardous drug spills. These writ-
at the beginning of the shift to ensure that it to prevent accidental falling. Because studies ten procedures must identify who is respon-
has been done. If the PEC is used for sterile have shown that the outer packaging or vials of sible for spill management and address the size
compounding, the PEC shall be disinfected hazardous drugs may be contaminated, all staff and scope of the spill. Large spills may require
with 70% sterile alcohol after cleaning and members should double glove when stocking, involvement of the institution’s hazmat team.
All spills must be contained and cleaned up immediately by trained be critical in this type of emergency. Commercial emergency kits
workers. containing isotonic eyewash supplies and soap are available and should
Spill kits are commercially available through several medical sup- be placed in all areas where hazardous drugs can be found. Exposed
pliers and should be readily available in all areas where hazardous workers require immediate treatment. The sidebar titled Occupational
drugs are handled. Delivery personnel should carry a kit with them. Safety and Health Administration-recommended Steps for Immediate
The sidebar titled American Society of Health-System Pharmacists’ Treatment of a Contaminated Worker contains the OSHA’s recom-
Recommended Contents of Hazardous Spill Kit lists the recommended mended steps for immediate treatment of workers with direct skin or
contents of a hazardous drug spill kit. ASHP guidelines also offer de- eye contact with hazardous drugs. Exposed workers should be monitored
tailed recommendations for spill cleanup procedures for general spills for changes in medical or health status.
and spills within a BSC or CACI.
HAZARDOUS WASTE
WORKER CONTAMINATION CONTAINMENT AND DISPOSAL
OSHA provides recommended steps for treatment in the event a
The Resource Conservation and Recovery Act (RCRA) of 1976 was
worker is contaminated with a hazardous substance.23 Written proce-
dures must be available to address worker contamination and protocols enacted to provide a mechanism for tracking hazardous waste from its
developed for medical attention before an occurrence because time may generation to disposal and is enforced by the Environmental Protection
Agency (EPA).24 The RCRA applies to pharmaceutical and chemicals
discarded by pharmacies, hospitals, clinics, and other commercial enti-
ties. The RCRA contains lists (P and U) of agents that are considered
hazardous waste when discarded. Unfortunately, the lists have not been
substantially updated since 1976. The P-listed chemicals are considered
“acutely hazardous” by the EPA and the U-listed chemicals include a
broader range of pharmaceuticals, including chemotherapy drugs. The
listed drugs include (on the P-list) arsenic trioxide, epinephrine, nico-
tine, nitroglycerin, physostigmine, and warfarin over 0.3%, as well as (on
the U-list) chloral hydrate, chorambucil, chloroform, cyclophosphamide,
daunomycin, diethylstilbestrol, formaldehyde, melphalan, mitomycin
C, phenol, streptozotocin, and mechlorethamine. There is also a D-list
of chemicals that are toxic at certain regulatory levels. For a complete
listing, refer to Section 4, 40 CFR Section 261.33 (for P and U lists) and
Section 4, 40 CFR 261.24 (for D list).
The RCRA also defines the four characteristics of hazardous waste:
ignitability, toxicity, corrosivity, and reactivity. MSDSs should contain
information on these characteristics if bulk chemicals are being used
in compounding. Pharmaceuticals containing 24% or more alcohol
or oxidizers, such as silver nitrate and potassium permanganate, are
ignitable. Only 10 chemicals used in pharmaceuticals and compounded
preparations are defined as toxic (see Table 2).25 Corrosivity involves
very acidic (pH ≤2) and very basic (pH ≥12.5) chemicals. Hydrochloric
acid 37% is often used to prepare hydrochloric acid parenteral solutions
to treat metabolic alkalosis. The only relevant chemical with reactivity is
nitroglycerin, but the EPA has exempted drug dosage forms from federal
regulation.
Hospital administrators should check state regulations for hazardous
waste disposal. Many states are authorized to implement their own haz-
ardous waste programs and may be stricter than the federal regulations.
There is an exemption in the RCRA of empty containers from
hazardous waste regulations. Empty containers are defined as those that
have held U-listed (not P-listed) drugs or characteristic wastes that have
been removed using common practices and no more than 3% by weight
of the total capacity of the container remains in the container. This is
also called “trace-contaminated” waste in the disposal guidelines by the
National Institutes of Health (NIH) published in 1984.26 Trace-contam-
inated waste include RCRA-empty containers, needles, or sharps used
to prepare hazardous drugs, syringes, gloves, pads, and empty IV sets. All
of this type of waste should be collected in hazardous waste containers
and incinerated at a regulated medical waste incinerator.
Chemo Test™
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XXXRJNFEJDBMDPNt800.837.8361 tJOGP!RJNFEJDBMDPN
are monitored for health problems or adverse 7. Kromhout H, Hoek F, Uitterhoeve R et al. 17. Connor TH, Xiang Q. The effect of iso-
effects associated with potential exposure to Postulating a dermal pathway for exposure propyl alcohol on the permeation of gloves
hazardous drugs or chemicals. If the medi- to anti-neoplastic drugs among hospital exposed to antineoplastic agents. J Oncol
cal facility is too small to provide a medical workers. Applying a conceptual model to Pharm Pract 2000; 6(3): 109–114.
surveillance program, the employee should be the results of three workplace surveys. Ann 18. The National Institute for Occupational
monitored by his or her personal physician. Occup Hyg 2000; 44(7): 551–560. Safety and Health. Centers for Disease
8. The National Institute for Occupational Control & Prevention. I. Summary for Respi-
Safety and Health. Centers for Disease rator Users. [Department of Health and Hu-
CONCLUSION Control & Prevention. NIOSH Alert. man Services. The National Institute for
All healthcare facilities are different, and Preventing Occupational Exposures to Antine- Occupational Safety and Health Website.]
there are no comprehensive guidelines or USP oplastic and Other Hazardous Drugs in Health April 9, 1996. Available at: www.cdc.gov/
standards that will address all of a facility’s Care Settings. DHHS (NIOSH) Publication niosh/respsumm.html. Accessed March 27,
needs. All physicians and healthcare profes- Number 2004–165. [Department of Health 2009.
sionals at a facility need to work together and and Human Services. The National Insti- 19. Sessink PJ, Boer KA, Scheefhals AP et al.
rely on credible published guidelines, state tute for Occupational Safety and Health Occupational exposure to antineoplastic
and federal regulations, their own professional Website.] September 2004. Available at: agents at several departments in a hospital:
judgment, experience, and common sense to www.cdc.gov/niosh/docs/2004-165/ Environmental contamination and excre-
create their own comprehensive program for pdfs/2004-165.pdf. Accessed April 24, tion of cyclophosphamide and ifosfamide
handling hazardous drugs and chemicals. 2007. in urine of exposed workers. Int Arch Occup
9. ASHP Council on Professional Affairs. Environ Health 1992; 64(2): 105–112.
REFERENCES American Society of Health-System 20. Kiffmeyer TK, Ing KG, Schoppe G. Exter-
1. Valanis BG, Vollmer WM, Labuhn KT Pharmacists. ASHP guidelines on handling nal contamination of cytotoxic drug pack-
et al. Association of antineoplastic drug hazardous drugs. Am J Health Syst Pharm ing: Safe handling and cleaning procedures.
handling with acute adverse effects in 2006; 63: 1172–1193. J Oncol Pharm Pract 2000; 6: 13.
pharmacy personnel. Am J Hosp Pharm 10. International Academy of Compounding 21. Connor TH, Sessink PJ, Harrison BR
1993; 50(3): 455–462. Pharmacists. Hazard Alert: Compounding with et al. Surface contamination of chemo-
2. Harrison BR. Risks of handling cytotoxic Hazardous and/or Potent Pharmaceuticals. therapy drug vials and evaluation of new
drugs. In: Perry MC, ed. The Chemotherapy [International Academy of Compounding vial-cleaning techniques: Results of three
Source Book. 3rd ed. Philadelphia, PA: Pharmacists Website.] 2004. Available at: studies. Am J Health Syst Pharm 2005; 62(5):
Lippincott, Williams and Wilkins; 2001: www.iacprx.org/site/DocServer/Haz- 475–484.
566–582. ardAlert.pdf ?docID=443. Accessed March 22. Polovich M, Belcher C, Glynn-Tucker
3. Hemminki K, Kyyrönen P, Lindbohm ML. 13, 2009. EM et al. Safe Handling of Hazardous Drugs.
Spontaneous abortions and malforma- 11. United States Pharmacopeial Convention, Pittsburgh, PA: Oncology Nursing Society;
tions in the offspring of nurses exposed Inc. USP Pharmacists’ Pharmacopeia. Rock- 2003: 1–56.
to anaesthetic gases, cytostatic drugs, and ville, MD: US Pharmacopeial Convention, 23. Occupational Safety and Health Adminis-
other potential hazards in hospitals, based Inc.; 2008: 779–831. tration. OSHA Technical Manual. Control-
on registered information of outcome. J 12. Tilyou S. Study uncovers variations in ling Occupational Exposure to Hazardous
Epidemiol Community Health 1985; 39(2): hazardous drug handling. Pharmacy Practice Drugs. TED 1-0.15A. Section VI. Chapter
141–147. News 2007; 34(4): 1, 14–15. 2. [United States Department of Labor. Oc-
4. National Toxicology Program. Report 13. Devon Robotics. Press Release. Devon cupational Safety & Health Administration
on Carcinogens, 11th ed. [Department of Robotics Announced as U.S. Distributor of Life- Website.] Available at: www.osha.gov/dts/
Health and Human Services. National Critical Chemotherapy Drug Preparation Robot osta/otm/otm_vi/otm_vi_2.html. Accessed
Toxicology Program Website.] Available CytoCare™. [Devon Robotics Website.] April 3, 2009.
at: http://ehis.niehs.nih,gov/roc/toc9.html. December 4, 2008. Available at: www.de- 24. Resource Conservation and Recovery Act
Accessed March 13, 2009. vonrobotics.com/pressrelease-2008-12-04. of 1976. 42 USC 82 §6901-92.
5. McDiarmid MA, Kolodner K, Humphrey aspx. Accessed March 27, 2009. 25. Smith CA. Managing pharmaceutical
F et al. Baseline and phosphoramide mus- 14. [No author listed.] Special devices. J Oncol waste: What pharmacists should know. J
tard-induced sister-chromatid exchanges Pharm Pract 2007; 13: 27–30. Pharm Soc Wis November-December 2002:
in pharmacists handling anti-cancer drugs. 15. Jorgenson JA, Spivey SM, Au C et al. Con- 17–22.
Mutat Res 1992; 279(3): 199–204. tamination comparison of transfer devices 26. Vaccari PL, Tonat K, DeChristoforo R et
6. Sessink PJ, Van de Kerkhof MC, Anzion intended for handling hazardous drugs. al. Disposal of antineoplastic wastes at the
RB et al. Environmental contamination Hosp Pharm 2008; 43(9): 723–727. National Institutes of Health. Am J Hosp
and assessment of exposure to antineoplas- 16. American Society for Testing and Ma- Pharm 1984; 41(1): 87–93.
tic agents by determination of cyclophos- terials. Standard Practice for Assessment of
phamide in urine of exposed pharmacy Resistance of Medical Gloves to Permeation by Address correspondence to Linda F. McElhiney,
technicians: Is skin absorption and impor- Chemotherapy Drugs. West Conshohocken, PharmD, RPh, Clarian Health Partners, Inc., 550
tant exposure route? Arch Environ Health PA: American Society for Testing and N. University Boulevard UH 1451, Indianapolis, IN
1994; 49(3): 165–169. Materials; 2005. 46202. E-mail: [email protected]
website:
search engine optimization, pay per click, email marketing
“As Internet use continues to grow at a rapid pace, two forms of Patricia L. Storey, RPh, FACA
interactive marketing have emerged as the clear winners in the customer Storey Marketing
acquisition space: Search Engine Marketing and Email Marketing.”1 Meadville, Pennsylvania
Nearly 90% of all new visitors to a website originate from major search
engines. Email marketing brings in $15.50 per campaign dollar spent.2 then are subjected to a vetting process in
Search engine marketing and traditional marketing should complement order to identify which ones are most effec-
each other, and traditional marketing campaigns should not be aban- tive. The setup phase leads directly into the
doned for “e-marketing.”3 ongoing management phase where results and conversions are tracked
Search engine optimization (SEO) is the process of structuring a and the campaign is adjusted, often on a daily basis in order to maximize
website’s code and visible attributes so that search engines can find, read, the campaign effectiveness. An effective PPC campaign can mean instant
and index the pages, optimizing the potential for the site to be found website traffic, and since you’re only paying for actual visits, you are, in
when relevant keywords are used in a search query.4 SEO is important essence paying for results. Because a significant portion of the cost of
whether your target audience is national or local. It is estimated that PPC is based on the number of “click-throughs,” business owners can
40% of all search engine searches are for local businesses and services establish daily/monthly budgets. A properly managed campaign has the
and that 92% of all local searches will eventually convert to a sale. And, capacity to dramatically increase your website return-on-investment
it is considerably easier in terms of SEO for a local keyword phrase to (ROI).
rank well than it is for a more general phrase that one may use to market
nationally. seo: natural or ppc?
Search engine marketing can be broken down into two distinct mod- The websites appearing in the natural listings are the ones that the
els: Natural (or Organic) and Pay Per Click (PPC). search engines have deemed the most important for the given search
term. Approximately 85% of searchers click on the natural search
natural (organic) search engine marketing results after performing a web search. In general, searchers who under-
Natural search engine listings refer to the search results typically stand the difference between paid and natural results are more likely to
found on the left three-quarters of the search results page. Search favor the natural results versus PPC, which is essentially a paid adver-
engines consider hundreds of factors in determining which websites tisement. However, a PPC campaign can drive some immediate traffic to
are most relevant to a query, including the popularity of the site (as your website upon launch, and PPC is a valuable marketing tool for new
determined by the quality of inbound links to the website from websites sites or sites that don't already have established traffic. In general, PPC
the engines deem to be worthy and related, and popular themselves), the ads attract searchers who are ready to buy versus those who click on
position and density of the search terms within the site, the proximity the natural listing, who are often still in the research phase. Therefore,
of the search terms to one another on the page, and keyword cross- a well-managed PPC campaign can provide valuable and instantaneous
linking to other sections of the website. Providing free content, such as insight into the keyword phrases that are most effective. This informa-
access “white papers” can improve search engine rankings. Perhaps most tion can be used in a natural search engine marketing campaign to
important, however, is the website content itself. Search engines such as ensure the optimal keyword phrases are being targeted. A website that
Google closely guard the exact formulas they use to calculate relevance, is properly optimized for natural rankings will lend itself to higher PPC
and tweak the formulas to improve quality and performance, so it re- conversion rates, which increase the success of PPC campaigns. For
quires a consistent effort to attain and retain a high-relevant ranking for these reasons, it is recommended that businesses consider both natural
important keyword phrases. and PPC search engine marketing.
email marketing which will integrate with your traditional marketing plan and provide
Email is becoming a key facet of marketing and advertising. By strik- the best return for your marketing dollars.
ing the right balance with consumers, email can advocate benefits of new
and existing products, while also serving as a resource for medical infor- references
mation. It is far more effective to send email to those who have chosen 1. Li C, Charron C, Baxter S et al. Searching for Digital Marketing’s Growth. [For-
to receive it (opt-in permission based email) versus random recipients rester Website.] October 31, 2003. Available at: www.forrester.com. Accessed
(SPAM), and to use an Email Management System. Email programs May 5, 2009.
2. Allis R. Why Email Marketing Matters. [Winterberry Group Website.] Available
such as Outlook cannot dynamically customize email messages based at: www.niche-aticles.com/res/permission-based-email-marketing/. Accessed
on individual recipient preferences (i.e., graphical or text-based). While May 5, 2009.
sending only text-based emails will ensure that all recipients will be 3. netStride Internet Solutions. Building an Effective Online Sales Channel Through
equipped to read the email, doing so completely eliminates the dramatic Search Engine Marketing and Permission-based Email Marketing. [netStride Inter-
boost in response rate that graphical emails enjoy; therefore, a robust net Solutions Website.] Available at: www.netstride.com/company_whitepa-
pers.asp. Accessed May 5, 2009.
email marketing application/server is preferred.
4. netStride Internet Solutions. The Case for Search Engine Marketing. [netStride
In a national survey5 conducted in October, 2008, 52% of respon- Internet Solutions Website.] Available at: www.netstride.com/company_
dents said that professional emails give them a more favorable opinion whitepapers.asp. Accessed May 5, 2009.
of the store; 48% feel "more loyal" toward the retailer as a result of the 5. Epsilon. Epsilon Study Shows ‘Healthy’ Response to Email from Pharmaceutical Com-
messages; 88% said a retailer's email prompted them to download/print panies. [epsilon.com Website.] March 3, 2009. Available at: www.epsilon.com/
out a coupon; 75% said it led them to buy a product online; 67% said About-Us/Press-Releases/030309-Email-Branding-Study-–Pharma/p93-I3.
Accessed May 5, 2009.
email prompted an offline purchase; and 60% were moved to try a new 6. Epsilon. A Prescription for Customer Engagement: An Inside Look at Email Marketing
product. for the Pharmaceutical Industry. [epsilon.com Website.] Available at: www.epsilon.
com. Accessed May 5, 2009.
email marketing brings in
$15.50 per campaign dollar spent. Address correspondence to Patricia L. Storey, RPh, FACA, Storey Marketing, 19487
East Cole Road, Meadville, PA 16335-9673. E-mail: [email protected]
Specifically regarding email from pharmaceutical companies:6
Safety of
Maternal Testosterone
Therapy During
BREAST FEEDING
Rebecca L. Glaser, MD, FACS
Wright State University School of Medicine
Millennium Wellness LLC
Dayton, Ohio
Mark Newman, MS
ZRT Laboratory
Beaverton, Oregon
Melanie Parsons, MASc
Millennium Wellness Australia
Sydney, Australia
David Zava, PhD
ZRT Laboratory
Beaverton, Oregon
Daniel Glaser-Garbrick
Centerville High School
Dayton, Ohio
Methanol was dried and samples reconstituted effective in relieving maternal symptoms of
with assay buffer. Samples were added to a depression, anxiety, fatigue, decreased libido,
96-well enzyme immunoassay for testosterone aches, pains, and memory problems without
(DRG International, Inc.) and were analyzed side effects.
by ZRT Laboratory. From this point, the stan-
dard procedure for serum testing was followed Conclusion of
according to kit instructions and results given Presentation
in ng/dL. Testosterone delivered by sublingual
Summary of Study Results drops, vaginal cream, and pellet implant was
absorbed (measurable in maternal blood) but
Testosterone was measurable in maternal
not measurably excreted into breast milk.
blood by all three methods of delivery (Tables
Testosterone, delivered by a 100-mg subcuta-
1 and 2). No significant increase of testoster-
neous pellet implant was effective in relieving
one was seen in breast milk when testosterone
symptoms of testosterone deficiency and was
was delivered by vaginal cream (P = .57),
not measurably increased in breast milk or
sublingual drops (P = .12), or subcutaneous
measurable in infant serum. Maternal testos-
pellet implant (P = .17) (Figure 2). Testoster-
terone therapy is safe for the breast-fed infant.
one was very low in infant blood (<10 ng/dL)
Testosterone by pellet implant may be a safer
at baseline and during testosterone therapy
and more physiologic alternative to psycho-
by pellet implant. Serial measurements were
tropic medications. Further studies should be
obtained at days 2, 7, and 20, and at month
done and unsubstantiated guidelines should be
5. There were no adverse clinical affects in
questioned and revised.
the male infant after 7 months of continuous
testosterone therapy to the mother by subcu-
taneous pellet implant. Testosterone therapy References
1. Burger HG, Hailes J, Menelaus M et al. The
by 100-mg subcutaneous pellet implant was
management of persistent menopausal symp- 2. Brincat M, Magos A, Studd JW et al. Subcu-
toms with oestradiol-testosterone implants: taneous hormone implants for the control of
TABLE 1. Absorption of Clinical, lipid and hormonal results. Maturitas climacteric symptoms. A prospective Study.
Testosterone from Vaginal Cream 1984; 6(4): 351–358. Lancet 1984; 1(8367): 16–18.
and Sublingual Drops.a
Maternal Capillary Testosterone (ng/dL) FIGURE 2. The graph shows the testosterone levels in breast milk
Time (H) Vaginal Cream Sublingual Drops (pg/mL).a
0 <10 16
2 284 186
4 104 155
6 10 58
8 <10 10
10 <10 ---
12 --- <10
aMeasured by capillary bloodspot at 2-hour intervals.
TABLE 2. Absorption of
Testosterone from Subcutaneous
Pellet Implant.a
Maternal Capillary Testosterone (ng/dL)
Time (Days) Pellet Implant
0 <10
2 283
3 (AM) 170
3 (PM) 93
7 (AM) 148
7 (PM) 123
aMeasured at day 2, day 3 morning and evening, and day aLevels taken at baseline, after maternal use of vaginal cream, after maternal use of sublingual testosterone drops, and after
7 morning and evening. maternal subcutaneous testosterone pellet implant.
3. Cardozo L, Gibb DM, Tuck SM et al. The ef- 20. Cedars MI, Judd HL. Nonoral routes of estro- terone acetate, enhances the beneficial effect
fects of subcutaneous hormone implants dur- gen administration. Obstet Gynecol Clin North Am of estrogen on exercise-induced myocardial
ing climacteric. Maturitas 1984; 5(3): 177–184. 1987; 14(1): 269–298. ischemia in postmenopausal women. J Am Col
4. Montgomery JC, Appleby L, Brincat M et al. 21. Carlström K, Pschera H, Lunell NO. Serum Card 2000; 36(7): 2154–2159.
Effect of oestrogen and testosterone implants levels of oestrogens, progesterone, follicle- 26. Oriba H, Bucks D, Maibach H. Percutaneous
on psychological disorders in the climacteric. stimulating hormone and sex-hormone- absorption of hydrocortisone and testosterone
Lancet 1987; 1(8528): 297–299. binding globulin during simultaneous vaginal on the vulva and forearm: Effect of the meno-
5. Garnett T, Studd J, Watson N et al. A cross- administration of 17beta-oestradiol and pause and site. Br J Derm 1996; 134: 229–233.
sectional study of the effects of long-term progesterone in the pre- and post-menopause. 27. Thom M, Collins WP, Studd JW. Hormonal
percutaneous hormone replacement therapy Maturitas 1988; 10(4): 307–316. profiles in postmenopausal women after
on bone density. Obstet Gynecol 1991; 78(6): 22. Suh-Burgmann E, Sivret J, Duska LR et al. therapy in subcutaneous implants. Br J of
1002–1007. Long-term administration of intravaginal Obstetrics and Gynaecology 1981; 88: 426–433.
6. Dimitrakakis C, Jones RA, Liu A et al. Breast dehydroepiandrosterone on regression of low- 28. Gambrell RD Jr, Natrajan PK. Moderate
cancer incidence in postmenopausal women dosage estrogen-androgen therapy improves
grade cervical dysplasia—a pilot study. Gynecol
using testosterone in addition to usual hor- continuation rates in postmenopausal women:
Obstet Invest 2003; 55(1): 25–31.
mone therapy. Menopause 2004; 11(5): 531–535. Impact of the WHI reports. Climacteric 2006;
23. Keller PJ, Riedmann R, Fischer M et al.
7. Berlin CM Jr. Sensitivity of the young infant 9(3): 224–233.
Oestrogens, gonadotropins and prolactin after
to drug exposure through human milk. Adv 29. Glaser R, Wurtzbacher D, Dimitrakakis C.
intra-vaginal administration of oestriol in
Drug Deliv Rev 2003; 55(5): 678–693. Efficacy of testosterone therapy delivered by
8. Fleishaker JC. Models and methods for post-menopausal women. Maturitas 1981; 3(1):
pellet implant. Maturitas 2009; 63(1): S73.
predicting drug transfer into human milk. Adv 47–53.
Drug Deliv Rev 2003; 55(5): 643–652. 24. Rigg LA, Hermann H, Yen SS. Absorption of
9. Ito S, Lee A. Drug excretion into breast milk: estrogens from vaginal creams. N Engl J Med Address correspondence to Rebecca L. Glaser, MD,
Overview. Adv Drug Deliv Rev 2003; 55(5): 1978; 298(4): 195–197. FACS, Millennium Wellness LLC, 228 E. Spring
617–627. 25. Rosano G, Webb CM, Chierchia S et al. Natu- Valley Road, Dayton, OH 45458. E-mail: rglaser@
10. McManaman JL, Neville MC. Mammary ral progesterone, but not medroxyproges- woh.rr.com
physiology and milk secretion. Adv Drug Deliv
Rev 2003; 55(5): 629–641.
11. Heinemann K, Ruebig A, Potthoff P et al.
The Menopause Rating Scale (MRS) scale:
A methodological review. Health Qual Life
Outcomes 2004; 2: 45.
12. Kuhl H. Pharmacology of estrogens and
progestogens: Influence of different routes of
administration. Climacteric 2005; 8(Suppl 1):
3–63.
13. Glaser RL, Zava DT, Wurtzbacher D. Pilot
study: Absorption and efficacy of multiple
hormones delivered in a single cream applied
=;8C`Z\ej\Ef%('*
to the mucous membranes of the labia and va- LJ;8C`Z\ej\Ef%-)0
gina. Gynecol Obstet Invest 2008; 66(2): 111–118.
14. Schiff I, Tulchinsky D, Ryan KJ. Vaginal ab-
sorption of estrone and 17beta-estradiol. Fertil
Steril 1977; 28(10): 1063–1066.
15. Schiff I, Wentworth B, Koos B et al. Effect of
estriol administration on the hypogonadal
woman. Fertil Steril 1978; 30(3): 278–282.
16. Punnonen R, Vilska S, Grönroos M et al. The
vaginal absorption of oestrogens in post-
menopausal women. Maturitas 1980; 2(4):
321–326.
17. Heimer GM, Englund DE. Estriol: Absorption
after long-term vaginal treatment and gastro-
intestinal absorption as influenced by a meal.
Acta Obstet Gynecol Scand 1984; 63(6): 563–567.
18. Heimer GM, Englund DE. Plasma oestriol
following vaginal administration: Morning
versus evening insertion and influence of food.
Maturitas 1986; 8(3): 239–243.
19. Mattsson LA, Cullberg G. Vaginal absorption
of two estriol preparations. A comparative
study in postmenopausal women. Acta Obstet
Gynecol Scand 1983; 62(5): 393–396.
<
Analytical Methods
< <
Joe Cabaleiro, RPh, BS Pharm
Triangle Compounding Pharmacy
Cary, North Carolina
The terms “quality control,” “quality assurance,” and “quality im- capsules. As a result, their rate of dented capsules was less than half that
provement” are often used interchangeably in compounding pharmacy of pharmacy B.
circles. This causes some confusion among compounding pharmacists Pharmacy C had a quality-assurance program, defined by the ASQ as
because, while these terms are related, they have different meanings. “the planned and systematic activities implemented in a quality system
Understanding each term and incorporating them into your practice is so that quality requirements for a product or service are fulfilled.” (See
vital if your compounding pharmacy’s goal is to remain competitive in suggested resource information.)
the current quality and cost-conscious market. The pharmacy decided to eliminate the problem of dented capsules
While pharmacists are often responsible for quality-control, quality- because the problem was resulting in too much wasted material and
assurance, and quality-improvement activities, most pharmacists receive employee time. The following steps were taken by the pharmacy to
very little training in these areas. Example scenarios often help to clearly eliminate dented capsules:
define the differences, therefore, for a clear illustration, we offer the
1. The percent of dented capsules in a representative sample were
scenario of three different compounding pharmacies and examine their
measured.
procedure of a single quality measure—undented capsules. In this ex-
2. Improvements of the capsule filling procedure and the machine’s
ample, all three pharmacies make the same capsules for a local hospital.
setup were made.
The capsules contain an expensive ingredient that is valued at $0.50 per
3. Several brands of capsules were evaluated to determine which cap-
capsule.
sules worked best with their equipment.
4. Throughout the process, the pharmacy continued to sample for
Scenario for Each Pharmacy: Dented Capsule dented capsules.
Procedure >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> 5. Required changes were identified and made to reduce the number of
Pharmacy A dented capsules to nearly zero.
Every day, the pharmacist at pharmacy A observed dented capsules 6. The technicians who made the capsules were taught to dispose of the
in pill vials. When patients acknowledged their concern, the pharmacist now rare dented capsule.
explained that the capsules were sometimes dented by the capsule ma- As a result of the above changes, the pharmacists at pharmacy C
chine, and he expressed his apology that this occurred but did nothing to could be confident that a dented capsule would not be vialed.
resolve the problem.
Clearly, pharmacy A had no established quality-control, quality-
assurance, or quality-improvement processes.
Pharmacy B
The pharmacist at pharmacy B, faced with the same scenario as
pharmacy A, recognized that if the capsules didn’t look good, patients
might question if the capsule and its ingredients were made correctly.
Therefore, when the pharmacist checked prescriptions, he painstakingly
examined every vial, removed and discarded every dented capsule, and
replaced each discarded capsule with an undented capsule.
Other examples of quality-control activities within Pharmacy B
included:
t Sterility testing of sterile preparations
t Verification that a technician had pulled and properly prepared the
correct medication
t Verification that the prescription label agreed with the prescription
t Verification that each prescription was made according to its
compounding record
Pharmacy B had a quality-control program, complying with the
American Society for Quality’s (ASQ) definition of quality control: “The
observation techniques and activities used to fulfill requirements for
quality.” (See suggested resource information.)
Pharmacy C
Pharmacy C, faced with the same scenario as pharmacies A and B,
checked capsules before they were dispensed to the patient and any
dented capsules were removed and discarded. This pharmacy had
a training program that taught their technicians how to operate the
capsule machine, which included hands-on training under the super-
vision of a lead technician. Technicians were not allowed to produce
capsules until they could make a sample batch with less than 5% dented
Pharmacy C implemented a system of tially mandates for specific quality-control and communications and poor customer service
quality improvement, defined by ASQ as “…an quality-assurance procedures that compliant may make it the last choice for the community.
ongoing effort to improve products, services, pharmacies should maintain. Another pharmacy may not be as skilled in
or processes. These efforts can seek ‘incremen- Although a few capsules may be sampled sterile compounding but may have outstanding
tal’ improvement over time or ‘breakthrough’ to assure they meet certain specifications, for customer service and communication skills in-
improvement all at once.” (See suggested cost, productivity, and practicality reasons, no stilled in their staff. To improve the services in
resource information.) pharmacy, manufacturer, or other business can these examples, the pharmacies would have to
check every product or dosage unit it produces implement very different quality-improvement
Discussion >>>>>>>>>>>>>>>>>>>> to be sure it meets specifications. Quality- programs and measures.
Typically, most pharmacies have certain assurance procedures are the activities the
established quality-assurance procedures to pharmacy establishes to facilitate and ensure Conclusion >>>>>>>>>>>>>>>>>>>>
include: that the end product meets specifications. In Patient comments about the dented capsules
contrast, quality-control procedures are per- from pharmacy A eventually caused the hospi-
t Scales are calibrated to assure that prepara- formed on the end product itself. tal to question everything about the quality of
tions are weighed correctly. Most pharmacies probably incorporate all of the pharmacy’s preparations. After all, the
t Cleanroom surfaces and air are sampled to some quality-improvement processes into their patients and hospital can only judge the quality
assure that the compounding environment day-to-day operations, although they may not of the pharmacy’s work by the appearance of its
is properly disinfected, therefore improv- necessarily refer to them as “quality improve- preparations (in this case, capsules). As a result,
ing the odds that a sterile preparation is ment.” It is important to note that PCAB the hospital suggested to their patients that
produced. requires that quality-improvement activities be they should go to pharmacy B or C.
t Chemicals are purchased from quality documented. Pharmacy B and C were equal in quality in
vendors to assure that raw ingredients meet While PCAB and USP require that a phar- regards to dented capsules, but at pharmacy B,
compendial standards. macy have quality-improvement programs, if one out of every ten capsules were dented,
t Cleanroom staff must pass sterile process these requirements are less clear than the it represented a $5.00 extra cost in materials
stimulation tests to assure that they are ca- quality-control and quality-assurance require- alone, not to mention the waste of the phar-
pable of compounding sterile preparations. ments for a simple reason. Whereas most qual- macist’s valuable time in having to correct the
ity-control and quality-assurance procedures problem.
It is important to note that standards such are common to every pharmacy, every organi- Because of its efforts to eliminate the prob-
as those published by the Pharmacy Com- zation has something that can be improved, but lem rather than correct defects, pharmacy C
pounding Accreditation Board (PCAB) and only that organization can identify those things enjoyed a profit-and-time advantage over phar-
the United States Pharmacopeial Convention and the needed improvements. For example, macy B. In addition, pharmacists at pharmacy
(USP) (United States Pharmacopeia Chapters a particular pharmacy may have outstanding C seemed a little less rushed to customers be-
<795> and <797>) are at their core essen- sterile compounding capabilities, but its poor cause as a result of their quality-improvement
activity, they shifted a quality-control function
to their technicians. Technicians at this phar-
macy were more productive because defective
capsules were so rare that quality control for
dented capsules took little employee time.
Why should compounding pharmacies care
about quality? Of course, the answer to this
question is evident; patients deserve quality
procedures and high-quality preparations. The
question should be, “Why shouldn’t compound-
ing pharmacies care about quality?” The
scenarios outlined in this article clearly show
the importance that three different pharmacies
placed on just one particular procedure, dented
capsules. This same scenario could be echoed
on all compounding procedures.
Environmental Quality
and Control (Continued)
Claudia C. Okeke, PhD, RPh
Claumek PharmaScience
Rockville, Maryland
Abstract
The design and location of the pri-
mary engineering controls within a
compounding facility in order to main-
tain an expected controlled environ-
ment is well worth the time and
expense involved. If the airflow within
the compounding area is not properly
designed and maintained, the results
can be tragic to not only the com-
pounding personnel but to those pa-
This article represents
the 14th in a series tients for whom the preparations are
of articles pertaining being compounded. Knowledge of
to the implementation the placement of primary engineering
of United States
Pharmacopeia controls, air sampling, cleaning and
Chapter <797> disinfecting, and additional person-
Pharmaceutical nel requirements in the area of ster-
Compounding—
Sterile Preparations.
ile compounding is essential. Once
the guidelines have been studied,
compounding personnel should ap-
ply practicality and common sense
to avoid problems with compounded
sterile preparations.
As a continuation on the subject of environmental quality and con- no more than 3520 particles (0.5 mm and larger) per m3 counted during
trol, which began with Part 13 of this series,1 this article discusses United material transfer, with the particle counter probe located as near to the
States Pharmacopeia (USP) Chapter <797> sections on: transfer door as possible without obstructing the transfer.
Compounding personnel should seek training if there is inadequate
t Placement of primary engineering controls (PEC) knowledge on how to perform particle counts. The compounding
t Air sampling personnel must obtain documentation from the manufacturer of the
t Cleaning and disinfecting CAI/CACI that the equipment will meet this standard when located in
t Additional personnel requirements to the practice of sterile com- environments where the background particle counts exceed ISO Class 8
pounding for 0.5-mm and larger particles.
When isolators are used for sterile compounding, the recovery time
This module will address these sections in a practical manner and to achieve ISO Class 5 air quality shall be documented. There must be
provide practice clarification to the standards. internal procedures in place to ensure that adequate recovery time is
allowed after material transfer, before and during compounding opera-
Placement of Primary Engineering tions.
If the PECs are a CAI or CACI that does not meet the placement
Controls requirements discussed above or if the PECs are a LAFW or BSC that
In a compounding facility, the design and location of the PECs are cannot be located within an ISO Class 7 buffer area, and, therefore, fails
crucial to establishing good quality airflow. Most modern compounding to meet the requirements above, then compounding will apply to only
facilities take time to invest in the development of a good buffer area low-risk level nonhazardous and radiopharmaceutical compounded
and PECs to maintain the expected controlled environment. The PECs sterile preparations (CSP), pursuant to a physician’s order for a specific
which includes laminar airflow workbenches (LAFW), biological safety patient. Only these types of CSPs may be prepared, and the administra-
cabinets (BSC), compounding aseptic isolators (CAI), and compounding tion of this CSP must begin within 12 hours of preparation or as recom-
aseptic containment isolators (CACIs) should be located within areas mended in the manufacturer’s package insert, whichever is less. The
of restricted access in an International Organization for Standardiza- rationale for the administration of the CSPs to begin within 12 hours
tion (ISO) Class 7 environment such as a buffer area or cleanroom. The complies with the requirements discussed in the section Low-Risk Level
PECs usually provide an ISO Class 5 environment. In situations where CSPs with 12-Hour or Less (Beyond-Use Date [BUD]).
the PECs cannot be placed in a buffer or in an ISO Class 7 air-quality
environment, then some exceptions for the placement of CAI/CACI
are to be met as discussed in Chapter <797>. These exceptions apply Viable and Nonviable Environmental Air
to both the environment and the personnel performing the operation. Sampling Testing
These exceptions are discussed below. The key to having an environmental air-sampling ES program is to
ensure that compounding personnel and management staff have ad-
t Because of the limitation of the air quality, for example, if the CAI or equate knowledge and information that demonstrate the functionality of
CACI is placed in an air quality worse than ISO Class 7, such as ISO the PEC to ensure acceptably low viable and nonviable particle levels.
Class 8, then it is paramount that ONLY authorized personnel and There must be consistent educational training in place to make sure that
materials required for compounding and cleaning be permitted in that all personnel are on the same knowledge level. The areas where these
area. This will help reduce the air-quality interference due to traffic particles must be checked include the PEC, buffer areas, ante-areas, and
in the area. segregated compounding areas.
t Subsequently, when high-risk level compounded sterile preparations Environmental sampling must be conducted as part of a comprehen-
(CSP) are being prepared, the presterilization process, such as weigh- sive quality-management program and must be done minimally under
ing and mixing, must be completed in no worse than an ISO Class 8 conditions such as:
environment.
t The PECs must be placed in areas away from traffic patterns and away t Commissioning and certifying of new facilities and equipment
from room air currents that could disrupt the intended airflow pat- t Following any servicing of facilities and equipment
terns. t Recertifying of facilities and equipment every 6 months
t The CAIs and CACIs can be placed in worse than ISO Class 7 if the t Identifying problems with end products or staff technique, including
CAIs and CACIs provide isolation from the room and maintain ISO problems such as:
Class 5 during dynamic operating conditions, in addition to when
transferring ingredients, components, and devices into and out of the - Solving problems with CSPs
isolator and during preparation of CSPs. Pharmacy supervisors or - Observing work practices of compounding personnel
compounding personnel should have manufacturer’s documentation - Identifying problems in patient-related infections where the CSP
available to show that the CAI/CACI maintains ISO Class 5 air qual- is being considered as a potential source of the infection
ity.
Environmental Nonviable Particle Testing Program
There must be procedures in place where particle counts can be The program for nonviable airborne particles differs from that of the
sampled, and the sampling should be done approximately 6 to 12 inches viable particles program because it directly measures the performance
upstream of the critical exposure site to demonstrate that ISO Class 5 of the engineering controls (i.e., PECs or secondary engineering controls
level is maintained during compounding operations. There should be [SECs]) used to create the various levels of air cleanliness.
Engineering Control Performance Verification which could be developed as part of the facility’s standard operating
The PECs and SECs, such as buffer or ante-areas, are essential procedure (SOP) program.
components of the overall contamination control strategy for aseptic
compounding. These components must perform to yield levels of con- Sampling Plan
tamination that are within acceptable limits. A certification procedure The compounding facility should develop an environmental sam-
must be performed,2 and this certification must be performed by a quali- pling plan for airborne viable particles based on a risk assessment of
fied individual no less than every 6 months AND whenever the device compounding activities performed. Remember, in certified and properly
or room is relocated or altered or when major service to the facility is functioning PECs and SECs, for low- and medium-risk level CSPs,
performed. the risk of contamination is highly dependent on proper hand hygiene
and garbing practices, compounding personnel aseptic technique, and
Total Particle Counts the presence of surface contamination. This is quite different from a
This is a certification that ensures that each ISO classified area within high-risk level CSP which poses the greatest risk of contamination since
the PEC and SEC remains within established guidelines. This must be compounding personnel are tasked with the requirement of processing
done no less than every 6 months AND whenever the PEC is relocated nonsterile components and devices in order to achieve sterility.
or the physical structure of the buffer area or ante-area has been altered.
The testing must be done by qualified operators using current, state-of- A sampling plan must include:
the-art electronic equipment with results of the following:
t Sample location
t ISO Class 5: Not more than 3520 particles 0.5-mm and larger size per t Method of collection
cubic meter of air for any LAFW, BSC, CAI, and CACI t Frequency of sampling
t ISO Class 7: Not more than 352,000 particles of 0.5-mm size and t Volume of air sampled
larger per cubic meter of air for any buffer area t Time of day as related to activity in the compounding area and action
t ISO Class 8: Not more than 3,520,000 particles or 0.5-mm size and levels
larger per cubic meter of air for any ante-area
Certification Records
All certification records must be maintained and reviewed by su-
pervising compounding personnel. This will ensure that the controlled
environments comply with the proper air cleanliness, room pressures,
and air changes per hours (ACPHs).
Environmental Viable Airborne Particle Testing Program 9OUR SINGLE SOURCE FOR EVERYTHING FROM
This program, designed to evaluate the competency of the work CONCEPT AND COMPLIANCE TO EQUIPMENT AND
practices of compounding personnel, should be developed in addition to
observational audits. This will allow for the implementation of correc-
EVERYDAY CLEAN ROOM SUPPLIES
tive actions on an ongoing basis. There must be a sampling plan in place,
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Data must be reviewed and corrective measures developed where of microorganisms are counted and reported as cfu and documented on
there are dissatisfied results. A review of the data generated during a an environmental sampling form. Air sampling counts should be con-
sampling event may detect elevated amounts of airborne microbial verted into cfu per cubic meter of air and evaluated for adverse trends.
bioburden, and such changes may be indicative of adverse changes
within the environment. Action Levels, Documentation, and Data Evaluation
The following practices should be applied as part of the action level
Growth Medium protocol, documentation, and data evaluation:
A general microbiological growth medium such as Soybean–Casein
Digest Medium is used to support the growth of bacteria. Malt extract t Action levels protocol should be developed.
agar or some other media that support the growth of fungi is used in t Sampling data must be collected and reviewed on a periodic basis as a
high-risk level compounding environments. Media used for surface means of evaluating the overall control of the compounding environ-
sampling must be supplemented with additives to neutralize the effects ment.
of disinfecting agents (e.g., TSA with lecithin and polysorbate 80). t An activity that consistently shows elevated levels of microbial growth
gives a red flag and competent microbiology personnel must be con-
Viable Air Sampling sulted to provide input.
The volumetric collection methods are used in the PEC and SEC t Any cfu count that exceeds its respective action level must be re-
areas to evaluate airborne microorganisms. Well-trained personnel for viewed thoroughly to identify the source of contamination.
all compounding risk levels are expected to perform the sampling test. 1. Re-evaluate the adequacy of personnel work practices, cleaning
Volumetric air sampling by impaction is the preferred method. The procedures, operational procedures, and air filtration efficiency
use of settling plates for qualitative air sampling does not determine within the aseptic compounding location.
adequately the quality of air in the controlled environment. The settling 2. Initiate and conduct investigation into the source of the contami-
of particles by gravity onto culture plates depends on the particle size nation.
and, therefore, can be affected by air movement. Relatively, the number 3. Inspect the HVAC systems, look for any damages to the HEPA
of colony-forming units (cfu) on a settling plate may not always relate to filters.
the concentrations of viable particles in the sampled environment. 4. Examine the effect of changes in personnel garbing and review
work practices.
Risk Levels
All risk levels are included. Perform air sampling at locations that Once the source of a problem is eliminated and the affected area
are prone to contamination during compounding activities and during cleaned up, then resampling must be performed to ensure that the cfu
activities such as staging, labeling, gowning, and cleaning. Locations counts are within the desired limits. Counts of cfu are used as an ap-
include zones of air backwash turbulence within LAFW and other areas proximate measure of the environmental microbial bioburden. Action
where air backwash turbulence may enter the PEC compounding area, levels are determined on the basis of cfu data gathered at each sampling
as well as areas that are close in proximity to the PEC area. location and trended over time.
There should be corrective actions applied to the identified micro-
Air Sampling Devices organism regardless of the number of cfu. This should be done with the
Various air sampling devices are manufactured and available. For assistance of competent microbiologists, infection control professionals,
volumetric air sampling, devices must be serviced and calibrated, and or industrial hygienists. Highly pathogenic microorganisms (e.g., gram-
the manufacturer’s recommended procedures must be followed. Trained negative rods, coagulase positive staphylococcus, molds and yeasts) are
personnel should test a sufficient volume of air (400 to 1000 liters) at potentially fatal to patients receiving CSPs and must be immediately
each location in order to maximize sensitivity when using electric air remedied.
sampling.
Additional Personnel Requirements
Air Sampling Frequency and Process Compounding personnel should apply common sense and use profes-
Perform at least semiannually (i.e., every 6 months) as part of the sional judgment as it applies to sterile compounding. Examples are:
recertification of facilities and equipment. An institution that offers
compounding at multi-locations (e.g., main pharmacy, satelite) must t Compounding professionals should make it a point to not allow
perform environmental sampling for each individual compounding area. food, drinks, or materials to be brought into the patient care areas
A sufficient volume of air must be sampled. and treatment or compounding areas regardless of how minimal the
compounding.
Incubation Period t Compounding and handling of blood, blood derived products, and
At the end of sampling activities, the microbial growth media plates biologics must be separate from normal or routine compounding.
are recovered and their covers secured or taped up, then inverted and t Separate compounding areas shall be controlled by specific SOPs in
incubated at a temperature and for a time period conducive to multipli- order to avoid any cross-contamination.
cation of microorganisms: TSA incubate at 308°C to 358°C for 48 to 72 t Packaged compounding supplies and components (e.g., needles,
hours; malt extract agar or other suitable fungal media should be incu- syringes, tubing sets, small- and large-volume parenterals) should be
bated at 268°C to 308°C for 5 to 7 days. The number of discrete colonies decartoned.
t Surfaces of all materials must be wiped down with a disinfectant that References
does not leave a residue (e.g., sterile 70% isopropyl alcohol [IPA]) in 1. Allen LV Jr, Okeke CC. Basics of Compounding: Considerations for
the ante-area before being passed into the buffer areas. Implementing United States Pharmacopeia Chapter <797> Pharma-
t Personnel hand hygiene and garbing procedures should be performed ceutical Compounding—Sterile Preparations, Part 13: Environ-
in the ante-area, which may contain a sink that enables hands-free mental Quality and Control. IJPC 2009; 13(3): 234–238.
use with a closed system of soap dispensing to minimize the risk of 2. [No author listed.] Controlled Environment Testing Association.
extrinsic contamination. CETA Certification Guide for Sterile Compounding Facilities: CAG-003-
t There shall be demarcations that show that the ante-area and the buf- 2006. [Controlled Environment Testing Association Website.] De-
fer areas are separate in facilities where there are no doors to separate cember 8, 2008. Available at: www.cetainternational.org/reference/
the two areas. CETAAsepticCompoundingCertificationGuide.pdf. Accessed April
t Hands should be antiseptically cleaned by use of an alcohol-based 28, 2009.
surgical hand scrub followed by the donning of sterile gloves in a 3. United States Pharmacopeial Convention, Inc. United States Pharma-
manner consistent with compounding activities upon entrance to the copeia 32—National Formulary 27. Rockville, MD: US Pharmacopeial
buffer area. Convention, Inc.; 2008: 332.
Conclusion
Knowledge of the placement of PECs, air sampling, cleaning and
disinfecting, and additional personnel requirements in the sterile
compounding area is essential. Once the guidelines have been studied,
compounding personnel should apply practicality and common sense to
avoid problems while compounding CSPs.
BSC = biological safety cabinet; CACI = compounding aseptic containment isolator; CAI = compounding aseptic isolator; CSP = compounded sterile preparation; IPA = isopro-
pyl alcohol; ISO = International Organization for Standardization; LAFW = laminar airflow workbench; SOP = standard operating procedure
1
Estrasorb (estradiol topical emulsion) contains 2.5 mg of estradi- 59.94 mg lactose/cap × 60 caps × 1 g/1000 mg = 3.596 g lactose
ol hemihydrate (EH) per gram of emulsion. Estrasorb is available
Weight of each capsule:
as foil packets each containing 1.74 g of emulsion. Daily topical
2 mg estriol + 0.5 mg estradiol + 50 mg progesterone + 1 mg
application of the contents of two foil packets provides systemic
testosterone + 59.94 mg lactose = 113.44 mg
delivery of 0.05 mg of estradiol per day.1
A. What is the ratio strength of EH in the emulsion?
3
The following is a formula for testosterone-menthol eutectic
1 g emulsion/2.5 mg EH × 1000 mg/g = 400 g emulsion/1 g EH =
ointment:3
1:400 w/w
Rx
B. How much estradiol is contained in each packet of the emulsion? Testosterone-menthol eutectic mixture 6.33 g
[C18H24O2t½H2O, MW 281.4; C18H24O2, MW 272.39] Hydrophilic petrolatum 93.67 g
2.5 mg EH × 272.39 estradiol/281.4 EH = 2.42 mg estradiol A. The testosterone-menthol eutectic mixture consists of 31.6 g of
2.42 mg est/g emulsion × 1.74 g emulsion/pkt = 4.21 mg est/pkt
testosterone and 68.4 g of menthol.3 What would be the percent
C. What percent of estradiol is absorbed from the emulsion? strength of menthol in this ointment?
4.21 mg est/pkt × 2 pkt/day = 8.42 mg estradiol applied daily 31.6 g testosterone + 68.4 g menthol = 100 g mixture
0.05 mg absorbed/8.42 mg applied × 100 = 0.59% absorbed 6.33 g mixture + 93.67 g hydrophilic pet = 100 g ointment
6.33 g mix/100 g oint × 68.4 g menthol/100 g mix × 100 = 4.33% w/w
2
The following is a formula for capsules containing 2 mg estriol, B. The formula for hydrophilic petrolatum is shown below:4
0.5 mg estradiol, 50 mg progesterone, and 1 mg testosterone:2
Rx For 1000 g
Rx Cholesterol 30 g
Estriol 200 mg Stearyl alcohol 30 g
Estradiol 50 mg White wax 80 g
Progesterone 5g White petrolatum 860 g
Testosterone 100 mg How much of each of these ingredients would be needed to pre-
Lactose 30 g
pare 2 oz. of the testosterone-menthol eutectic ointment?
This formula is used to fill 100 size #1 capsules. However, you have 2 oz. × 28.35 g/oz. = 56.7 g ointment
a patient that requests smaller capsules because of difficulty in swal- 93.67 g hydrophilic pet/100 g oint × 56.7 g oint =
lowing the size #1 capsules. You obtain size #5 capsules for this pre- 53.11 g hydrophilic pet
scription and decide to prepare 60 capsules for this patient. You fill
and weigh separate capsules with each ingredient with the following Formula conversion factor = 53.11 g/1000 g = 0.053
results: estriol = 90 mg, estradiol = 75 mg, progesterone = 120 mg, Cholesterol: 30 g × 0.053 = 1.59 g
testosterone = 105 mg, and lactose = 110 mg. Note: these numbers are Stearyl alcohol: 30 g × 0.053 = 1.59 g
theoretical and should not be used as actual measurements in compounding White wax: 80 g × 0.053 = 4.25 g
this formula. How much of each ingredient will be needed for this White petrolatum: 860 g × 0.053 = 45.68 g
prescription and how much should a properly filled capsule weigh?
2 mg estriol/cap × 60 caps = 120 mg estriol References
0.5 mg estradiol/cap × 60 caps = 30 mg estradiol &TUSBTPSC FTUSBEJPMUPQJDBMFNVMTJPO
<QSPEVDUMBCFMJOGPSNBUJPO>64'PPE
50 mg progesterone/cap × 60 caps × 1 g/1000 mg = 3 g progesterone BOE%SVH"ENJOJTUSBUJPO<%FQBSUNFOUPG)FBMUIBOE)VNBO4FSWJDFT64
1 mg testosterone/cap × 60 capsules = 60 mg testosterone Food and Drug Administration Website.] Available at: www.fda.gov/cder/foi/
label/2003/21371_estrasorb_lbl.pdf. Accessed March 12, 2009.
To calculate the amount of lactose needed, you must first calculate 2. Allen LV Jr. Estriol and estradiol 2.5 mg, progesterone 50 mg, and testoster-
the amount displaced by the active ingredients. one 1 mg capsules. IJPC 2000; 4(6): 458.
"MMFO-7+S5FTUPTUFSPOFNFOUIPMFVUFDUJDPJOUNFOU 5FTUPTUFSPOF
IJPC
90 mg estriol/110 mg lactose = 2 mg estriol/x 1999; 3(2): 137.
x = 2.44 mg lactose 6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO
*ODUSP Pharmacists’ Pharmaco-
75 mg estradiol/110 mg lactose = 0.5 mg estradiol/x peia.TUFE3PDLWJMMF
.%641IBSNBDPQFJBM$POWFOUJPO
*OD
x = 0.73 mg lactose
Address correspondence to Shelly J. Stockton, BS Pharm, PhD, RPh, College of
120 mg progesterone/110 mg lactose = 50 mg progesterone/x Pharmacy, Southwestern Oklahoma Sate University, 100 Campus Drive, Weather-
x = 45.83 mg lactose ford, OK 73096.