IJPC 13 4 Hormone Replacement Therapy

july/august 2009
march/april 2009
IIN
NTTEERRN
NAATTIIO
ONNAALL JJO
OUURRN
NAALL
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
276 Hormone Treatment Options for Males:

What to Do for Men with Low Testosterone
BRUCE BIUNDO, BS, RPH
280 Saliva Tests, Part 1: Clinical Use, Elements

of Testing, and Guidelines for
Posttreatment Interpretation
JOHN KELLS, CEO, PRESIDENT; CHARLES M. DOLLBAUM, PHD, MD
290 Preventing Nonmicrobiologic Airborne

Contamination in the Compounding
Pharmacy: Ensuring a Safe Environment
for Compounders, Staff, and Clients
BILL MIXON, RPH; GARY ILLE, MSIH
276 296 Compounding Naltrexone for the

Treatment of Autism
TOM WYNN, RPH; SARAH BRUNETTI
280 300 Preparing Nonsterile and Sterile Hazardous

Compounds in an Institutional Setting
LINDA F. MCELHINEY, PHARMD, RPH
Business of Compounding
312 Marketing
Optimizing Your Website: Search Engine Optimization, Pay Per Click, Email
Marketing
PATRICIA L. STOREY, RPH, FACA
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and Quality Improvement—What
PUBLICATION MANAGER
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Compounding Pharmacies Care? 330 Calculations LaVonn Williams
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322 Basics of Gigi Davidson, BSPh, RPh, FSVHP, DICVP

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332 Alcohol-based Carbomer Gel Harvey Ahl, RPh
333 Benzoyl Peroxide 10% Gel

Comparison Diane Boomsma, RPh, PharmD, FIACP
HARSH CHAUHAN, BS; EMAN ATEF, Marianna Foldvari, PhD, RPh
334 Clindamycin 100-mg Vaginal PHD Peter R. Ford, BSPharm, FACA, FIACP
Paul F. Grassby, PhD, MRPharmS
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335 Dexamethasone and Furosemide Dave Mason, DPh, FIACP
Injection 345 Women’s John Preckshot, RPh, FIACP
Lawrence A. Trissel, BS, RPh, FASHP
336 Instant Voice Perspective on David J. Woods, MPharm, MRPharmS, FHPA
337 Moxifloxacin 20-mg/mL Oral Liquid Progesterone: ( W EBSI TE )

338 Mupirocin 1% (20-mg) Vaginal A Qualitative Study www.ijpc.com
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339 Riley Butt Cream
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340 Selegiline Hydrocholoride Australia SUBSCRIPTION AND ADVERTISING

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266 Vol. 13 No. 4 | July/August 2009
Prescription
From the Editor
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

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Feature
p hy s io log ic rol e
e
th & use of estri
ol
Jim E. Paoletti, RPh, FAARFM

ZRT Laboratory
Beaverton, Oregon
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.

Feature
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

Feature
contain the same amount of the much stronger

FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 E2, and the 0.4 mg of the 50:50 preparation has
less E3-bound receptors to possibly interfere
with E2-bound receptors in the formation of
the dimer complex.
If for some reason you wish to switch a pa-
tient from a formula containing 80% E3 to one
that contains 50% or less E3, my suggestion
would be to convert to an equal amount of E2,
calculate the amount of E3 needed to produce
the new ratio, and then reduce the dose by
25% to 33% to start. For example, if a patient
is using 0.25 mg of a bi-est preparation with
80% E3 and you wish to convert to a 50% E3
preparation, first determine the amount of E2
in the original preparation. In this example, the
amount of E2 in the original formula is 0.05
mg. Adding the same amount of E3 (0.05 mg)
to the E2 produces a 50% E3 preparation, with
ER = Estrogen receptor; E2 = Estradiol; E3 = Estriol; ERD = ER Dimer Receptor Complex a total of 0.1 mg bi-est. Since the 0.1 mg of the
50% preparation is “stronger” than the original
0.25 mg of 80% E3, to get a similar response,
would produce the same genomic response, from Figure 1 to Figures 3 and 4, the amount reduce the total amount to no more than 0.075
the action of the E2 would persist for a much of E2-bound receptors has remained constant. mg of the 50:50 bi-est to start.
longer period of time than that of the E3. If However, the chance of obtaining the strongest If E3 is unavailable for a patient that was
two E2 molecules bound to estrogen receptors effect of E2 has been reduced. This illus- formally on a bi-est preparation, then the
formed the dimer receptor, then the strongest trates the efficiency of E2 decreases with an amount of E2 used alone should not increase
response possible would occur. If the dimer increase in the quantity of a substance that can from the amount originally in the bi-est for-
receptor is formed by receptors of which competitively inhibit receptor binding and the mulation. Instead, it may require less E2 since
one has E2 bound to it and the other has E3 formation of receptor complexes with E2. If there is less E3 present to regulate the activity
bound to it, E3 would dissociate much more Figure 4 was filled with more receptors bound of E2 at the receptor level. Additionally,
quickly than either E2 molecule in the previ- to E3, then the chance that the E2 present nutritional and lifestyle factors to help ensure
ous scenario, and the genomic response would would produce the strongest action would be safe estrogen metabolism become even more
not be as strong. In Figure 1, there are two E2 significantly reduced. This can also occur with important in the absence of E3.
molecules and one E3 molecule all in the same a very weak estrogen such as a phytoestro- Since E3 plays an important role at its
vicinity, each bound to an estrogen receptor. gen. Too much of a phytoestrogen can cause normal physiologic level in balance with the
Figure 2 shows the two possible combinations estrogen deficiency symptoms by blocking the normal physiologic ratio of E2, it is important
of dimer receptor complexes that could form stronger estrogens from forming the receptor to attempt to achieve a normal physiologic
from the receptors in Figure 1. The receptor dimer complex. level of both of these estrogens to obtain the
complex ERD-A made up of receptors bound For exogenous administration, increasing proper balance. If there is too much E2 in
to E2 produces the stronger effect. Assuming amounts of E3 may necessitate the need for relationship to E3, the possibility exists of
two of these three estrogen-bound receptors more E2 to obtain the effects of E2. Giving the excessive proliferative effects of E2. If there
are going to combine to form the dimer recep- least amount of estrogen possible to achieve is too much E3, it requires more E2 to obtain
tor complex, the odds that the two E2-bound physiologic levels and relieve symptoms benefits. Any time the total amount of E2 or
receptors would combine together are one should always be a goal of restoration therapy. E1 is increased there are increased estrogen
pair out of a possible three pairs. There would In giving a more physiologic ratio of E3 in metabolites created, and an increased risk of
be a 33% chance of getting the strongest re- combination estrogen preparations, the overall creating catechol quinone metabolites that can
sponse. In Figure 3, another receptor with E3 amount of estrogen required may be able to be lead to DNA adjuncts that have been shown to
bound to it has been added. In this scenario, reduced. cause cancer.84-87
the odds that the two receptors bound to E2 For illustration, compare 1.0 mg of a bi-est E3 does not need to be measured to initially
would combine to form the ERD-A complex preparation which contains 80% E3 and 20% access endogenous estrogen metabolism, as E2
pictured in Figure 2 would be decreased to E2 with 0.4 mg of a bi-est formulation, which levels reflect overall estrogen production well.
16.7% (one pair out of six possible pairs gives is 50% of each estrogen. Both preparations However, when estrogens are administered,
the maximum response). If we add one more contain the same amount of E2 (0.2 mg). Con- whether E2 alone or in combination with other
receptor bound to E3 (Figure 4), the odds sidering E2 as a much stronger estrogen overall estrogens, practicing bioidentical restoration
of the two receptors bound to E2 combining on effects in the body, the 0.4 mg of a 50:50 therapy would require monitoring the E3 level
and resulting in the strongest possible action bi-est would be considered the “stronger” of as well as the E2 level initially to make sure
decreases to 10% (one of ten pairs). In going these two preparations. Both preparations both are in a normal physiologic range.

Medisca
Feature
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
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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;
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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
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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
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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.
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Lemon HM, Wotiz HH, Parsons L et al. Reduced es- Frustrated trying to get physicians to
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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

Feature
Hormone Treatment Options for Males:
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

Feature
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.
Treatment Options without

Testosterone Supplementation
Luteinizing Hormone
LH is the primary messenger hormone produced in the pituitary that
signals the testes to produce testosterone. In many men 45 years and
older, the slowdown of LH secretion is a common thread, and it results
in lower testosterone production (hypogonadotropic hypogonadism).
While LH can slow down as a function of aging, it can also slow down as
a result of the hypothalamus perceiving that there is sufficient hormone
available at the time. Interestingly, this can result not only from abun-
dant or sufficient testosterone but also from the presence of estradiol.1
As mentioned, estradiol presence in the hypothalamus can cause the
slow down of LH production, resulting in low testosterone. Therefore,
the use of agents that slow down the production of estradiol or block its
action can be very useful, and we have ample evidence of their useful-
ness. Aromatase inhibitors, drugs such as anastrozole or letrozole, have
been studied for this kind of action, and the results bear out this concept.
When estradiol levels were lowered, the production and resulting
levels of LH were increased and more testosterone made.14-16 In the Treatment Options Involving
case of anastrozole, we recommend lower doses than used in females,
to lower—not stop—the production of estradiol. Oral dosing protocols Testosterone Supplementation
ranging from 0.1 mg daily to 0.25 mg 3 times weekly to 0.5 mg twice Once testosterone supplementation, an area of great interest, has
daily have been used successfully. It should be noted that some pharma- been decided upon, recommendations for the patient must be con-
cists have prepared this therapy using sublingual or buccal troches. The sidered. This section discusses the common dosage forms, including
estrogen blocker clomiphene has also been used, with the same thoughts parenteral, sublingual/buccal, and topical. While there is some interest
in mind and with similar results.17 Oral doses of 15 mg to 25 mg 3 times in preparing pellets, this article does not discuss their use due to various
daily have been used. compounding complexities.

Feature
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-
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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.

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chemical, and biotech industries for over 15 years.
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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
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tions. Nat Clin Pract Urol 2006; 3(12): 653–665. (UJRQRPLFGHVLJQDOORZVRSHUDWRUWRFRPIRUWDEO\LQWHUDFWZLWKFRPSRXQGV
24. Wittie J. Male hormonal contraceptives. Student paper. 2007 Feb.

25. Wang C, Swerdloff RS, Iranmanesh A et al. Transdermal testos- REGISTER ON OUR WEBSITE TO LEARN MORE ABOUT CONTAINMENT SOLUTIONS:
terone gel improves sexual function, mood, muscle strength, and ZZZIORZVFLHQFHVFRP

Feature
SALIVA TESTS, PART 1:

CLINICAL USE, ELEMENTS OF TESTING, AND
GUIDELINES FOR POSTTREATMENT INTERPRETATION
John Kells, CEO, President
Charles M. Dollbaum, PhD, MD
Aeron LifeCycles Clinical Laboratory
San Leandro, California
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.

Feature
t The collection time for saliva testing is more

INTRODUCTION controllable than that for serum testing. This
Over the past three decades, many research
is critical for the baseline testing of hormones
studies have validated the use of saliva for the
that vary diurnally and for the assessment of
measurement of the biologically active fraction
hormone replacement therapy (HRT) dosing
of steroid hormones in the bloodstream.1-7
(trough level [i.e., the hormone level just
Saliva is an excellent medium for that purpose
before the next dose testing] vs peak level
because it is a natural ultrafiltrate of blood,
testing).
and steroids not bound by carrier proteins in
t Saliva testing facilitates multiple collections
the blood freely diffuse into saliva. Only about
outside the hospital setting.
1% to 10% of the steroids in blood are in the
t Hormones are stable in saliva at room tem-
unbound or free form, and it is that fraction
perature for at least three weeks after their
that diffuses into target tissues of the body and
collection, so the U.S. Postal Service can be
into saliva.2,8-10
used to transport saliva samples to the labora-
Ninety percent to 99% of steroid hormones
tory for analysis.
in the blood are bound to carrier proteins
t Saliva testing for hormones, the cost of which
(cortisol-binding globulin, sex-hormone bind-
is covered by many insurance plans, is usually
ing globulin, albumin) and are unavailable to
less expensive than blood testing.
target tissues. Passive diffusion of unbound
(free) steroid hormones occurs because small
steroid molecules have a low molecular weight CLINICAL USE OF
(<450 Da) and are relatively nonpolar, so they
freely diffuse from blood to saliva. The steroid SALIVA TESTING
hormones that have been studied most exten- The baseline measurement of hormone
sively in saliva include cortisol, estrogens (es- levels in saliva provides an accurate assess- The saliva test kit contains a 10-mL
tradiol, estrone, and estriol), progesterone, and ment and can be used to identify or monitor collection vial, an identification label,
androgens (dehydroepiandrosterone [DHEA], a number of clinical conditions, including gum that the patient should chew to
testosterone, 5α-dihydrotestosterone). climacteric changes in perimenopausal or stimulate saliva flow, a pink absorbent
Free steroid hormones cross into the cells postmenopausal women, adrenal disorders material to prevent spillage during
of the salivary gland and then into the salivary such as Addison’s disease or Cushing’s transport, and a small plastic bag (not
gland ducts, where bulk fluid flow is gener- disease, and androgen deficiency. In men shown) that can be zipped closed to
ated by the sodium-potassium adenosine and women, the age-related decrease of hor- ensure that the sample is contained
triphosphatase mechanism. Sodium is pumped mones such as testosterone and DHEA can during shipping.
into the salivary gland lumen and fluid flows also be assessed and monitored. Laboratory
freely down the osmotic gradient, carrying the studies have established the expected normal can also be evaluated. The Table furnishes ex-
unbound hormones with it. Thus there is no range for unsupplemented saliva hormone amples of established ranges of unbound (free)
change in hormone concentration as the flow levels. The effects of bioidentical hormone hormone levels found in saliva after treatment
rate changes. Bound steroids are too large to replacement therapy (BHRT) produced by with a transdermal cream or gel, an oral dosage
diffuse freely through the salivary cells into the branded pharmaceuticals such as Prometrium form, or a transdermal patch.
salivary gland lumen because the molecular or Estrace and compounded hormones can also
weight cutoff is approximately 450 kd. Total be measured in saliva. Monitoring the trough
blood hormone levels are not identical to saliva level after a period of therapeutic intervention DERIVATION OF RANGES
levels, which are only a small percent of total (2 to 4 weeks of continuous therapy) permits The expected hormone ranges (according
blood levels. The availability of accurate saliva the titration of individual hormone dosages to the type of hormone, the patient’s sex and
testing is increasing, and many segments of the to maximize the clinical effect and minimize age, and the prescribed treatment) cited in the
medical community use saliva instead of blood dose-related adverse effects. Variations in the Table were determined by testing volunteers
for steroid hormone analyses for the following levels of those hormones that result from pre- representative of designated populations and
reasons: scription therapy or over-the-counter supple- by reviewing their hormone ranges in an
mentation can be evaluated via saliva testing, extensive internal patient database. Each hor-
t Saliva testing is noninvasive, simple to and the dosage can be adjusted to achieve the mone range is based on as many as 800 such
perform and undergo, safe for the patient and target hormone level. In addition, changes in analyses that our laboratory has performed to
practitioner, stress free, painless, and private hormone levels associated with various routes date in-house. These salivary hormone ranges
and convenient for the patient and his or her (oral, subcutaneous, sublingual, transvaginal, represent 90% of normal female and male
physician. transdermal) and forms of administration hormone values, excluding the upper and low-
t Saliva reflects the biologically active (free) (creams, patches, suppositories, gels) can be er 5% of the ranges evaluated. The correlation
fraction of steroids in the bloodstream, unlike accurately measured in saliva. The influence of these ranges with those for saliva steroid
blood or urine, both of which are used to of precursor hormones thought to elevate pri- hormones (measured by similar methods) in
measure total steroid levels. mary hormones through an endocrine cascade the literature is excellent.

Feature
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

Feature
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

Feature
CONSUMER-DIRECT ORDERING OF SALIVA TESTING

At the time of this writing, compounding pharmacists and individual consumers could order saliva testing directly from
a clinical laboratory without the signature of a licensed medical provider in the following states, although the cost of
testing is not covered by insurance in those cases.
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

Feature
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?
In general, increasing or decreasing the hormone dose will result in a

proportionate change in the hormone levels found in saliva. Depending

Feature
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 variations in hormone levels in men

and women differ primarily in that most
healthy women have high estrogen levels and
low androgen levels and most healthy men
have high testosterone levels and low levels
of estrogen. All saliva test result interpreta-
tions should be adjusted for sex-related
differences in the range of hormone levels.
Estradiol peaks around day 14 and progester-
one peaks between day 20 to 23 of the typical
menstrual cycle, and baseline saliva testing
should be timed accordingly. If the objective
A note instructing is to measure hormone levels at the ovulatory
the patient to provide peak, then testing on day 14 of the menstrual
adequate saliva for the cycle is desirable. When patients experiencing
analysis of multiple menopausal symptoms are tested, measuring
hormones. hormone levels once between days 20 and 23
of the menstrual cycle is preferable. In women

Feature
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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-

Feature
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: johnk@aeron.com

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Feature
Preventing Nonmicrobiologic Airborne
in the Compounding Pharmacy: Ensuring a Safe Environment for

Compounders, Staff, and Clients
Bill Mixon, RPh
The Compounding Pharmacy
Hickory, North Carolina
Gary Ille, MSIH

Wilmington, North Carolina
Editor’s Note: The safety of employees involved in the

compounding of preparations containing hazardous
drugs is of utmost concern. In particular, airborne
exposure to hormones such as estradiol, estriol, estrone,
progesterone, and testosterone has been shown to ad-
versely affect both male and female employees. Infertility,
fetal abnormalities, and fetal loss have also been linked
with frequent exposure to hormone-containing medica-
tions. The results of periodic air-quality monitoring
can confirm the success of the environmental safe-
guards used in the pharmacy or indicate the need for
corrective action. In this article, effective, affordable air-
quality monitoring of hormone levels in the compound-
ing area and throughout a compounding pharmacy
is described, and the results of air-monitoring tests
conducted by an industrial hygienist and a compound-
ing pharmacist are presented. Readers can obtain ad-
ditional information about air-quality analysis from
the American Industrial Hygiene Association, 2700
Prosperity Avenue, Suite 250, Fairfax, VA 22031.
Website: www.aiha.org/Content
Abstract Preventing and minimizing exposure to nonmicrobiologic airborne contaminants in a com-

pounding pharmacy protects the health of pharmacy staff and clients. The inhalation of hazardous
substances has been linked to the development of diseases and disorders that range from cancer to
infertility. Although a workplace environmental exposure level has been established for some antibiot-
ics, at the time of this writing there were no exposure limits recommended by the National Institute for
Occupational Safety and Health or permitted by the Occupational Safety and Health Administration for
hazardous drugs or pharmaceutical compounds, nor were threshold limit values for those substances
specified by the American Conference of Governmental Industrial Hygienists. For that reason, an evalu-
ation of environmental air quality performed by an industrial hygienist can yield valuable information
that will reassure staff or provide the basis for remedial action. This report describes the assessment by
an industrial hygienist of airborne hormone levels in a compounding pharmacy and reviews the results
of that analysis.

Feature
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
%'#%'!$%'#(!%$""
,*** "$"+(!"%#

Feature
all workers are repeatedly exposed day after

day without adverse health effects, were of
particular interest in the air-quality study
performed in The Compounding Pharmacy. A
small percentage of workers may experience
discomfort at or below the threshold limit for a
given substance, and a smaller percentage may
be affected more seriously by the exacerbation
of a preexisting condition or by the develop-
ment of an occupational illness at relatively
low levels of exposure. Hypersusceptible
individuals, however, may not be protected
from the adverse health effects that can de-
velop after exposure at or below the threshold
limit for a specific airborne substance. Genetic
factors, age, personal habits (e.g., smoking,
alcohol consumption, illegal drug use), disease,
pregnancy, and cumulative exposure to the
same agent via hobbies or a second job can also
affect the threshold limit.
Although a workplace environmental
exposure level has been established for some
antibiotics, including chloramphenicol, at the
time of this writing there were no exposure 2. The collection and evaluation of data to Data that can be used to establish an
limits recommended by the National Institute determine the levels of chemicals that em- exposure control level are generated as part of
for Occupational Safety and Health or permit- ployees encounter daily the required research and development for all
ted by OSHA for hazardous drugs, and no 3. Recommendations for ensuring the new drugs.8 The U.S. Food and Drug Admin-
threshold limit values for those substances had reduction of exposure to those hazardous istration requires that a new drug application
been specified by the American Conference of substances include the results of specific studies of that
Governmental Industrial Hygienists.6 agent, including its effects in various animal
The results of IH assessment can reveal
chemical hazards within the industrial envi- models that receive the drug via different
routes of administration. The risk assessment
Monitoring the ronment (e.g., toxic chemicals in the form of a
liquid, dust, fume, mist, vapor, or gas), hazard- of a proposed new drug, which is performed to
Compounding ous levels of physical energy (e.g., electromag- establish an exposure control level, is usually
conducted by a multidisciplinary panel of sci-
Environment netic or ionizing radiation), harmful levels of
noise or vibration, dangerous extremes of tem- entists and medical personnel who are experts
Unfortunately, OSHA-permissible exposure in toxicology, industrial hygiene, chemistry,
perature, ergonomic stressors (e.g., improperly
limits and threshold limits for pharmaceutical medicine, pharmacology, etc. Because human
designed tools or work areas, improper lifting
compounds are also unavailable. For that rea- toxicity data on a particular pharmaceutical
or reaching, poor visual conditions, repeated
son, an evaluation performed by an industrial compound may not be available, the extrapola-
motions performed in an awkward position),
hygienist can provide a valuable assessment of tion of results from an animal model to the
and the presence of biologic stressors (insects,
environmental air quality in a compounding human model, risk assessment, informed judg-
mites, molds, yeasts, fungi, bacteria, viruses).
pharmacy. Industrial hygiene (IH) is defined ment, and safety factors have a role in defining
as… the exposure control level.
…a science and art devoted to the an-
Exposure Control Level
The exposure control level is defined as
ticipation, recognition, evaluation, and
control of those environmental factors
the time-weighted average concentration Evaluating the Pharmacy
for a normal 8-hour workday and a 40-hour The air-quality assessment performed in
or stressors arising in or from the workweek during which nearly all workers The Compounding Pharmacy was initiated by
workplace, which may cause sickness, may be repeatedly exposed to a substance day a co-author of this report (BM) as a proactive
impaired health and well-being, or sig- after day without adverse effect. If an exposure management decision to ensure the safety of
nificant discomfort among workers or control level for a pharmaceutical compound his staff and clients. Analysis by air sampling
among the citizens of the community.7 is needed, an article by Sargent and Kirk8 rather than by serum or saliva testing was used
provides guidelines for defining that param- to determine the exposure of employees to
IH evaluations can be divided into three eter. According to those authors, exposure airborne levels of two commonly compounded
stages: control levels, which are pharmacology-based, hormones (progesterone and testosterone)
1. The assessment of employee exposure to differ from threshold limit values, which are because of the rationale that elevated hormone
hazardous substances toxicity-based. levels can be caused by factors other than

Feature
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.

Feature
in this report is sound and accurate, and elimi-

Results of Analysis equipment and countertops and to the use of
two AirClean Powdersafe 700 series duct- nating or minimizing exposure to airborne
The results of the air-quality analysis
less balance enclosures (AirClean Systems, contaminants in the compounding pharmacy
performed for The Compounding Pharmacy
Raleigh, North Carolina); one is used to is essential. The results of periodic air-quality
in 2006 indicated that the tested staff members’
perform encapsulation, and the other is used monitoring can provide information for cor-
levels of hormones were either nondetected
for weigh-outs. rective action or confirm the success of current
or were less than the reporting limit used by
environmental safeguards.
the laboratory. The final analysis stated that
“The results continue to indicate that airborne Cost
exposure levels are well controlled and below
the detection limit for the analytical labora-
The cost of each assessment for airborne
contaminants for The Compounding Pharma-
References
1. ASHP Council on Professional Affairs. Drug
tory method used.” The industrial hygienist cy totaled less than $1000. That expense can Distribution and Control: Preparation and
who conducted the study did not conclude, usually be divided into the cost for laboratory Handling—Guidelines. ASHP Guidelines on
however, that the levels of progesterone and analysis and labor. The expense of testing is Handling Hazardous Drugs. Am J Health-Syst
testosterone were safe or met any regulatory relatively less when multiple samples from a Pharm 2006; 63: 1172–1193. [ASHP Website.]
standard because no such standard existed single-filter sample are analyzed. Available at: www.ashp.org/bestpractices/new/
when the analysis was performed. The results Haz_AJHP.pdf. Accessed November 30, 2006.
of all three air-quality analyses performed 2. United States Department of Labor. Occu-
in The Compounding Pharmacy revealed an Conclusion pational Safety and Health Administration.
environmental exposure level that was non- In the future, the analysis of airborne levels Potential health hazards associated with the
detectable. The successful long-term control of additional substances, such as estradiol, may process of compounding medications from
of airborne contamination in that pharmacy be scheduled at The Compounding Pharmacy pharmaceutical grade ingredients. Technical
Information Bulletin 01-12-21. [United States
is due in large part to strict adherence to if the methodology becomes available. In our
Department of Labor. Occupational Safety &
standard operating procedures for cleaning opinion, the air-quality assessment described
Health Administration Website.] Available at:
www.osha.gov/dts/tib/tib_data/tib20011221.
html. Accessed November 5, 2006.
3. Allen LV Jr. Basics of compounding for hazard-
ous drugs, part 2: Regulation and sources of
Free Weekly contamination. IJPC 2006; 10(6): 446–448.

4. Kiffemeyer TK, Kube C, Opiolka S et al. Vapour
Newsletter pressures, evaporation behavior and airborne

concentrations of hazardous drugs: Implications
for occupational safety. Pharmaceut J 2002; 268:
331–337.
Letter from the 5. deWerk Neal A, Wadden RA, Chiou WL.
Editor, Loyd V. Allen, Exposure of hospital workers to airborne anti-
Jr., Ph.D., R.Ph. neoplastic agents. Am J Hosp Pharm 1983; 40(4):
597–601.
6. Allen LV Jr. Basics of compounding for hazard-
Examples of Inclusions: ous drugs, part 1: An introduction. IJPC 2006;
r$VSSFOU$PNQPVOEJOH 10(5): 377–379.
News from Around the 7. United States Department of Health and
World Human Services. National Institute for Oc-
r#PPL3FWJFXT cupational Safety and Health. The Industrial
r401T Environment—its Evaluation and Control. NIOSH
Publication No. 74–117. [United States Depart-
r$PNQPVOEJOH5JQT
ment of Health and Human Services. NIOSH
Website.] 1973; 3–4. Available at: www.cdc.gov/
Emailed every Friday Niosh/74-117.html. Accessed November 30,
2006.
8. Sargent EV, Kirk GD. Establishing airborne
exposure control limits in the pharmaceuti-
cal industry. Am Ind Hyg Assoc J 1988; 49(6):
309–313.
For additional information, contact Bill Mixon, RPh,

The Compounding Pharmacy, 750 4th Street, SW,
Available at: Hickory, NC 28602; E-mail: wmixon@thecom-
CompoundingToday.com poundingrx.com or Gary Ille, MSIH, 4609 Archer
The World’s Largest Compounding Resource Drive, Wilmington, NC 28409.

Feature
Compounding Naltrexone for the Treatment of
Tom Wynn, RPh

Sarah Brunetti
Tri-State Compounding Pharmacy
Cincinnati, Ohio
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.

Feature
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

Feature
alleviate his symptoms of AD. MB has a history of stimming by banging
Rx NALTREXONE HYDROCHLORIDE 25-MG

CAPSULES
For 100 capsules

two sticks together repetitively without any awareness of what is going
on around him. As noted by his mother, he has tried numerous prescrip-
tion medications, including Depakote, Seroquel, fluoxetine, sertraline,
and Concerta, with either worsening of symptoms or no improvement.
MB has tried the gluten- and casein-free diet, numerous nutritional
supplements, and numerous chelation therapies with no improvements.
Naltrexone hydrochloride 2.5 g In December of 2008, MB’s mother presented at the pharmacy with a
Lactobacillus acidophilus 13.5 g prescription for naltrexone 25 mg. She was immediately concerned that
the starting dose of the medication may be too high, and after careful
METHOD OF PREPARATION consideration decided to start lower and to slowly titrate up the dose.
1. Calculate the required quantity of each ingredient for the total MB was started on 3 mg of naltrexone in the evening. MB’s mother
amount to be prepared. noted significant improvement in his behavior by the next day. While
2. Weigh and/or measure each ingredient accurately. MB was still stimming, the intensity was less. He would also pause to
3. Punch out capsules using #3 size capsule. Note: Capsules should be full. look up in between stimming and smile. Over the next several months,
4. Verify that each capsule weighs approximately 0.160 g. MB’s naltrexone dose was slowly titrated to 5 mg a day, and finally up
to 25 mg a day. The only side effect noted was insomnia which subsided
STABILITY when the dose was given in the morning.
The beyond-use date for this preparation is 3 months.12 MB’s mother displayed great enthusiasm for her son’s improvement
with naltrexone 25 mg a day. She states that her son smiles more often
STORAGE and is more playful. He is more responsive to the world around him,
Keep refrigerated. more present, and will now giggle or laugh. She commented that he
now “flirts” with his female caregiver and is sweeter and more affection-
systems for replacement behavior, antipsychotics, lithium, antidepres- ate. MB’s mother and his teachers feel that MB has an improved ability
sants, and physical restraints. to learn with naltrexone therapy.
Naltrexone therapy was initiated at 50 mg/day and dramatic im- During the course of MB’s naltrexone therapy, his mother noted a
provement occurred the same day naltrexone was started. Attempts at decrease in appetite. The decision was made to decrease MB’s nal-
self-abuse were accompanied by crying or screaming and for the next 14 trexone from 25 mg to 20 mg to see if a decrease in dose would help
days there were no incidents of SIB. On the 15th day, she began a pattern to stimulate his appetite. With the slight decrease in dose of 5 mg, MB
in which self-abuse occurred once every four to five days. However, the severely regressed and his stimming behavior severely returned. His
severity of episodes of self-injury was greatly reduced. Over the next 10 parents stated that the banging of sticks was so loud and rigorous that it
weeks of the naltrexone trial, the frequency of blows to the jaw increased was difficult to tolerate. MB also started experiencing insomnia at night.
intermittently until they were a daily occurrence. However, the severity Also noteworthy, MB’s appetite did not improve with a decrease in the
of the blows was less and resulted in no bleeding or jaw dislocation. naltrexone dose. After a week on the dose of 20 mg, the decision was
At the end of 10 weeks, naltrexone was discontinued and the patient’s made to increase the dose back to 25 mg a day. Again, MB’s stimming
SIB returned to baseline in frequency and severity. After 4 weeks, the subsided and improvement was noted. MB’s mother notes that while
naltrexone was restarted and after 2 weeks the injurious behavior had naltrexone therapy has not normalized her son, she has seen great im-
diminished. At the time of this report Ms. A had continued on naltrex- provements with the drug and feels it has significantly improved her son’s
one 50 mg/day for 1 year with no escalation in frequency or severity of behavior and feels he is now more present with the world around him.
episodes, and the episodes remained accompanied by pain. The above analysis only points towards one of many possible neuro-
Many individuals with AD show repetitive behaviors such as preoc- chemical abnormalities that may participate in AD. Opioid antagonist
cupation with nonfunctional routines or rituals and stereotypes and therapy may only be effective for a subpopulation of autistic children
repetitive motor mannerisms such as hand or finger flapping. Stimming having elevated brain opioid activity. Given the limited pharmaco-
is a term used to describe repetitive body movement that self-stimulates therapeutic options in the treatment of AD, naltrexone treatment
one or more senses in a regulated manner.13 There are theories for should be considered in children with AD who portray symptoms of
the function of stimming and why there is an increased incidence in SIB or stimming, starting at a low dose and titrating upward accord-
AD. One theory states it may provide nervous system arousal, releasing to response. Although the efficacy of naltrexone in the treatment
ing β-endorphins that provide the person with some type of internal of AD remains controversial, a majority of studies have indicated some
pleasure.14 Another theory states that these behaviors may calm a person beneficial effects of naltrexone in individuals with AD. Naltrexone may
because of over stimulation from the environment. As a result, the offer benefits in the treatment of AD, especially when other attempts at
autistic individual participates in repetitive behavior to block out the therapy have failed.
over-stimulating environment. In several case reports, naltrexone has
been noted to decrease or alleviate stereotypy or stimming behaviors
most likely because of its effects of decreasing β-endorphin levels. Conclusion
Children presenting with symptoms of AD require a comprehen-
sive evaluation by a multidisciplinary team including a psychologist,
Case Report 2 neurologist, psychiatrist, speech therapist, and other professionals who
The second case study is a patient at Tri-state Compounding diagnose children with ASD. Following the diagnosis, a treatment plan
Pharmacy. MB is a 10-year-old male who has tried numerous options to is developed, which in most cases involve educational and behavioral

Feature
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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0311-09-0109

Feature
Preparing Nonsterile & Sterile
Hazardous Compounds
in an Institutional Setting
Linda F. McElhiney, PharmD, RPh
Clarian Health Partners, Inc.
Indianapolis, Indiana
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

Feature
TABLE 1. Hazardous Drugs Used in the Ohio Northern University Study.
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 VVìÌ>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 -«ÊÀiÃ«Ãi
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>ì`
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-

Feature
gram demonstrates recommended procedures Testing a compounder’s competency for
for cytotoxic and hazardous drug prepara-

tion, administration, spill cleanup, and waste
management. A preview of the VHS tape can
nonsterile hazardous drug preparation may be
difficult. Currently, there are no commercial
kits available to aid in verifying this compe-
Content for Policies be watched on the ASHP website at www.ashp. tency. However, the compounding supervisor
org in the bookstore section. may create a test on-site using similar materi-
and Procedures There is also a chemotherapy training and als found in ChemoTest. Fluorescein powder
Manual for Handling certification program called ChemoChek can be purchased through chemical whole-
Hazardous Drugs (available through Health Care Logistics) that salers, and the compounding supervisor can
provides the trainee with self-administered, create tests that simulate nonsterile hazardous
UÊ iÌ>i`Ê«ÀVi`ÕÀiÃÊvÀÊ«Ài«>À}]Ê hands-on training for techniques required compounding done at the facility using the
administering, and disposing of to handle chemotherapy drugs. The training flourescein powder.
hazardous drugs manual provides education about the risks as-
sociated with handling cytotoxic drugs, as well
UÊ ÛÀiÌ>ÊVÌÀÃ
as one certificate application. The kit includes
ESTABLISHING
UÊ µÕ«iÌÊ>`ÊìÛViÃ
flourescein dye, ultraviolet light, five 10” × 17” POLICIES
UÊ >Li} prep mats, and five transport bags. Refill kits According to ASHP and NIOSH guide-
UÊ ÌÀ}Ê>`ÊÕ«`>Ì}ÊÌiÊ are available for ongoing training. lines, work policies and procedures specific to
material safety data sheets A commercial test kit is also available the handling of hazardous drugs must be in
UÊ *iÀÃiÊÃÃÕiÃÊ°i°]Ê«Ài}>VÞ® through Q.I.medical, inc (www.qimedical.com) place for all situations in which these drugs are
UÊ *ÀiÃiViÊvÊ>â>À`ÕÃÊ`ÀÕ}Ã called ChemoTest, which tests the compound- used throughout a facility. The sidebar titled
er’s hazardous drug manipulation technique Content for Policies and Procedures Manual
UÊ ,iVi«ÌÊvÊ>â>À`ÕÃÊ`ÀÕ}Ã
and can be used to verify and document the for Handling Hazardous Drugs lists the issues
UÊ -«ÊVÌÀ compounder’s competence in handling cyto- that should be addressed and defined in these
UÊ -ÌÀ>}i toxic and hazardous drugs. The kit includes policies and procedures. The development of
UÊ /À>Ã«ÀÌ>ÌÊ>`ÊìÛiÀÞ fluorescein dye in 3-mL and 50-mL vials, the safety program must be a collaborative ef-
directions for use, and a log sheet. fort, with input from all affected departments:

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).
UÊ -ÌÀiÊ>â>À`ÕÃÊ`ÀÕ}ÃÊÃi«>À>ÌiÞÊvÀÊÌiÀÊÛiÌÀÞ°
UÊ -Õ`Ê>ÛiÊ£ÓÊ>ÀÊV>}iÃÊ«iÀÊÕÀÊ>`Ê>ÌÊi>ÃÌÊä°ä£ÊVÊÜ>ÌiÀÊVÕÊi}>ÌÛiÊ«ÀiÃÃÕÀiÊÊVi>ÀÃÊ
containing compounding aseptic containment isolators or where hazardous compounding and drugs are stored.
UÊ ÌÀÊÀÊ«ÀiÃÃÕÀâ>ÌÊ>`Ê`VÕiÌÊÀiÃÕÌÃ°
UÊ >ìÊ>â>À`ÕÃÊ`ÀÕ}ÃÊÜÌÊViÌiÀ>«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
>ÃÃÊxÊiÛÀiÌÊÜÌÊVÃi`ÃÞÃÌiÊÌÀ>ÃviÀÊìÛViÃÊ
and primary engineering controls in place.
UÊ VViÃÃÊÌÊ>Ài>ÊÃÕ`ÊLiÊÌi`ÊÌÊÌÀ>i`Ê«iÀÃi°
UÊ VÕiÌÊ«iÀÃiÊÌÀ>}Ê>Õ>Þ°
UÊ i}>ÌÛiÊ«ÀiÃÃÕÀiÊiÛÀiÌÊÌÊÀiµÕÀi`ÊvÀÊÜÛÕiÊV«Õ`}Ê«iÀ>ÌÃÊÜiÊVÃi`ÃÞÃÌiÊÌÀ>ÃviÀÊ
devices are used.
UÊ "LÌ>ÊÜÀÌÌiÊ>VÜi`}iiÌÊvÊ«iÀÃiÊvÊÀi«À`ÕVÌÛiÊV>«>LÌÞÊVViÀ}ÊÀÃÃÊ>ÃÃV>Ìi`ÊÜÌÊ>`}Ê
hazardous drugs.
UÊ Ã«Ã>ÊvÊÜ>ÃÌiÊiiÌÃÊ>Ê>««V>LiÊviìÀ>Ê>`ÊÃÌ>ÌiÊÀi}Õ>ÌÃ°
UÊ VÕiÌÊÌÌ>ÊiÝ>ÕÃÌÊvÊ«À>ÀÞÊi}iiÀ}ÊVÌÀÃ°
UÊ VµÕÀiÊ>ÃÃ>ÞÊvÊÃÕÀv>ViÊÜ«iÊÃ>«iÃÊiÛiÀÞÊÈÊÌÃ°

Feature
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
by three independent systems. ,_WLY[:[HMM7O`ZPJPHUZ

Needle-free closed-system vial-transfer
EQUIPMENT AND devices (CSTDs) are being used in healthcare
:LJ\YL6USPUL9LWVY[PUN
DEVICES facilities to minimize the risk of exposure
There are several options for cabinets for compounding personnel and medical -69469,05-694(;065
SHIYP_JVT
or hoods used to prepare hazardous drugs. personnel that administer hazardous drugs.
Preferably, the facility should use a ventilated These systems are recommended by NIOSH.
cabinet, such as a Class II Type B BSC. This
type of BSC must be totally exhausted to the
A CSTD is defined by the NIOSH and the
International Society of Oncology Pharmacy

outside and can be expensive. An acceptable, Practitioners (ISOPP) as “…a drug transfer
less-expensive alternative is a Class II Type device which mechanically prohibits the trans-
A BSC. This type of BSC may be partially fer of environmental contaminants into the
exhausted to the outside, but it can operate as system and the escape of hazardous drug or
a self-contained hood if venting to the outside vapor concentrations outside of the system.”14
is not possible. Class II BSCs can be used for The system cannot be “semi-closed” and must
sterile compounding because they provide an be leak-proof and airtight. As of 2008, only
ISO Class 5 environment. For facilities that one commercial CSTD product, PhaSeal, has
are small and cannot build a negative-pressure met the criteria or definition of a CSTD ac-
room for hazardous compounding, a CACI cording to a study by Jorgenson et al.15 Other
may be a suitable option. CSTDs are also commercially available on the
If nonsterile hazardous compounding is market. The CLAVE, by ICU Medical, Inc., is
a needle-free system that has been available
NEW YORK
done, a second hood dedicated to this type
of compounding is recommended. A Class I since 1992, is compatible with chemotherapeu- CERTIFIED
BSC or a CACI are suitable options. Balances tic agents, and is marketed as a microbiologi-

Feature
packaging of hazardous drugs. All gloves used at the time of this publication. Sterile surgical
should be labeled as “chemotherapy gloves”

and meet the American Society for Testing and
Materials (ASTM) standards that assess the
gloves may be worn over the chemotherapy
gloves during the compounding or the chemo-
therapy drugs may be disinfected with sterile
Tips on Preparing resistance of medical gloves to permeation by isopropyl alcohol (IPA) without affecting the
Hazardous Compounded chemotherapy drugs.16 Use double gloves for integrity of the gloves.17 Once compounding is
all activities involving hazardous drugs. The complete, the outer gloves should be removed
Sterile Preparations outer glove should extend over the cuff of the and contained inside the BSC. The inner glove
from American Society gown, while the inner glove should be under should remain on while affixing the labels on
of Health-System the cuff. Gloves should be inspected for defects the final containers and sealing the preparation
prior to use and changed every 30 minutes or in a sealable bag for transportation. After the
Pharmacists Guidelines
when damaged or contaminated. United States final preparation has been checked, the gloves
UÊ "ÞÊÃÕ««iÃÊ>`Ê`ÀÕ}ÃÊiÃÃiÌ>Ê Pharmacopeia (USP) Chapter <797> requires should be carefully removed, preferably inside
to compounding should be that sterile gloves be worn when preparing ster- out, and placed in the designated hazardous
placed in work area of primary ile hazardous drugs; however, sterile chemo- waste container. Hands should be washed be-
engineering controls. therapy gloves were not commercially available fore donning and after removing the gloves.
UÊ 1ÃiÊÕiÀVÊìÛViÃÊÜiÊ
manipulating hazardous drugs.
UÊ 1ÃiÊVÃi`ÃÞÃÌiÊÌÀ>ÃviÀÊ
devices with dry connections.
UÊ iÛiÀÊ«>ViÊÌÀ>Ã«ÀÌÊL>}ÃÊÃìÊ
primary engineering controls.
UÊ >Ê«Ài«>À>ÌÃÊÕÃÌÊLiÊ
surface decontaminated after
compounding is complete and,
while wearing clean gloves, placed
into a sealable bag to contain any
leakage.
UÊ ÊvÀiÃÊ}ÛiÃÊÜiiÛiÀÊ
there is a doubt of cleanliness or
contamination.
UÊ 1ÃiÊ>Ãi«ÌVÊÌiVµÕi°
UÊ Û`Ê«ÀiÃÃÕÀâ}ÊÌiÊVÌiÌÃÊ
of vials if closed-system transfer
devices are not in use.
cally closed system. Spiros and Genie, also

by ICU Medical, Inc., were developed to use
with the CLAVE in order to prepare hazard-
ous drugs with a needle-free system CSTD.
The CLAVE is being used in the CytoCare
system. For more information about the ICU
Medical products, visit their website at http://
setsource.net/index.asp.
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

Feature
Gowns should be worn during compound-

ing, during administration, when handling
waste from patients recently treated with haz-
ardous drugs, and during clean up of hazard-

ous spills. The gowns should be disposable and American Society of Health-System Pharmacists’
made of a polyethylene-coated polypropylene Recommendations for Handling and Compounding
material which is nonlinting and nonabsorb-
ent. They cannot be re-used during the shift Hazardous Nonsterile Hazardous Drugs
like the gowns used for nonhazardous sterile
UÊ >â>À`ÕÃÊ`ÀÕ}ÃÊÃÕ`ÊLiÊ>Lii`ÊÀÊìÌwi`Ê>ÃÊ>â>À`ÕÃÊÌÊ
compounding and should be disposed as con-
ensure proper handling.
taminated waste. All gowns should have closed
fronts, long sleeves, and elastic or knit closed UÊ />LiÌÊ>`ÊV>«ÃÕiÊ`Ã>}iÊvÀÃÊvÊ>â>À`ÕÃÊ`ÀÕ}ÃÊÃÕ`ÊÌÊLiÊ
cuffs. A gown should be changed every three placed in automated packaging or counting machines.
hours during continuous use or when dam- UÊ *iÀÃiÊii`ÊÌÊ`ÕLi}ÛiÊÜÌÊViÌiÀ>«ÞÊ}ÛiÃÊ>`ÊÜi>ÀÊ
aged. The compounder should always wash nonpermeable gowns.
his or her hands after removal and disposal of UÊ
i>ÊiµÕ«iÌÊÃÕ`ÊLiÊì`V>Ìi`ÊÌÊ>â>À`ÕÃÊV«Õ`}Ê>`Ê
gowns. not used in other areas of the pharmacy.
A simple surgical mask does not protect a UÊ
Ì>>Ìi`ÊiµÕ«iÌÊÃÕ`ÊLiÊVi>i`ÊÌ>ÞÊÜÌÊ}>ÕâiÊ
compounder from inhaling hazardous drug saturated with sterile water, further cleaned with detergent,
particles, aerosols, or vapors. A respirator of
sodium hypochlorite (Dakin’s) solution, and neutralizer; then rinsed.
correct size and appropriate to the aerosol size,
Contaminated cleaning materials are disposed as contaminated
particulate or vapor, and concentration of the
airborne drug should be used. According to the waste.
OSHA Respiratory Protection Standard, any UÊ
ÀÕÃ}ÊÌ>LiÌÃÊÀÊ«i}ÊV>«ÃÕiÃÊÃÕ`ÊLiÊ>Ûì`ÊvÊµÕ`Ê
staff member who may use a respirator must be dosage forms are available.
fit-tested and trained on how to use it.18 UÊ
«Õ`}ÊÃÕ`ÊÌ>iÊ«>ViÊÊ>ÊÛiÌ>Ìi`ÊV>LiÌ°
Goggles or safety glasses may not provide UÊ ««À«À>ÌiÊVÌ>iÌ]Êì>VÌÛ>Ì]Ê>`Ê`ÃviVÌÊÌiVµÕiÃÊ
adequate protection. A face shield may be a must be utilized when preparing nonsterile compounds in equipment
suitable alternative because it provides more designated for sterile compounding.
skin protection. UÊ >â>À`ÕÃÊ`ÀÕ}ÃÊÃÕ`ÊLiÊ`Ã«iÃi`ÊÊÌiÊw>Ê`ÃiÊ>`ÊvÀÊ
Shoe and hair covers should be worn during whenever possible. Unit-of-use containers for oral liquids have not
the sterile compounding process, although it
been tested for containment properties.
is probably prudent to wear them during all
hazardous compounding to prevent contami- UÊ ÕÊVÌ>iÀÃÊvÊ>â>À`ÕÃÊ«Ài«>À>ÌÃÊÃÕ`ÊLiÊ`Ã«iÃi`Ê
nation of the compounder’s hair and shoes and maintained in sealable plastic bags to avoid any inadvertent
and contamination of the entire compounding contamination.
laboratory. All coverings should be removed UÊ Ã«Ã>ÊvÊÕÕÃi`ÊÀÊÕÕÃ>LiÊ`Ã>}iÊvÀÃÊvÊ>â>À`ÕÃÊ`ÀÕ}ÃÊ
with gloved hands just prior to leaving the should be performed in the same manner as sterile hazardous drugs
compounding area and disposed of in contami- and waste.
nated waste containers.
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

Feature
used to prepare these compounds. Without suspension is prepared. The final suspension is
the proper equipment or environment, fine

dust formation or leakage may contaminate
the area. Type I BSCs, CACIs, and powder
added to a clean, amber bottle, capped, sealed,
and labeled. The mixing is basically a closed
system and contained within the syringes,
American Society containment hoods are discussed under the minimizing the risk of contaminating the
of Health-System equipment section of this article. If parenteral entire BSC or CACI. All of the used materials
dosage forms are used to prepare the oral liq- can be disposed of in the appropriate hazard-
Pharmacists’ uids, CSTDs should still be used to reconsti- ous waste containers.
Recommended Contents tute and withdraw the drug for compounding. Use an absorbent pad with a waterproof
of Hazardous Spill Kit Use disposable equipment when pos- backing to contain any inadvertent spills or to
sible so that the compounder does not have catch any spilled powder that occurred during
UÊ LÃÀLiÌ]Ê«>ÃÌVL>Vi`Ê to decontaminate the equipment or possibly the opening of capsules or while crushing tab-
sheets or spill pads contaminate the laboratory. There are dispos- lets. The pad will make the cleanup easier. Ev-
UÊ ««À«À>ÌiÊ«iÀÃ>Ê able stirrers, beakers, and funnels available erything can be wrapped up in the pad, placed
protective equipment to through a variety of different compounding in a plastic bag, and disposed of properly.
protect the worker suppliers; therefore, it is not necessary to Although separate PECs are preferable for
UÊ ÌÊi>ÃÌÊÌÜÊ«Ài>Lii`]Ê take any labware into the PEC. For example, sterile and nonsterile hazardous compounding,
sealable, thick plastic disposable, sterile 16-ounce mortar and pestles they can be done in the same PEC as long as
are available through Health Care Logistics. the PEC is decontaminated and disinfected
hazardous waste disposal bags
These mortar and pestles are hard plastic between compounds. Sterile and nonsterile
UÊ Ã«Ã>LiÊÌÜi} and suitable for mixing powders and liquids hazardous compounds should not be prepared
UÊ "iÊ`Ã«Ã>LiÊÃV«ÊvÀÊ together or topical preparations, such as two simultaneously in the same PEC due to the
collecting glass fragments creams together. Although they cannot be particulate contamination that may be generat-
UÊ "iÊ«ÕVÌÕÀiÀiÃÃÌ>ÌÊ used to crush large tablets, most tablets will ed from the nonsterile hazardous compounds.
container for glass fragments disintegrate in water or syrup over a short Currently, there are no United States
UÊ -ÕvwViÌÊÃÕ««iÃÊÌÊ>LÃÀLÊ time period. These tablets can be placed in Pharmacopeial standards for preparing and
1000 mL of fluid the disposable mortar in a PEC, covered with handling nonsterile hazardous compounds. It is
water or syrup, soaked for a few minutes or up to the compounding supervisor or manager
overnight until they disintegrate, and mixed at each institution to develop these handling
into the final suspension. Prior to entering the and compounding procedures based on the

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

Feature
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.

Feature
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.

Feature
TABLE 2. D List of Chemicals25 QUALITY ASSURANCE

Seek input from all healthcare workers who routinely work with
Name Hazardous Waste No. Regulatory Level (mg/L)
hazardous drugs to assess the quality and effectiveness of training, safety,
Arsenic D004 5.0
and prevention programs. Use this information to improve procedures
Barium D005 100.0
and provide the safest possible equipment, devices, and environmental
Cadmium D006 1.0
conditions for minimizing exposure. According to USP <797>, the ef-
Chloroform D022 6.0
fectiveness of a good quality-assurance program should be reassessed at
Chromium D007 5.0
least annually, although considering the risks associated with handling
M-Cresol D024 200.0
hazardous drugs, assessment of these programs, and procedures should
Lindane D013 0.4
be ongoing.
Mercury D009 0.2
Standard operating procedures (SOPs) should be written for all tasks
Selenium D010 1.0
involving handling hazardous drugs and chemicals as part of a good
Silver D011 5.0
quality-assurance program. These SOPs should be readily available for
all of the hospital staff.
Bulk hazardous waste, such as unused hazardous drugs or expired The environment in which hazardous drugs are prepared and admin-
hazardous chemicals should be segregated, and the disposal may be istered should be routinely monitored. Gauges and monitoring devices
managed by internal expertise, such as a hazmat department or through should be checked at least daily to ensure that the compounding room
a commercial or contracted hazardous waste broker. Since the facility is is maintaining a negative-pressure, proper airflow, and ventilation. The
liable for mismanagement of hazardous waste, the hospital administra- room and PECs should be routinely tested for surface contamination.
tor should verify the contractor’s possession and type of license before All of the results should be documented.
the contractor is used by the facility. Hazardous waste must be properly Medical surveillance should be used as part of a good safety and
manifested and transported by a federally permitted hazardous waste health program. It involves collecting and interpreting data to detect
transporter to a federally permitted hazardous waste storage, treatment, changes in the health status of employees that are potentially exposed to
or disposal facility. hazardous drugs. After a baseline of workers’ health is established, they
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Feature
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
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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:
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create their own comprehensive program for pdfs/2004-165.pdf. Accessed April 24, tion of cyclophosphamide and ifosfamide
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.BSLFUJOH
optimizing your
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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.
pay per click search engine marketing complementary marketing

Pay Per Click (PPC) search engine marketing works like an auction Besides SEO and PPC, other online and offline activities can drive
where advertisers bid for placement of their website in the search results traffic to your website. Links from email newsletters, newspaper ads,
page when a web searcher uses their keyword phrases. The two big play- handouts in your pharmacy, social networking sites, blogs, online con-
ers in PPC are Google and Yahoo, and separate campaigns can be devel- sultation forms, seminar registration forms, online refills, and an online
oped for each. The most effective PPC campaigns begin with a business store for recurring purchases (supplements) all encourage visits to your
analysis in order to develop a list of keyword phrases. An individual website. It is important to update your website regularly, as repeat visi-
experienced in SEO will typically develop multiple PPC ads, which tors will appreciate new, current information.

.BSLFUJOH
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: info@storeymarketing.com
Specifically regarding email from pharmaceutical companies:6
t 56% subscribe to hear about new products.

t 47% subscribe to learn about existing products.
t 39% subscribe to help manage a condition affecting them or someone
ŵĂƌŬĞƟŶŐ͘ĐŽŵ
close to them.
t 67% of respondents want to receive personalized content based on
their website activities, condition, or healthcare history. t^/d^ – your ĐƵƐƚŽŵĚĞƐŝŐŶ and new
^ĞĂƌĐŚŶŐŝŶĞKƉƟŵŝǌĞĚĐŽŶƚĞŶƚƌĞŐƵůĂƌůǇ
These statistics have obvious implications for compounding pharma- ƵƉĚĂƚĞĚǁŝƚŚůŝŶŬƐƚŽWƵďDĞĚƌĞĨĞƌĞŶĐĞƐ͘ Online
cies and emphasize the benefit of having an automated function, which ƌĞĮůůƐ͕ĐŽŶƐƵůƚĂƟŽŶĨŽƌŵƐ͕ŶĞǁƐůĞƩĞƌĂƌĐŚŝǀĞƐ͕
allows visitors to sign up on your homepage to receive your free email
newsletter.
ŽŶůŝŶĞƐƚŽƌĞʹǇŽƵŶĂŵĞŝƚʹŽƵƌƉƌŽĨĞƐƐŝŽŶĂůĚĞƐŝŐŶ
ƚĞĂŵĐĂŶĚŽŝƚ͊
conversion power EĞǁƐůĞƩĞƌƐĨŽƌWĂƟĞŶƚƐŽƌWƌĂĐƟƟŽŶĞƌƐ ʹƉƌŝŶƚĞĚ
Once visitors are attracted to your website, the true value comes
or email͕ĐĂŶďĞĐŽŵƉůĞƚĞůǇĐƵƐƚŽŵŝǌĞĚ
in having them engage in a manner that will provide a ROI. When
designing a website, it is important to focus on increasing the conversion ƌŽĐŚƵƌĞƐĂŶĚŽŽŬůĞƚƐ – WƌĂĐƟƟŽŶĞƌǀĞƌƐŝŽŶ
power. It doesn’t matter how much traffic your website receives if no ŝŶĐůƵĚĞƐWƵďDĞĚĂďƐƚƌĂĐƚƐ͕ŽƌĂďďƌĞǀŝĂƚĞĚWĂƟĞŶƚ
one is engaging your services or ordering products. It could simply be
ǀĞƌƐŝŽŶ
that your services are so unique and outstanding that the impression left
by a well-designed website will lead visitors to stop by your pharmacy. ŝƐƉůĂǇƐ͕ĚƐ͕ĂŶŶĞƌƐ
However, you will save staff time and make money, and increase the
value of your website for both you and your patients by adding interac- sŝƐŝƚǁǁǁ͘,ZdŵĂƌŬĞƟŶŐ͘ĐŽŵŽƌ
tive features which will permit visitors to engage 24/7, such as: ǁǁǁ͘^ƚŽƌĞǇDĂƌŬĞƟŶŐ͘ĐŽŵĨŽƌĞǀĞƌǇƚŚŝŶŐǇŽƵŶĞĞĚƚŽ
ƐƵĐĐĞƐƐĨƵůůǇŵĂƌŬĞƚǇŽƵƌĐŽŵƉŽƵŶĚŝŶŐƉƌĂĐƟĐĞ͘
t An online store where your current and prospective patients can buy
recommended supplements, books, skin care, and other products
Ăůů800-270-8878
ĨŽƌŵŽƌĞŝŶĨŽƌŵĂƟŽŶĂŶĚ&ZƐĂŵƉůĞƐ͘
t Consultation forms that can be submitted online
t Online ordering of prescription refills
A professional website designer experienced in SEO who understands

your goals and your clients’ needs can develop and optimize a website
The Compounder’s Choice since 1991.

Poster Presentation Report
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
Abstract This article is an adaptation of an abstract/poster presentation made at the 13th

International Congress on Steroidal Hormones and Hormones & Cancer, Quebec City, Canada
(September 2008), concerning the topic of breast feeding as a contraindication to testosterone
therapy. The purpose of the presentation and this article is to provide a summary of the findings of
a study that was conducted to evaluate maternal absorption of testosterone and its excretion into
breast milk by using three methods of delivery: sublingual drops, vaginal cream, and pellet implant.
Testosterone was measurable in maternal blood by all three methods of delivery. No significant
increase of testosterone was seen in breast milk when testosterone was delivered by vaginal cream,
sublingual drops, or subcutaneous pellet implant. Testosterone was very low in infant blood at
baseline and during testosterone therapy by pellet implant. There were no adverse clinical affects
in the infant after seven months of continuous testosterone therapy to the mother by subcutane-
ous pellet implant. Testosterone delivered by sublingual drops, vaginal cream, and pellet implant
was absorbed but not measurably excreted into breast milk. Testosterone, delivered by a 100-mg
subcutaneous pellet implant, was effective in relieving symptoms of testosterone deficiency and
was not measurably increased in breast milk or measurable in infant serum. Maternal testosterone
therapy is safe for the breast-fed infant. Testosterone by pellet implant may be a safer and more
physiologic alternative to psychotropic medications.

delivered by pellet implant, shows continuous Methodology: Breast Milk

Presentation Topic serum levels above endogenous ranges with Samples of breast milk were analyzed by
Testosterone, delivered by pellet implant,
diurnal variation (Figure 1). Elevated serum ZRT Laboratory, Beaverton, Oregon. Breast
has been successfully used to treat anxiety,
emotional lability, memory loss, depression, testosterone levels, above normal “endog- milk samples (collected into specimen tubes,
and fatigue in women.1-6 These symptoms can enous” ranges, are expected with exogenous labeled, and frozen) were liquid extracted with
be seen in post-partum females. “Breast feed- testosterone, delivered by pellet implant. hexane. After removal of the hexane layer, an
ing” has been listed as a contraindication to Doses of 100 mg and above have been shown additional liquid extraction was performed by
testosterone therapy, despite a paucity of data to relieve symptoms without evidence of major adding acetonitrile to the hexane solution to
to support this recommendation. The Millen- side effects or complications.1,2,27-29 remove nonpolar lipids. After removal of the
nium Wellness Center has previously withheld The mother was monitored for sympto- acetonitrile layer, the solvent was dried under
testosterone therapy from nursing mothers matic improvement (MRS validated survey) nitrogen, and the sample reconstituted in an
until they discontinued breast feeding. and signs of testosterone excess (none). The aqueous buffer. The same procedure was fol-
male infant was monitored for clinical signs of lowed for assay commercially with purchased
testosterone excess (none). whole milk spiked with known amounts of tes-
Summary of Pur- tosterone. Reconstituted samples were assayed
Specimen Collection on a commercially available serum testoster-
pose, Hypothesis, Baseline testosterone levels were obtained one enzyme immunoassay (DRG Internation-
Materials, Meth- from maternal capillary blood (finger stick) al, Inc., Mountainside, New Jersey) following
and breast milk (foremilk). During sublin- the addition of extracted standards and breast
ods, and Results gual and vaginal testosterone therapy, serial
milk samples, and the samples were analyzed
Study Purpose and by ZRT Laboratory, Beaverton, Oregon.
testosterone levels were measured at 2-hour
Hypothesis intervals in maternal capillary blood and breast
The purpose of the study was to evaluate milk. Methodology: Capillary
maternal absorption of testosterone and its With maternal “long-acting” testosterone Bloodspot
excretion into breast milk by three methods of therapy delivered by subcutaneous pellet A minimum of 6 drops of capillary blood
delivery: implant, testosterone levels were measured from the fingertip (or heel of the infant) were
in maternal capillary blood and breast milk collected onto filter paper and allowed to dry.
t Sublingual drops, 1 mg twice daily at once/twice daily intervals. Infant capillary Clinical dried blood spot samples (0.6 cm), stan-
t Vaginal cream, 0.5 mg applied daily in the bloodspot (heel stick) testosterone was moni- dards, and controls were punched from dried
morning tored day 2, day 7, week 4, and month 5. samples and extracted twice with methanol.
t Pellet implant, 100 mg implanted in subcu-
taneous tissue
Based on the pharmacokinetics of drug

FIGURE 1. /iÊ}À>«ÊÃÜÃÊÌiÊ`ÕÀ>ÊÛ>À>ÌÊÛiÀÊ>ÊÓÈÕÀÊ«iÀ`Ê
excretion in breast milk, testosterone was not
expected to be measurably excreted in breast
with estradiol (50 mg) and testosterone (112.5 mg) pellet implants.a
milk (molecular size >200, nonbasic pH,
significant protein binding) or absorbed into
infant blood.7-11 In addition, testosterone has a
low/no intrinsic toxicity.
Materials and Methods

A 34-year-old breast-feeding mother pre-
sented with symptoms of depression, anxiety,
irritability, memory loss, aches, and pains
(Menopause Rating Scale [MRS] validated
survey). Testosterone tested low by capillary
bloodspot (ZRT Laboratory, Beaverton, Or-
egon) and serum. The patient was treated with
testosterone, delivered by compounded prepa-
rations of sublingual drops, vaginal cream, and,
lastly, subcutaneous pellet implant.
Sublingual hormones are known to peak
rapidly in serum and are measurable for up to
4 hours.12 Vaginal hormones have been shown
to be readily absorbed and peak in serum
between 4 and 6 hours.12-26 Testosterone, aMeasured by venous bloodspot (ZRT Laboratory, Portland, Oregon).29

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;
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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
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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.
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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.
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estriol administration on the hypogonadal
woman. Fertil Steril 1978; 30(3): 278–282.
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Quality Control
<
Analytical Methods
< <
Joe Cabaleiro, RPh, BS Pharm
Triangle Compounding Pharmacy
Cary, North Carolina
Quality Control, Quality Assurance, and Quality Improvement—
What is the Difference and

Why Should Compounding
Pharmacies Care?
Abstract
This article provides scenarios of three different pharmacies in the areas of quality
control, quality assurance, and quality improvement. The scenarios show the impor-
tance that each pharmacy placed on a problem of dented capsules and the potential
impact that an unresolved problem can have on a compounding pharmacy’s business.
Although this article focuses on one particular procedure, the purpose of the article is
to help pharmacists understand the difference between quality control, quality assur-
ance, and quality improvement.

Quality Control
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

Quality Control
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.
Suggested Resource >>>>>>>>>

American Society for Quality. [ASQ Website.]
Available at: www.asq.org
Address correspondence to Joe Cabaleiro, RPh, BS
Pharm, Triangle Compounding Pharmacy, 550 New
Waverly Place, Suite 110, Cary, NC 27513. E-mail:
info@trianglecompounding.com

Basics of Compounding
Basics of Compounding: Considerations for Implementing
United States Pharmacopeia Chapter <797> Pharmaceutical
Compounding—Sterile Preparations, Part 14:
Environmental Quality
and Control (Continued)
Claudia C. Okeke, PhD, RPh
Claumek PharmaScience
Rockville, Maryland
Loyd V. Allen, Jr., PhD, RPh

International Journal of Pharmaceutical Compounding
Edmond, Oklahoma
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.

Basics
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.

Basics
COMPOUNDING AREA CLEANING AND DISINFECTING REQUIREMENTS

s (OUSEKEEPINGSURFACESSUCHASWALLSANDCEILINGSARECONSIDEREDTHEhCRITICALvSITESANDREQUIREDISINFECTIONMORE
FREQUENTLYINTHEPRIMARYENGINEERINGCONTROLS0%# THANINTHESECONDARYENGINEERINGCONTROLS3%#
s 3TERILECOMPOUNDINGAREADISINFECTIONMUSTOCCURONAREGULARBASISATTHEINTERVALSOUTLINEDin United States
Pharmacopeia (USP) Chapter <797>.
s #OMPOUNDINGAREASMUSTBEIMMEDIATELYDISINFECTEDWHENSPILLSOCCURORWHENTHEsurfaces are visibly soiled,
or when microbial contamination is known to have been or is suspected of having been introduced into the
compounding areas.
s (EAVILYSOILEDSURFACESREQUIREACLEANUPPRIORTOTHEAPPLICATIONOFTHEDISINFECTANTASoutlined in USP Chapter
<797>.
s #LEANINGPROCEDURESSTARTBYlRSTREMOVINGTHEITEMSFROMALLAREASTOBECLEANEDand surfaces are cleaned by
removing loose materials and residues from spills. Water-soluble solid residues are removed with sterile water
(for injection or irrigation) and low-shedding wipes. Upon completion, the surfaces are wiped with a residue-free
disinfecting agent like sterile 70% isopropyl alcohol (IPA), then allowed to dry before starting the compounding
process. The most critical process is cleaning and disinfecting the PEC area before the preparation of CSPs. The
SURFACESINTHE0%#AREASMUSTBECLEANEDANDDISINFECTEDFREQUENTLYINADDITIONTOTHEPROCESSATTHEBEGINNING
of each work shift, before each batch preparation is started, every 30 minutes during continuous compounding
periods of individual CSPs, when there are spills, and when surface contamination is known or suspected from
procedural breaches. Work surfaces in the SEC areas, including the segregated compounding areas, must be
cleaned and disinfected at least daily.
s 2EMOVEDUSTANDDEBRISWHENNECESSARYFROMSTORAGESITESFORCOMPOUNDINGINGREDIENTSANDSUPPLIESUSINGA
METHODTHATDOESNOTAFFECTTHE3%#AREASAIRQUALITY
s !LLCLEANINGMATERIALSSUCHASWIPERSSPONGESANDMOPSMUSTBENONSHEDDINGPREFERABLYCOMPOSEDOF
SYNTHETICMICROlBERSANDDEDICATEDTOUSEINTHE3%#AREASINCLUDINGTHESEGREGATEDCOMPOUNDINGAREASAND
ONLY removed from the areas for disposals.
s &LOORMOPSARETOBEUSEDFROMTHECLEANESTTOCLEANAREASEGFROMBUFFERAREATOANTE AREAANDTHENTOOUTER
surrounding areas).
s $ISCARDALLCLEANINGTOOLSAFTERONEUSEBYCOLLECTIONINSUITABLEPLASTICBAGS3UCHREMOVALSHOULDBEMADEWITH
minimal agitation.
s )NCASESWHERECLEANINGMATERIALSEGMOPS AREREUSEDWRITTENPROCEDURESMUSTBEDEVELOPEDBASEDON
manufacturers’ recommendations) to ensure that cleaning devices maintain effectiveness and repeated use will not
increase the bioburden of the area being cleaned.
s 3UPPLIESANDEQUIPMENTREMOVEDFROMSHIPPINGCARTONSMUSTBEWIPEDWITHASUITABLEDISINFECTINGAGENTEG
sterile 70% IPA).
s 4HEDISINFECTANTPROCEDUREISASFOLLOWSTHEDISINFECTANTISSPRAYEDORWIPEDONASURFACETOBEDISINFECTEDANDTHE
disinfectant is allowed to dry, during which time the item is not be used for compounding purposes.
s %NTRYPOINTSONBAGSANDVIALSAREWIPEDWITHSMALLSTERILE)0!SWABSTHATARECOMMERCIALLYAVAILABLEIN
individual foil-sealed packages. Then, allow the IPA to dry before piercing stoppers with sterile needles or before
breaking the necks of ampules. The surface of the sterile 70% IPA swabs used for disinfecting entry points of sterile
packages and devices must not touch any other object before contacting the surface of the entry point. Sterile 70%
IPA-wetted gauze pads or other particle-generating materials are not to be used to disinfect the sterile entry points
of packages and devices.
s 7HENSTERILESUPPLIESARERECEIVEDINSEALEDPOUCHESDESIGNEDTOKEEPTHEMSTERILEUNTILOPENINGTHESTERILE
supplies may be removed from the covering pouches as the supplies are introduced into the PEC without the need
to disinfect the individual sterile supply items.
s $ONOTPLACESHIPPINGOROTHEREXTERNALCARTONSINTHE3%#AREAORSEGREGATEDCOMPOUNDINGAREA

Basics
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).
Pressure Differential Monitoring

For pressure differential monitoring (PDM), there must be a pressure
gauge or velocity meter in place to monitor airflow between the buffer
area and the ante-area and between the ante-area and the general envi-
ronment outside the compounding area, per the following equation: #LEANROOMSOLUTIONSTHAT
PDM = airflow buffer/ante-area + airflow ante-area/outer
surrounding area
WONTBREAKTHEBANK
The results must be documented at least every work shift (minimum
frequency shall be at least daily) or by a continuous recording device.
The result must be reviewed by the responsible personnel, and proper
protocols must be in place for adjustments where the pressure does not
meet the requirement. For facilities where low- and medium-risk level
CSPs are prepared, the differential airflow shall maintain a minimum ve-
locity of 0.2 meters per second (40 feet per minute) between buffer area
and ante-area. For the pressure between the ISO Class 7 or buffer area
and the general pharmacy area, it must not be less than 5 Pa (0.02 inch
water column).
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-
EVERYDAYCLEANROOMSUPPLIES
tive actions on an ongoing basis. There must be a sampling plan in place, s&AX s4OLL&REE sWWWPCSCOM

Basics
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.

Basics
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.
Cleaning and Disinfecting the

Compounding Area Address correspondence to Claudia C. Okeke, PhD, RPh, Claumek PharmaScience,
Environmental contact is a major source of microbial contamination 1427 Templeton Place, Rockville, Maryland 20852. E-mail: cvcokeke@gmail.
of CSPs. Pharmacy supervisors and compounding personnel should com
make the minimization of CSP contamination a priority. Frequency of
cleaning the PEC, SEC, and segregated compounding areas should be
ensured by compounding personnel. Additional guidelines for cleaning
and disinfecting can be reviewed in USP Chapter <797>.3 Compound-
ing personnel should be adequately informed and trained on disinfect-
ing products to be used and why. Trained compounding personnel
must develop, implement, and practice the procedures for cleaning and
disinfecting the compounding areas written in the SOPs.
Compounding personnel must clean and disinfect the compound-
ing areas before compounding is performed. There should be a written
SOP on cleaning and disinfecting practices and related policies for the
compounding of CSPs. All compounding personnel must adhere to the
established guidelines for cleaning and disinfecting.
The selection and use of disinfectants in healthcare facilities is
guided by several properties, such as microbicidal activity, inactivation
by organic matter, residue, and shelf life. More highly toxic disinfec-
tants, such as glutaraldehyde, are not used on housekeeping surfaces
(e.g., floors, countertops). Quite a number of disinfectants registered by
the Environmental Protection Agency are one-step disinfectants where
the disinfectant is formulated to be effective in the presence of light to
moderate soiling without a precleaning step.
Included with this article is an environmental quality and con-
trol checklist related to the areas of: placement of PECs, viable and
nonviable environmental air sampling testing, additional personnel
requirements, and cleaning and disinfecting the compounding area. The
information contained on the checklist can be used to determine the sta-
tus of a pharmacy’s activities associated with environmental quality and
control. Additional cleaning and disinfecting requirements are listed in a
sidebar to this article, which may include some of the same information
shown on the checklist but in more detail.
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.

Basics
ENVIRONMENTAL QUALITY AND CONTROL CHECKLIST

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ITEM REQUIREMENTS YES NO COMMENT/SOP

Placement of Primary Engineering Controls (PEC)
PECs (LAFWs, BSCs, CAIs, and CACIs) are located within an ISO
Class 7 buffer area unless an exception is met according to the
chapter.
If an exception is desired, documentation from the manufacturer
THATTHE#!)#!#)WILLMEETTHEREQUIREDSTANDARDSINTHEAREAIN
WHICHITISTOBELOCATEDMUSTBEONlLE
Viable and Nonviable Environmental Air Sampling (ES)
Testing
ES is done under any of the conditions listed UNDERTHE2EQUIRE s #OMMISSIONING
ments column: and certifying of
new facilities and
EQUIPMENT
s !FTERTHEFACILITYOR
ANYEQUIPMENTIS
serviced
s 2EGULARSCHEDULED
RECERTIlCATION
of facilities and
EQUIPMENT
s !SARESPONSETOANY
IDENTIlEDPROBLEMS
with preparations or
PERSONNELTECHNIQUES
s !SARESPONSETO
any issues with
CSPs, observed work
practices, or patient-
related infections as
appropriate
Total particle counts are done no less than every 6 months and
whenever the PEC is relocated or any part of the physical structure
OFTHEBUFFERAREAORTHEANTE AREAHASBEENMODIlED
Monitoring of the pressure differential or airflow between the buffer
area and the ante-area and between the ante-area and the general
environment outside the compounding area is done and recorded at
LEASTEVERYWORKSHIFTTOCONlRMITMEETSTHESTANDARD
SOPs are in place and followed governing an environmental viable
airborne particle testing program.
The sampling plan includes locations within each ISO Class 5
environment and in the ISO Class 7 and 8 areas, as well as in the
segregated compounding areas at greatest risk of contamination.
The sampling plan includes sample location, method of collection,
FREQUENCYOFSAMPLINGVOLUMEOFAIRSAMPLEDANDTHETIMEOFDAY
as related to compounding activities. It also includes action levels.
An appropriate growth medium is documented and used and is
SUPPLEMENTEDWITHADDITIVESASREQUIRED
Individuals involved in air sampling are properly trained and expe-
rienced.
Volumetric collection methods are used in the controlled air envi-
ronments.
Manufacturers recommended procedures are followed when using
commercial air sampling devices.

Basics
ENVIRONMENTAL QUALITY AND CONTROL CHECKLIST CONTINUED

ITEM REQUIREMENTS YES NO COMMENT/SOP
Air sampling is done at least every 6 months.
Proper incubation periods are used for the growth media depending
upon the type of media used and types of microbes being tested.
!PPROPRIATEh!CTION,EVELSvHAVEBEENDETERMINEDBASEDONSAMpling
location and trending over time.
3/0SAREINPLACEANDFOLLOWEDRELATEDTOACTIVITIESREQUIREDWHENAc-
tion Levels are met or exceeded.
Additional Personnel Requirements
No food, drinks, or materials exposed in patient-care and treatment
areas are permitted where components and ingredients of CSPs are
present.
Blood-derived materials or other designated biological material manip-
ulations are clearly separated from routine CSP preparation activities.
Packaged components and supplies are uncartoned and wiped down
with a non-residue generating disinfectant in an ante-area of ISO Class
8, if possible, before transporting into buffer areas.
There is a demarcation between the ante-area and the buffer area.
After entry into the buffer area, provision is made for personnel to
perform antiseptic hand cleansing using an alcohol-based surgical hand
scrub with persistent activity followed by donning of sterile gloves.
Cleaning and Disinfecting the Compounding Area
An appropriate disinfectant solution is selected and is appropriately
used according to the manufacturer’s recommendations.
The work area is cleaned, sanitized, and organized at the beginning of
each work shift.
Disinfection of the immediate work area is repeated using sterile 70%
IPA at the beginning of each work shift, before each batch preparation
is started, every 30 minutes during continuous compounding periods of
individual CSPs, when there are spills, and when surface contamination
is known or suspected.
For cleaning, all materials are removed from the surfaces and the area
appropriately sanitized.
All contact surfaces, including counter tops and supply carts are
cleaned at the beginning of each shift.
At least monthly, storage shelving in the clean area is emptied of all
supplies and then cleaned and sanitized, using approved agents.
Floors in the buffer or clean area are cleaned by mopping once daily,
by appropriately trained personnel, proceeding from the buffer or clean
area to the anteroom area.
Monthly, the walls and ceilings are cleaned and disinfected.
Only approved cleaning agents are used and are rotated appropriately.
All cleaning tools, wipers, mops, sponges are nonshedding and dedi-
cated to the buffer or clean area.
Trash is collected in suitable plastic bags and removed with minimal
agitation.
Precleaning of heavily soiled areas is done as needed.
No shipping or other cartoning material is taken into the buffer or clean
area.
In the anteroom area, storage shelving is emptied of all supplies and
cleaned and sanitized preferably monthly.
These cleaning procedures apply to all risk level operations.
IPA sterile swabs do not contact any surface prior to disinfecting the
sterile entry points of containers, etc. The alcohol is allowed to dry prior
to entering the container.
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

Calculations
Shelly J. Stockton, BS Pharm, PhD, RPh 105 mg testosterone/110 mg lactose = 1 mg testosterone/x
College of Pharmacy x = 1.05 mg lactose
Southwestern Oklahoma State University Total amount of lactose displaced:
Weatherford, Oklahoma 2.44 mg + 0.73 mg + 45.83 mg + 1.05 mg = 50.06 mg
Amount of lactose/capsule:
110 mg - 50.06 mg = 59.94 mg
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.

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Formulations
Alcohol-based Carbomer Gel
The pH of an 0.5% to 1.0% dispersion is in the range of 2.5 to 3.5, and
Rx they have a tapped density of 1.4 g/mL. They are soluble in water and,
after neutralization, in 95% ethanol and glycerin. When carbomers are
For 100 g dispersed in water, an acidic colloidal solution of low viscosity will form,
Isopropyl alcohol 72 mL which will thicken when an alkaline material, such as triethanolamine,
Carbopol 940 500 mg is added. To ease the initial dispersion process, the carbomer should
Triethanolamine 0.7 mL be sprinkled on rapidly agitated water being careful to minimize the
Purified water qs 100 g formation of lumps. Effort should be made to minimize the incorpora-
tion of air bubbles into the gel. Maximum viscosity can generally be
obtained in a pH range of 6 to 11. These gels should be protected from
METHOD OF PREPARATION light and should contain an antimicrobial preservative. Some preserva-
1. Calculate the required quantity of each ingredient for the total tives, such as benzalkonium chloride, benzoic acid, and sodium benzoate
amount to be prepared. can actually decrease the viscosity of the dispersion. These gels can be
2. Weigh and/or measure each ingredient accurately. autoclaved.4
3. Place about 28 mL of purified water on a magnetic mixer and
stir rapidly. Triethanolamine (C6H15NO3, MW 149.19, TEA, trolamine) is an
4. Add the isopropyl alcohol and mix well. alkalizing and emulsifying agent. It occurs as a variable mixture of
4QSJOLMFUIF$BSCPQPMTMPXMZPOUPUIFTVSGBDFBOEBMMPXUP alkanolamines and is a clear, colorless to pale yellow-colored viscous
hydrate. liquid with a slight ammoniacal odor. Its specific gravity is about 1.120
6. Add the triethanolamine slowly and mix to form the gel. to 1.128 g/mL, and it has a pH of 10.5 in a 0.1N aqueous solution. It is
7. Add sufficient purified water to final weight and mix well. miscible with water, 95% ethanol, methanol, and acetone and is soluble
1BDLBHFBOEMBCFM in chloroform.5
PACKAGING Purified water is water that is obtained by distillation, ion exchange, re-
Package in tight, light-resistant containers.1 verse osmosis, or some other suitable process. Water has a specific grav-
ity of 0.9971 at room temperature, a melting point at 0°C, and a boiling
LABELING point at 100ºC. It is miscible with most polar solvents and is chemically
Keep out of reach of children. Use only as directed. For external use stable in all physical states (ice, liquid, steam).6
only.
REFERENCES
6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO *ODUSP Pharmacists’
STABILITY
PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$PO
A beyond-use date of up to 6 months can be used for this preparation.1
vention, Inc.; 2008: 775–779.
"MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSQFSGPSNJOHQIZTJ
USE
cal quality assessment of ointments/creams/gels. IJPC 1998; 2(4):
Alcohol-based carbomer gels are used as vehicles for topical application.
308–309.
.D$PZ$1*TPQSPQZMBMDPIPM*O3PXF3$ 4IFTLFZ1+ 0XFOT
QUALITY CONTROL 4$ FETHandbook of Pharmaceutical Excipients. 5th ed. Washing-
Quality-control assessment can include theoretical weight compared ton, DC: American Pharmaceutical Association; 2006: 371–373.
to actual weight, pH, specific gravity, active drug assay, color, clarity, ,PMFOH++ .D(JOJUZ+8$BSCPNFS*O3PXF3$ 4IFTLFZ1+
texture-surface, texture-spatula spread, appearance, feel, rheological 0XFO4JBO FETHandbook of Pharmaceutical Excipients. 5th ed.
properties, and physical observations.2 Washington, DC: American Pharmaceutical Association; 2006:
111–115.
DISCUSSION (PTLPOEB43 -FF+$5SJFUIBOPMBNJOF*O3PXF3$ 4IFTLFZ
Isopropyl alcohol (C3H8O, MW 60.10, isopropanol) is a clear, colorless, 1+ 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
mobile, volatile flammable liquid with a characteristic odor resembling Washington, DC: American Pharmaceutical Association; 2006:
a mixture of ethanol and acetone, with a bitter taste. Isopropyl alcohol 794–795.
boils at 82.4ºC and has a specific gravity of 0.786. It is miscible with (BMJDIFU-:8BUFS*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
ethanol, glycerin, and water; soluble in acetone; and insoluble in salt Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
solutions. It should be stored in a cool place.3 American Pharmaceutical Association; 2006: 802–806.
Carbopol 940 is a carbomer. Carbomers are synthetic, high molecular

weight polymers. They are composed of acrylic acid cross-linked with
either allyl sucrose or allyl ethers of pentaerythritol and occur as white-
colored, fluffy, acidic, hygroscopic powders with a slight characteristic
odor. The molecular weight of carbopol 940 is approximately 4 × 106.

Formulations
Benzoyl Peroxide 10% Gel
in acetone and ether. It possesses mild antibacterial properties, is mildly

Rx irritant, and exerts moderate keratolytic and antiseborrheic actions.2
For 100 g
Carbopol 934 is a carbomer. Carbomers are synthetic, high molecular
Benzoyl peroxide 10 g weight polymers. They occur as white-colored, fluffy, acidic, hygro-
Carbopol 934 1 g scopic powders with a slight characteristic odor. The molecular weight
Propylene glycol 5 g of carbopol 934 is approximately 3 × 106. When carbomers are dispersed
Triethanolamine qs in water, an acidic colloidal solution of low viscosity will form, which
Purified water qs 100 g will thicken when an alkaline material, such as triethanolamine, is added.
Maximum viscosity can generally be obtained in a pH range of 6 to 11.4
METHOD OF PREPARATION
1. Calculate the required quantity of each ingredient for the total Propylene glycol (C3H8O2, MW 76.09) occurs as a clear, colorless, vis-
amount to be prepared. cous, practically odorless liquid with a sweet taste, somewhat resembling
2. Weigh and/or measure each ingredient accurately. glycerin. It has a specific gravity of 1.038 g/mL and is miscible with
3. Blend the benzoyl peroxide with the propylene glycol and about acetone, 95% ethanol, glycerin, and water. It is not miscible with fixed
20 mL of purified water and mix well. oils or light mineral oil. It will, however, dissolve some essential oils.5
4. Add purified water to about 90 g and mix well.
5. Incorporate the Carbopol 934 slowly and mix well. Triethanolamine (C6H15NO3, MW 149.19, TEA, trolamine) is an
6. Add the triethanolamine slowly until the desired viscosity is alkalizing and emulsifying agent. It occurs as a variable mixture of
obtained. alkanolamines and is a clear, colorless to pale yellow-colored viscous
7. Add sufficient purified water to final weight and mix well. liquid with a slight ammoniacal odor. Its specific gravity is about 1.120
1BDLBHFBOEMBCFM to 1.128 g/mL and has a pH of 10.5 in a 0.1N aqueous solution. It is
miscible with water, 95% ethanol, methanol, and acetone and is soluble
in chloroform.6
PACKAGING
Package in tight, light-resistant containers.1
Purified water is water that is obtained by distillation, ion exchange,
reverse osmosis, or some other suitable process. Water has a specific
LABELING
gravity of 0.9971 at room temperature, a melting point at 0°C and a boil-
Keep out of reach of children. Use only as directed. For external use
ing point at 100ºC.7
only.
REFERENCES
STABILITY 6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO *ODUSP Pharmacists’
A beyond-use date of 30 days can be used for this preparation.1 PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$PO
vention, Inc.; 2008; 775–779.
USE </PBVUIPSMJTUFE>5PQJDBMESVHT*O(FOOBSP+3 FERemington:
Benzoyl peroxide 10% gel has been used in the treatment of acne.2 The Science and Practice of Pharmacy. 21st ed. Baltimore, MD:
-JQQJODPUU8JMMJBNT8JMLJOT
QUALITY CONTROL "MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSQFSGPSNJOHQIZTJ
Quality-control assessment can include theoretical weight compared cal quality assessment of ointments/creams/gels. IJPC 1998; 2(4):
to actual weight, pH, specific gravity, active drug assay, color, clarity, 308–309.
texture-surface, texture-spatula spread, appearance, feel, rheological ,PMFOH++ .D(JOJUZ+8$BSCPNFS*O3PXF3$ 4IFTLFZ1+
properties, and physical observations.3 0XFO4JBO FETHandbook of Pharmaceutical Excipients. 5th ed.
Washington, DC: American Pharmaceutical Association; 2006;
DISCUSSION 111–115.
Benzoyl peroxide gel is used in the treatment of mild acne vulgaris 0XFO4$ 8FMMFS1+1SPQZMFOFHMZDPM*O3PXF3$ 4IFTLFZ
and acne rosacea. It is also used in the treatment of decubital and stasis 1+ 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
ulcers. Upon initial application, it may cause stinging or burning for a Washington, DC: American Pharmaceutical Association; 2006:
brief time and later these effects mostly disappear. It can bleach hair and 624–626.
fabrics. Additional precautions can be found in reference texts.2 (PTLPOEB43 -FF+$5SJFUIBOPMBNJOF*O3PXF3$ 4IFTLFZ
1+ 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
Benzoyl peroxide (C14H10O4, MW 242.23) contains between 65% Washington, DC: American Pharmaceutical Association; 2006:
and 82% of benzoyl peroxide and about 26% water for the purpose of 794–795.
reducing flammability and shock sensitivity. It occurs as a white, granu- (BMJDIFU-:8BUFS*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
lar powder with a characteristic odor. It melts at about 104ºC and may Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
explode with heat. It is sparingly soluble in water or alcohol and soluble American Pharmaceutical Association; 2006: 802–806.

Formulations
Clindamycin 100-mg Vaginal Suppositories
practically odorless and has a bitter taste. It is freely soluble in water and
Rx slightly soluble in dehydrated alcohol.1
For each suppository Fattibase (fatty-acid base) is a preblended suppository base that is used
Clindamycin phosphate (equivalent to 100 mg) 112 mg when a fatty-acid base is preferred, occurring as an opaque white solid.
Fatty-acid base or cocoa butter qs It contains triglycerides derived from palm, palm kernel, and coconut
oils with self-emulsifying glyceryl monostearate and polyoxyl stearate
Note: It is necessary to calibrate the specific mold to be used to accommodate the base as emulsifying and suspending agents. It is stable, has a bland taste and
used in the preparation. odor, and a controlled melting range. It is widely used as a cocoa butter
replacement for suppositories, lipsticks, and lip balms. It has a melting
METHOD OF PREPARATION point between 35ºC and 37ºC and a specific gravity of 0.890.3
1. Calculate the required quantity of each ingredient for the total
amount to be prepared. Cocoa butter (Theobroma oil) is a yellowish or white-colored brittle
2. Weigh and/or measure each ingredient accurately. solid with a slight odor of cocoa. It is derived from natural sources and is
3. Melt the fatty-acid base or cocoa butter, using low heat, at about composed primarily of triglycerides of saturated and unsaturated fatty
37ºC to 40ºC. acids. It melts between 31ºC and 34ºC; is freely soluble in chloroform,
4QSJOLMFUIFDMJOEBNZDJOQIPTQIBUFPWFSUIFNFMUFECBTFBOE ether; and slightly soluble in 95% ethanol. Heating cocoa butter to a
mix well. temperature greater than 36ºC results in a lowering of the solidification
5. Pour into suitable molds, cool, and trim, if necessary. point due to its polymorphic nature and the formation of a metastable
1BDLBHFBOEMBCFM form. It should be stored at temperatures less than 25ºC. It is used as a
suppository base and is also a major ingredient in chocolate.4
PACKAGING
Package in tight, light-resistant containers.1 REFERENCES
LABELING PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$PO
Keep out of reach of children. Use only as directed. Store in a refrigerator. vention, Inc.; 2008: 131, 775–779, 1431.
STABILITY cal quality assessment of suppositories, troches, lollipops and
A beyond-use date of up to 6 months can be used for this preparation.1 TUJDLTIJPC 1999; 3(1): 56–57.
'BUUJCBTF<QSPEVDUJOGPSNBUJPO>.JOOFBQPMJT ./1BEEPDL
USE Laboratories, Inc.
Clindamycin vaginal suppositories have been used in the treatment of 4. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed.
bacterial vaginosis. Remington: The Science and Practice of Pharmacy. 19th ed. Easton,
1".BDL1VCMJTIJOH$PNQBOZ
QUALITY CONTROL
Quality-control assessment can include weight, specific gravity, active
drug assay, color, texture of surface, appearance, feel, melting test, dis-
solution test, physical observation, and physical stability.2
DISCUSSION
Generally, polyethylene glycol bases are used vaginally but in some
situations, a fatty-acid base of cocoa butter base may be indicated, as
presented here.
Clindamycin is a semisynthetic antibiotic that is a derivative of lincomy-

cin. It is used in the treatment of serious infections caused by susceptible
gram-positive bacteria and susceptible anaerobic bacteria. It is used in
the treatment of bacterial vaginosis (Haemophilus vaginitis, Gardnerella
vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic
vaginosis). It is used intravaginally as a cream or as suppositories. The
formula presented here can be modified in strength, and the base can be
changed dependent upon the needs of the patients.
Clindamycin phosphate (C18H34ClN2O8PS, MW 504.97) occurs as

a white to off-white, hygroscopic, crystalline powder. It is odorless or

Formulations
Dexamethasone and Furosemide Injection
properties. It is used in the treatment of shock, cerebral edema, allergic

Rx For 10 mL
conditions, inflammatory diseases, bacterial meningitis, and tuberculous
meningitis, and is used in the prevention of hyaline membrane disease
in premature infants and of cancer chemotherapy-induced nausea and
Dexamethasone sodium phosphate 10 mg
vomiting.5
Furosemide sodium 50 mg
0.9% Sodium chloride injection qs 10 mL
Furosemide (C12H11ClN2O5S, MW 330.74, frusemide) occurs as a
white to slightly yellow, odorless, crystalline powder with a pKa of 3.9.
Note: This formulation should be prepared according to strict aseptic compound- It is practically insoluble in water. Furosemide, a sulfonamide-type, loop
ing technique in a laminar airflow hood in a cleanroom or via isolation barrier diuretic, is used in the treatment of edema associated with a number of
technology by a compounding pharmacist who is validated in aseptic compounding. disorders, including congestive heart failure, nephrotic syndrome, and
This is a low-risk preparation. hepatic cirrhosis; it also has been an adjunct in the treatment of acute
pulmonary edema. It is freely soluble in solutions of alkali hydroxides
METHOD OF PREPARATION and sparingly soluble in alcohol. It is subject to photodegradation by
1. Calculate the required quantity of each ingredient for the total several mechanisms; consequently, it should be preserved in light-resis-
amount to be prepared. tant containers. This photodegradation is minimized at pH 7, and the
2. Weigh and/or measure each ingredient accurately. degradation rate increases as the pH becomes more acidic or basic. The
3. Withdraw the required quantity of dexamethasone sodium phos- injection has a pH in the range of 8.0 to 9.3 and contains not more than
phate injection and place in a sterile vial. 3.6 USP Endotoxin Units per mg of furosemide.1
4. Withdraw the required quantity of furosemide sodium injection
and add to the sterile vial and mix. 0.9% Sodium chloride injection contains not less than 95.0% and not
8JUIESBXUIFSFRVJSFERVBOUJUZPGTPEJVNDIMPSJEFJOKFD more than 105.0% of the labeled amount of sodium chloride in water
tion to complete the required volume and add to the sterile vial for injection. It has a pH between 4.5 and 7.0 and contains no added
and mix. antimicrobial agents. Sodium chloride solutions are chemically and
6. Withdraw the solution into polypropylene syringe(s) and label. physically stable. They can be sterilized by filtration or autoclaving.
Aqueous sodium chloride solutions will react to form precipitates with
PACKAGING silver, lead, and mercury salts. When mixed with strong oxidizing agents,
Package in tight, light-resistant containers.1 chlorine can be liberated from acidified sodium chloride solutions.
Sodium chloride is soluble in water to the extent of 1 g in 2.8 mL water,
LABELING and is slightly soluble in alcohol (1 g in 250 mL of 95% ethanol).1,6
Keep out of reach of children. Use only as directed. For professional use
only. REFERENCES
STABILITY PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$POWFO
As a low-risk preparation, if no sterility testing program is in place, a tion, Inc.; 2008: 148, 186, 775–779, 975–994, 1434, 1439.
beyond-use date of 48 hours when stored at room temperature can be /FHSP4 3FOEPO"- "[VBSB.-FUBM$PNQBUJCJMJUZBOETUBCJMJUZ
used for this preparation.1 of furosemide and dexamethasone combined in infusion solutions.
Arzneimittelforschung 2006; 56(10): 714–720.
"MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSQBSUJDVMBUFUFTUJOHGPS
If a sterility testing program is in place, a beyond-use date of 5 days can
sterile products. IJPC 1998; 2(1): 78.
be used for this preparation when stored at either room or refrigerated
"MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSF2VBMJUZBTTFTTNFOUGPS
temperature.1,2 injectable solutions. IJPC 1999; 3(5): 406–407.
5. McEvoy GK. AHFS Drug Information–2008. Bethesda, MD: Ameri-
QUALITY CONTROL DBO4PDJFUZPG)FBMUI4ZTUFN1IBSNBDJTUTm
Quality-control assessment can include weight/volume, physical obser- $BCMF$(4PEJVNDIMPSJEF*O,JCCF") FEHandbook of Pharma-
vation, pH, specific gravity, osmolality, assay, color, clarity, particulate ceutical Excipients. 3rd ed. Washington, DC: American Pharmaceuti-
matter, sterility, and pyrogenicity.3,4 cal Association; 2000: 478–481.
DISCUSSION
Dexamethasone sodium phosphate (C22H28FNa2O8P, MW 516.40)
occurs as a white or slightly yellow, crystalline powder. It is odorless or
has a slight odor of alcohol and is very hygroscopic. It is freely soluble
in water and slightly soluble in alcohol.1 The injection has a pH between
7.0 and 8.5, and it contains not more than 31.3 USP Endotoxin Units per
mg of dexamethasone phosphate. Dexamethasone is an anti-inflammato-
ry and immunosuppressant agent with only minimal mineralocorticoid

Formulations
Instant Voice
solvent in topical products (60% to 90% concentration). Alcohol USP
refers to 95% ethanol, and dehydrated alcohol refers to 99.5% alcohol.
Rx Its specific gravity is between 0.812 and 0.816, and its boiling point is
78.15°C. It is miscible with chloroform, glycerin, and water, and its solu-
For 100 mL
Menthol 300 mg tions may be sterilized by autoclaving or by filtration. It should be stored
Alcohol 95% 20 mL in a cool place. It is incompatible with oxidizing materials in acidic
Honey 30 mL conditions. With alkalies, it may darken in color. When added to aqueous
Syrup qs 100 mL solutions of organic salts or acacia, they may precipitate. Alcohol is in-
compatible with aluminum containers; it may interact with some drugs.4
Note: It is necessary to calibrate the specific mold to be used to accommodate the base Honey (clarified honey, strained honey) is the sugar secretion that is
used in the preparation. deposited in the honeycomb by bees, Apis mellifera, Linne’ (Fam Apidae).
This secretion must be free from foreign substances such as insect parts,
METHOD OF PREPARATION leaves, and other materials, but may actually contain pollen grains.
1. Calculate the required quantity of each ingredient for the total Honey is actually one of the oldest medicinal products, being used for
amount to be prepared. many ailments throughout history, as well as one of the oldest foods. It
2. Weigh and/or measure each ingredient accurately. contains about 62% to 83% invert sugar, sucrose 0% to 8% and 0.26%
3. Dissolve the menthol in the alcohol. to 7% dextrin. It occurs as a thick, syrup liquid of a light yellowish to
4. Add the honey and mix well. reddish brown color that is translucent when fresh but often becomes
5. Add sufficient syrup to volume and mix well. opaque and granular through crystallization of the dextrose. It has a
1BDLBHFBOEMBCFM characteristic odor and a sweet, faintly acrid taste. Its use is primarily as
a sweetening agent.5
PACKAGING
Package in tight, light-resistant containers.1 Syrup (simple syrup) is a clear, sweet vehicle used as a sweetening agent
and the base for many flavored and medicated syrups. It contains 85%
LABELING w/v sucrose in water and has a specific gravity of not less than 1.30.
Keep out of reach of children. Use only as directed. It is generally self-preserving as long as the sucrose concentration is
maintained sufficiently high. Preferably, it is prepared without the use of
STABILITY heat but can be prepared by the use of boiling water. It should be stored
A beyond-use date of up to 6 months can be used for this preparation.1 in tight containers, preferably in a cool place.1
USE REFERENCES
This preparation has been used to enable actors and speakers to perform 1. United States Pharmacopeial Convention, Inc. USP Pharmacists’
when experiencing throat irritation. Pharmacopeia. 2nd ed. Rockville, MD: US Pharmacopeial Convention,
Inc.; 2008: 326, 775–779, 1462.
QUALITY CONTROL 2. Allen LV Jr. Standard operating procedure for quality assessment of
Quality-control assessment can include weight/volume, pH, specific oral and topical liquids. IJPC 1999; 3(2): 146–147.
gravity, active drug assay, color, clarity, rheological properties/pour- 3. Langdon BA, Mullarney MP. Menthol. In: Rowe RC, Sheskey PJ,
ability, physical observation, and physical stability (discoloration, foreign Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed. Washing-
materials, gas formation, mold growth).2 ton, DC: American Pharmaceutical Association; 2006: 459–461.
4. Owen SC. Alcohol. In: Rowe RC, Sheskey PJ, Owen SC, eds. Handbook
DISCUSSION of Pharmaceutical Excipients. 5th ed. Washington, DC: American Phar-
Menthol (C10H20O, MW 156.27) is an alcohol obtained from diverse maceutical Association; 2006: 18–20.
mint oils or is synthetically prepared. It may be levorotatory, from 5. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Rem-
natural or synthetic sources, or racemic. It should be preserved in tight ington: The Science and Practice of Pharmacy. 21st ed. Baltimore, MD:
containers, preferably at controlled room temperature. It melts between Lippincott Williams & Wilkins; 2006: 1092.
41ºC and 44ºC. It occurs as colorless, hexagonal crystals, usually needle-
like, or in fused masses, or as a crystalline powder. It has a pleasant,
peppermint-like odor. It is slightly soluble in water and very soluble in
alcohol. It is freely soluble in fixed and volatile oils.3
Alcohol (C2H5OH, MW 46.07, ethyl alcohol, ethanol, grain alcohol)

is a clear, colorless mobile and volatile liquid with a slight, character-
istic odor and a burning taste. It is used as an antimicrobial preserva-
tive (>10% concentration), disinfectant (60% to 90% concentration),
solvent in injectable and oral liquids (variable concentration), and as a

Formulations
Moxifloxacin 20-mg/mL Oral Liquid
cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan,
Rx For 100 mL
sodium phosphate, and citric acid as buffering agents; simethicone as
an antifoaming agent; and potassium sorbate and methylparaben as
preservatives.5
Moxifloxacin 2 g
Ora-Plus 50 mL Ora-Sweet syrup is a flavoring vehicle for oral extemporaneous prepa-
Ora-Sweet or Ora-Sweet SF qs 100 mL rations. It is flavored with a citrus-berry flavor blend and contains glyc-
erin and sorbitol to prevent "cap-lock," problems associated with many
syrups. It is buffered to a pH of approximately 4.2 and has an osmolality
METHOD OF PREPARATION of about 3240 mOsm/kg. It contains purified water, sucrose, glycerin,
1. Calculate the required quantity of each ingredient for the total sorbitol (5%), flavoring, sodium phosphate, and citric acid as buffering
amount to be prepared. agents; and potassium sorbate and methylparaben as preservatives.6
2. Weigh and/or measure each ingredient accurately.
3. Weigh the moxifloxacin powder or obtain the required number Ora-Sweet SF is a sugar-free, alcohol-free flavoring vehicle for oral
of tablets and pulverize in a mortar. extemporaneous preparations. It is a syrup flavored with a citrus-berry
"EEBCPVUN-PGUIF0SB1MVTBOENJYVOUJMBTNPPUIQBTUF flavor blend. It is buffered to a pH of approximately 4.2 and may be
is formed. used alone or in combination with other vehicles. It will tolerate a dilu-
"EEUIFSFNBJOEFSPGUIF0SB1MVTBOENJYXFMM tion to 50% with dissolved actives in water or suspending agents and
"EEFJUIFSUIF0SB4XFFUPSUIF0SB4XFFU4'UPWPMVNFBOE still retain an acceptable taste. It has an osmolality of 2150 mOsm/kg. It
mix well. contains water, sodium saccharin, xanthan gum, glycerin, sorbitol, citric
1BDLBHFBOEMBCFM acid, and sodium citrate as buffers; methylparaben, propylparaben, and
potassium sorbate as preservatives; and flavoring agents.7
PACKAGING
Package in tight, light-resistant containers.1 REFERENCES
LABELING PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$POWFO
Keep out of reach of children. Use only as directed. Shake well. tion, Inc.; 2008: 775–779.
)VUDIJOTPO%+ +PIOTPO$& ,MFJO,$4UBCJMJUZPGFYUFNQPSBOF
STABILITY ously prepared moxifloxacin oral suspensions. Am J Health Syst
A beyond-use date of up to 90 days when stored at room temperature Pharm 2009; 66(7): 665–667.
can be used for this preparation.1,2 "MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSRVBMJUZBTTFTTNFOU
of oral and topical liquids. IJPC 1999; 3(2): 146–147.
USE (FMPOF4 0%POOFMM+""OUJJOGFDUJWFT*O(FOOBSP"3 FE Rem-
Moxifloxacin oral liquid has been used in the treatment of susceptible ington: The Science and Practice of Pharmacy. 21st ed. Baltimore, MD:
infections in patients that cannot take an oral solid dosage form. -JQQJODPUU8JMMJBNT8JMLJOT
0SB1MVT<QSPEVDUJOGPSNBUJPO>.JOOFBQPMJT ./1BEEPDL-BCP
QUALITY CONTROL ratories, Inc.
0SB4XFFU<QSPEVDUJOGPSNBUJPO>.JOOFBQPMJT ./1BEEPDL
Quality-control assessment can include weight/volume, pH, specific
Laboratories, Inc.
gravity, active drug assay, color, clarity, rheological properties/pour-
0SB4XFFU4'<QSPEVDUJOGPSNBUJPO>.JOOFBQPMJT ./1BEEPDL
ability, physical observation, and physical stability (discoloration, foreign
Laboratories, Inc.
materials, gas formation, mold growth).3
DISCUSSION
Moxifloxacin (C21H24FN3O4.HCl, MW 437.89) is an 8-methoxy
fluoroquinolone with enhanced activity against gram-positive organisms
and moderate anti-anaerobic activity. It is not clinically active against
Pseutomonas aeruginosa. It is used in the treatment of upper and lower
respiratory tract infections. It occurs as slightly yellow to yellow crystals
with a melting point of about 325ºC. Commercially, it is available in oral
and parenteral dosage forms.4
Ora-Plus is an oral suspending vehicle that accepts dilution of up to

50% or more with water, flavoring agents, or syrups and still retains its
suspending properties. It has a pH of approximately 4.2 and an osmolal-
ity of about 230 mOsm/kg. It is thixotropic with a viscosity of approxi-
mately 1000 cps at 25ºC. It contains purified water, microcrystalline

Formulations
Mupirocin 1% (20-mg) Vaginal Suppository
The drug is commercially available as mupirocin calcium 2% cream,

Rx mupirocin 2% calcium nasal ointment (base of paraffin and glycerin es-
For each suppository ters mixture), and mupirocin 2% ointment (Polyethylene Glycol Oint-
Mupirocin 20 mg ment NF). Mupirocin calcium 2.15% is equivalent to mupirocin 2%.3,4
Polybase qs 2 g
Polybase is a preblended water-soluble, water-miscible suppository base
consisting of a homogenous mixture of various molecular weight poly-
Note: It is necessary to calibrate the mold to be used for this preparation and, if ethylene glycols. It contains polyethylene glycols (average molecular
necessary, adjust the quantity of Polybase to be used. weight about 3440) and polysorbate 80. It is used in the preparation of
suppositories and lozenges where a water soluble or water-miscible base
is preferred. It releases its medication by dissolving in the local fluids. It
is a white solid with a mild polyethylene glycol odor and has a specific
gravity of 1.177. Products prepared from this base should not be stored
amount to be prepared.
or dispensed in polystyrene containers.5
2. Weigh and/or measure each ingredient accurately.
4MPXMZ IFBUUIF1PMZCBTFUPBCPVU$VOUJMNFMUFE
REFERENCES
4QSJOLMFPOUIFNVQJSPDJOBOENJYXFMM
5. Pour into molds, cool, and trim, if necessary.
1BDLBHFBOEMBCFM
vention, Inc.; 2008: 775–779.
PACKAGING
cal quality assessment of suppositories, troches, lollipops and
Package in tight, light-resistant containers.1
TUJDLTIJPC 1999; 3(1): 56–57.
3. McEvoy GK. AHFS Drug Information–2008. Bethesda, MD:
LABELING "NFSJDBO4PDJFUZPG)FBMUI4ZTUFNT1IBSNBDJTUT
Keep out of reach of children. Use only as directed. 3500–3503.
4. [No author listed.] Physicians Desk Reference. 63rd ed. Montvale,
STABILITY /+1IZTJDJBOT%FTL3FGFSFODF*ODm
A beyond-use date of up to 6 months can be used for this preparation.1 1PMZCBTF<QSPEVDUJOGPSNBUJPO>.JOOFBQPMJT ./1BEEPDL
Laboratories, Inc.
USE
Mupirocin vaginal suppositories have been used in the treatment of
susceptible vaginal infections.
QUALITY CONTROL
Quality-control assessment can include weight, specific gravity, active
drug assay, color, texture of surface, appearance, feel, melting test, dis-
solution test, physical observation, and physical stability.2
DISCUSSION
Mupirocin is an antibiotic with a narrow spectrum of activity primar-
ily against gram-positive bacteria. It is used topically for the treatment
of impetigo caused by Staphylococcus aureus (S. Aureus) and group A
β-hemolytic streptococci (Streptococcus pyogenes). It is used intranasally to
temporally eradicate S. Aureus, including methicillin-resistant S. Aureus
(MRSA). Mupirocin is generally well tolerated, and most adverse effects
from topical application are mild, transient, local reactions requiring
discontinuation of the drug in less than 1% of patients.3
Mupirocin (C26H44O9, MS 500.62) requires a vehicle pH between 4 and

9, as it is inactivated outside that range. Mupirocin ointment prepara-
tions are incompatible with salicylic acid 2% and should not be mixed
with water-containing formulations or vehicles such as Aquaphor or coal
tar solution. The mupirocin ointment is compatible with hydrocortisone
(1%), phenol (3%), sulfur (2%), and triamcinolone acetonide (0.1%)
and stable for at least 28 days when stored at room temperature.3

Formulations
Riley Butt Cream
Zinc oxide 20% ointment contains 20% zinc oxide in 15% mineral
Rx oil and 65% white ointment. Zinc oxide (ZnO, MW 81.39) occurs as
a very fine, odorless, amorphous, white or yellowish white powder,
For 97.5 or 112.5 g free from gritty particles. It is insoluble in water and in alcohol but is
Nystatin topical powder 15 g soluble in dilute acids. Zinc oxide is a mild astringent and is used topi-
Nystatin cream 15 g cally as a soothing and protective application in eczema and mild skin
Zinc oxide 20% ointment 30 g disorders.4
A & D ointment 30 g
Dibucaine 1% ointment 7.5 g A & D ointment generally contains fish liver oil and cholecalciferol in
Benzoin tincture 0.15 mL an ointment vehicle.
Hydrocortisone 1% Cream (Optional) 15 g
Dibucaine 1% ointment (Nupercainal) contains dibucaine in an oint-
ment vehicle of acetone, sodium bisulfite, lanolin, mineral oil, and white
METHOD OF PREPARATION petrolatum.
amount to be prepared. Benzoin is the balsamic resin obtained from Styrax benzoin (Dryander) or
2. Weigh and/or measure each ingredient accurately. Styrax paralleloneurus (Perkins), known in commerce as Sumatra Benzoin,
3. Mix the nystatin cream and the hydrocortisone cream (if used) as well as from other sources. Sumatra Benzoin occurs as blocks or
and incorporate the nystatin topical powder. Mix thoroughly. lumps of varying size made up of compacted tears, with a reddish brown,
4. Incorporate the zinc oxide ointment, A & D ointment, and dibu- reddish gray, or grayish brown resinous mass. Both Sumatra Benzoin
caine ointment and mix well. and Siam Benzoin are yellowish to rusty-brown externally and milky
5. Incorporate the benzoin tincture and mix well. white when fractured. They are hard and brittle at room temperature
1BDLBHFBOEMBCFM but will soften when heated. They have an aromatic and balsamic odor
and an aromatic and slightly acrid taste. The tincture and the compound
PACKAGING tincture have many uses and are often used in combination with zinc
Package in tight, light-resistant containers.1 oxide in baby ointments. Other applications are in the treatment of skin
irritations, ulcers, bedsores, cracked nipples, and fissures of the lips and
LABELING anus. It can be mixed with glycerin and water and used for throat and
Keep out of reach of children. Use only as directed. bronchial inflammations.5
STABILITY Hydrocortisone 1% cream contains hydrocortisone in a cream vehicle.

A beyond-use date of 30 days can be used for this preparation.1 Hydrocortisone (C21H30O5, MW 362.46, Cortisol, Compound F) is a
corticosteroid secreted by the adrenal cortex. It occurs as a white to
USE practically white, odorless, crystalline powder. It is very slightly soluble
Riley Butt Cream is used in the treatment of diaper rash and similar skin in water and sparingly soluble in alcohol.6
conditions.
REFERENCES
QUALITY CONTROL 6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO *ODUSP Pharmacists’
Quality-control assessment can include theoretical weight compared PharmacopeiaOEFE3PDLWJMMF .%641IBSNBDPQFJBM$PO
to actual weight, pH, specific gravity, active drug assay, color, texture- vention, Inc.; 2008: 775–779.
surface, texture-spatula spread, appearance, feel, rheological properties, "MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSQFSGPSNJOHQIZTJ
and physical observations.2 cal quality assessment of ointments/creams/gels. IJPC 1998; 2(4):
308–309.
DISCUSSION (FMPOF4 0%POOFMM+""OUJJOGFDUJWFT*O(FOOBSP+3 FE
Nystatin (C47H75NO17, MW 926.09) is a substance produced by the Remington: The Science and Practice of Pharmacy. 21st ed. Balti-
growth of Streptomyces noursei (Brown) (Fam. Streptomycetaceae). It NPSF .%-JQQJODPUU8JMMJBNT8JMLJOT
contains not less than 4400 units of nystatin activity per mg of substance. 4. Reynolds JE. MARTINDALE: The Extra Pharmacopoeia. London,
It is a mixture of four different tetraenes, nystatin A, nystatin A2, and 6,5IF1IBSNBDFVUJDBM1SFTTm
nystatin A3, and polyfungin B. It occurs as a yellow to light-tan hygro- 5. [No author listed.] Benzoin. In: Gennaro JR, ed. Remington: The
scopic powder with a cereal-like odor. It is affected by long exposure to Science and Practice of Pharmacy. 21st ed. Baltimore, MD: Lippin-
light, heat, or air. It has a pka of 4.5 and one at 8.64. It is soluble 1 mg in DPUU8JMMJBNT8JMLJOT
4 mL water and 1.2 mL alcohol.3 Nystatin topical powder generally con- 6. McEvoy GK. AHFS Drug Information–2008. Bethesda, MD:
tains about 100,000 units of nystatin per gram dispersed in talc. Nystatin "NFSJDBO4PDJFUZPG)FBMUI4ZTUFN1IBSNBDJTUTm
cream generally contains about 100,000 units of nystatin in a cream base. 2885.

Formulations
Selegiline Hydrochloride 1-mg/0.05-mL Oral Suspension in Oil
hot solutions of alkalai hydroxides. It is used as a desiccant, suspending

Rx For 100 mL
agent, and viscosity increasing agent.1,5
Stevia (honey leaf, yerba dulce) powder is a relatively new sweetening

Selegiline hydrochloride 2 g agent. It is the extract from the leaves of the Stevia rebaudiana Bertoni
Silica gel 5 g plant. It is natural, nontoxic, safe, and occurs as a white, crystalline,
Stevia 200 mg hygroscopic powder. It can be used in both hot and cold preparations.4
Saccharin 100 mg
Butylated hydroxytoluene (BHT) 100 mg Saccharin (C7H5NO3S, MW 183.18) is an intense sweetening agent
Flavor qs widely used in commercial products, including foods, drinks, and
Almond oil qs 100 mL pharmaceuticals. It is used in oral formulations as a sweetener, gener-
ally in concentrations ranging from 0.02% to 0.5%. It is about 500 times
METHOD OF PREPARATION sweeter than sucrose and can be used to mask some unpleasant tastes of
1. Calculate the required quantity of each ingredient for the total various medications. It occurs as odorless white crystals or as a white,
amount to be prepared. crystalline powder. Along with its intense sweet taste, it has a metallic af-
2. Weigh and/or measure each ingredient accurately. tertaste that is experienced by about 25% of the population. It is soluble
3. Blend all the powders together in a mortar. to the extent of 1 g in 290 mL of water, 50 mL of glycerin, and 31 mL of
4. Add about 90 mL of almond oil. 95% ethanol.6
5. Add flavor and mix well.
6. Add sufficient almond oil to volume and mix well. Butylated hydroxytoluene (C15H24O. MW 220.35, BHT) is an antioxi-
1BDLBHFBOEMBCFM dant used in cosmetics, foods, and pharmaceuticals primarily to delay or
prevent oxidative rancidity of fats and oils and to prevent loss of activity
PACKAGING of oil-soluble vitamins. It occurs as a white or pale yellow crystalline sol-
Package in tight, light-resistant containers that can accommodate mea- id or powder with a faint characteristic odor that is practically insoluble
suring small volumes.1 in water, glycerin, propylene glycol, solutions of alkali hydroxides, and
dilute aqueous mineral acids. It is freely soluble in ethanol, methanol,
LABELING fixed oils, and liquid paraffin.7
Keep out of reach of children. Use only as directed.
Almond oil (sweet almond oil) is a clear, pale straw-colored or colorless,
STABILITY almost odorless, oily liquid with a bland taste. Its specific gravity is 0.910
A beyond-use date of up to 6 months can be used for this preparation.1 to 0.915 and it is slightly soluble in alcohol. It is often used as an emol-
lient.1
USE
Selegiline oral suspension has been used as an antiparkinsonism agent in REFERENCES
those patients that cannot take oral solid dosage forms. 6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO *OD USP Pharmacists’
QUALITY CONTROL
vention, Inc.; 2008: 60, 775–779.
Quality-control assessment can include weight/volume, pH, specific
"MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSRVBMJUZBTTFTTNFOU
gravity, active drug assay, color, clarity, rheological properties/pour-
ability, physical observation, and physical stability (discoloration, foreign
3. McEvoy GK, ed. AHFS Drug Information–2008. Bethesda, MD:
materials, gas formation, mold growth).2
"NFSJDBO4PDJFUZPG)FBMUI4ZTUFN1IBSNBDJTUTm
DISCUSSION 2396.
Selegiline hydrochloride (C13H17N.HCl, MW 223.74) occurs as a 4. Reynolds JE. MARTINDALE: The Extra Pharmacopoeia. London,
white, odorless, crystalline powder. It is freely soluble in water. It is a 6,5IF1IBSNBDFVUJDBM1SFTTm
stereoselective monoamine oxidase (MAO) inhibitor and is the levorota- 0XFO4$$PMMPJEBMTJMJDPOEJPYJEF*O3PXF3$ 4IFTLFZ1+
tory isomer of dimethyl propynylphenethylamine and structurally 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
related to pargyline. It has a pKa of 7.5. Selegiline hydrochloride is used Washington, DC: American Pharmaceutical Association; 2006:
in the symptomatic treatment of parkinsonian syndrome. Selegiline 188–191.
is metabolized to methylamphetamine and amphetamine, which are 0XFO4$4BDDIBSJO*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
excreted in the urine.3,4 Handbook of Pharmaceutical Excipients. 3rd ed. Washington, DC:
American Pharmaceutical Association; 2006: 638–640.
Silica gel occurs as fine, white hygroscopic, odorless, amorphous powder (SPWFT.+#VUZMBUFEIZESPYZUPMVFOF*O(VFTU35 FE
with a usual particle size range between 2 mcg and 10 mcg. It is in- Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
soluble in water and alcohol and other organic solvents but is soluble in American Pharmaceutical Association; 2006: 81–82.

Formulations
Trolamine Oleate Otic Solution
Gelatin (Pharmagel A, Pharmagel B) occurs as a light-amber to faintly

Rx For 100 mL
yellow-colored vitreous, brittle solid that is practically odorless and
tasteless. It is available as translucent sheets and granules or as a powder.
It is widely used as a coating agent, film-former, gelling agent, suspend-
Trolamine 3.6 g ing agent, tablet binder, and a viscosity-increasing agent. The pH of a
Oleic acid 6.84 g 1% aqueous solution of Type A gelatin is between 3.8 to 6.0 and for the
Gelatin 60 mg Type B gelatin is between pH 5.0 to 7.4. Gelatin is soluble in glyc-
Purified water 1.4 mL erin, acids, and alkalis and, in water, swells and softens until absorbing
Propylene glycol qs 100 mL between 5 to 10 times its own weight of water. It is soluble in hot water.
Gelatin solutions are stable when stored under cool, sterile conditions.5
1. Calculate the required quantity of each ingredient for the total Purified water is water that is obtained by distillation, ion exchange, re-
amount to be prepared. verse osmosis, or some other suitable process. Water has a specific grav-
2. Weigh and/or measure each ingredient accurately. ity of 0.9971 at room temperature, a melting point at 0°C, and a boiling
3. Mix the trolamine and oleic acid together. point at 100ºC. It is miscible with most polar solvents and is chemically
4. Mix the gelatin and purified water together. stable in all physical states (ice, liquid, steam).6
5. Combine the two mixtures and mix well.
6. Add the propylene glycol to volume and mix well. Propylene glycol (C3H8O2, MW 76.09) occurs as a clear, colorless, vis-
7. Heat the mixture to about 60ºC, cool, and stir until homogenous. cous, practically odorless liquid with a sweet taste, somewhat resembling
1BDLBHFBOEMBCFM glycerin. It has a specific gravity of 1.038 g/mL and is miscible with
acetone, chloroform, 95% ethanol, glycerin, and water. It is not miscible
PACKAGING with fixed oils or light mineral oil. It will, however, dissolve some essen-
Package in tight, light-resistant containers.1 tial oils. Propylene glycol is used as a humectant in topicals.7
LABELING REFERENCES
Keep out of reach of children. Use only as directed. 6OJUFE4UBUFT1IBSNBDPQFJBM$POWFOUJPO *ODUSP Pharmacists’
STABILITY vention, Inc.; 2008: 775–779.
A beyond-use date of up to 6 months can be used for this preparation.1 "MMFO-7+S4UBOEBSEPQFSBUJOHQSPDFEVSFGPSRVBMJUZBTTFTTNFOU
USE (PTLPOEB43 -FF+$5SJFUIBOPMBNJOF*O3PXF3$ 4IFTLFZ
Trolamine otic solution has been used to treat minor ailments of the ear, 1+ 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
including wax removal. Washington, DC: American Pharmaceutical Association; 2006:
794–795.
QUALITY CONTROL $BCMF$(0MFJDBDJE*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
Quality-control assessment can include weight/volume, pH, specific Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
gravity, active drug assay, color, clarity, rheological properties/pour- American Pharmaceutical Association; 2006: 494–495.
ability, physical observation, and physical stability (discoloration, foreign 1SJDF+$(FMBUJO*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
materials, gas formation, mold growth).2 Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
American Pharmaceutical Association; 2006: 295–298.
DISCUSSION (BMJDIFU-:8BUFS*O3PXF3$ 4IFTLFZ1+ 0XFO4$ FET
Trolamine (C6H15NO3, MW 149.19, TEA, triethanolamine) is an Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC:
alkalizing and emulsifying agent. It occurs as a variable mixture of American Pharmaceutical Association; 2006: 802–806.
alkanolamines and is a clear, colorless to pale yellow-colored viscous 0XFO4$ 8FMMFS1+1SPQZMFOFHMZDPM*O3PXF3$ 4IFTLFZ
liquid with a slight ammoniacal odor. Its specific gravity is about 1.120 to 1+ 0XFO4$ FETHandbook of Pharmaceutical Excipients. 5th ed.
1.128 g/mL and has a pH of 10.5 in a 0.1N aqueous solution.3 Washington, DC: American Pharmaceutical Association; 2006:
624–626.
Oleic acid (C18H34O2, MW 282.47) is used as an emulsifying agent and
as a penetration enhancer in transdermal formulations. It occurs as a yel-
lowish to pale brown oily liquid with a characteristic lard-like odor and
taste. It is miscible with ethanol (95%), ether, and fixed and volatile oils,
but is practically insoluble in water. It has a density of 0.895 g/cm3 and
a melting point of 4ºC. It decomposes when heated at 80ºC to 100ºC. It
should be stored in well-filled and well-closed containers and protected
from light in a cool, dry place.4

Peer Reviewed
Quality of Progesterone Suppositories Prepared by
FIRST-Progesterone Vaginal Suppository 50 Kit or
Traditional Compounding Method: In Vitro Comparison
Harsh Chauhan, BS ABSTRACT
Eman Atef, PhD The objective of this study was to compare the quality of progesterone
Massachusetts College of Pharmacy and suppositories prepared by using the FIRST-Progesterone Vaginal Suppos-
Health Sciences itory Kit to that of progesterone suppositories compounded extempo-
Boston, Massachusetts raneously by using the traditional method. The comparison parameters
were weight variation, content uniformity, pH, yield, and compounding
time. Each of five compounders prepared two batches, one batch us-
INTRODUCTION ing each method. The results indicate that the quality of the supposito-
Progesterone is a female sex hormone ries prepared by both methods, including weight variation and content
of paramount importance in the reproduc- uniformity, fell within the United States Pharmacopeial accepted limits
tive cycle. It is secreted by the ovaries and (± 10% of the label concentration). However, preparation time and yield
facilitates implantation of the fertilized ovum
in the uterus. It is frequently prescribed in
were significantly different. The time spent compounding the supposito-
the treatment of infertility, and in prevention ries with the FIRST-Progesterone Vaginal Suppository 50 kit was signifi-
of preterm birth.1 Progesterone is delivered cantly shorter (five times shorter) than that spent compounding the sup-
through oral, parenteral, or local routes. positories by the traditional method (P <0.05). Although all compounders
Vaginal administration is an important were advised to use an extra 10% during traditional compounding, three
route of local progesterone delivery.2 Formula-
of the compounders failed to fill the prescribed number and ended with
tors should consider all physiological factors
that may alter vaginal absorption, such as fewer suppositories than required. The reasons for this deficiency were
vaginal lining thickness, and viscosity, pH, and either conventional mold leakage or spilling during mold filling.
volume of the vaginal fluid. The patient’s age
and hormone levels could affect the vaginal
absorption as well.3 Progesterone for intravagi-
nal administration is available either in com- including higher and lower concentrations The objectives of our study were to investi-
mercial preparations or in extemporaneously than the accepted United States Pharmaco- gate the quality of progesterone suppositories
compounded preparations.4 Lately, there has peial (USP) range; lack of content uniformity; prepared by a kit, and to compare this to the
been great interest in local routes of progester- and contamination.9 A national survey of quality of progesterone suppositories prepared
one administration, which minimize the side compounding pharmacists that was conducted by traditional extemporaneous compounding.
effects encountered with oral or parenteral ad- in 2005 showed the need for more information
ministration, such as local pain and extensive on compounded preparations’ stability, as well
first-pass metabolism.5,6 Furthermore, local as the need for accreditation and more training MATERIALS AND
administration has a higher rate of absorption for compounding pharmacists.10 METHODS
than systemic administration, and thus greater Therefore, it is crucial that compounding Materials
bioavailability.7,8 pharmacists follow the regulations of United FIRST-Progesterone Vaginal Suppository
Progesterone vaginal suppositories are States Pharmacopeia (USP) Chapter <795> (VGS) 50 kits (Lot E140), bulk Progesterone
extemporaneously prepared in pharmacies in Pharmaceutical Compounding—Nonsterile USP (Lot VD1036), and bulk suppository
accordance with a prescription. The challenge Preparations to guarantee that compounded fatty-base (Lot 15219301) were kindly sup-
faced in compounding progesterone supposi- progesterone suppositories fall within the USP plied by CutisPharma (Woburn, Massachu-
tories is that the preparation is not tested for acceptable range of weight variation and con- setts). Methanol high-performance liquid
uniform drug distribution, weight variation, tent uniformity, and to select the proper base chromatography (HPLC) grade Lot S00933)
or release characteristics. Two U.S. Food and that provides appropriate drug release.11 These and denatured ethyl alcohol HPLC grade (Lot
Drug Administration studies, in 2001 and quality issues are becoming more significant, 47015) were purchased from VWR Interna-
2007, reported numerous formulation prob- especially with the expected increase in tional (San Dimas, California). N-propyl alco-
lems with various compounded prescriptions. demand for compounded suppositories associ- hol HPLC grade (Lot 68135) was purchased
The most common problems were potency, ated with the aging of the population. from Fisher Scientific (Pittsburgh, Pennsylva-

Peer Reviewed
nia). All ingredients were used as purchased,

without further purification. Table. Content Uniformity and Weight Variation Results.
Content Uniformity Weight Variation
Suppository Preparation (mg of progesterone/suppository ± Relative (Suppositories average weight in grams ±
A total of ten batches of suppositories were Standard Deviation) Relative Standard Deviation)
compounded by four graduate students and Traditional Compounding Kit Traditional Compounding Kit
one senior student in the B.S. of Pharmaceuti- (n = 10) (n = 10) (n = 10) (n = 10)
cal Sciences program. Each student prepared Student 1 47.28 ± 0.74 50.62 ± 0.56 2.62 ± 0.02 2.18 ± 0.04
a suppository batch by using a FIRST- Student 2 47.18 ± 0.57 51.18 ± 1.58 2.56 ± 0.05 2.29 ± 0.05
Progesterone VGS 50 kit, and another batch Student 3 47.85 ± 1.11 51.69 ± 1.70 2.56 ± 0.04 2.22 ± 0.04
by using the traditional method. Suppository Student 4 48.27 ± 1.22 51.83 ± 1.60 2.57 ± 0.03 2.26 ± 0.03
preparation procedures were explained to the Student 5 48.61 ± 0.83 51.96 ± 1.64 2.55 ± 0.04 2.28 ± 0.03
students. Students were asked to record the
compounding time needed for both methods
and to perform the calculations needed to
compound the suppositories by a traditional mobile phase was used, at a flow rate of significantly lower than the average pH of
method. 1 mL/minute. 15 suppositories prepared by the traditional
The density of the fatty-suppository-base compounding method (6.1 ± 0.2 SD). The pH
was 0.9 g/mL, and the capacity of the plastic pH of Progesterone Suppositories difference may be attributable to the differ-
molds used was 2.8 mL per cavity. Thus, the Three suppositories from each of the ten ence in the total weight of the suppositories
expected average weight of the suppository batches were selected for pH testing. Each prepared by the two methods. The results are
prepared by the traditional method was around individual suppository was melted in 10 mL of shown in Figure 1.
2.52 g. The students were advised to weigh an water that was preheated to 45°C. After each
extra 10% of the calculated quantities of drug mixture was cooled to room temperature, the Suppository Preparation Time
and base to make up for any loss during com- pH was measured by a pH meter (Model MP Using the t-test, we found that the average
pounding. No calculations were required for 225; Mettler Toledo, Columbus, Ohio).12 time needed to compound progesterone sup-
compounding the suppositories from the kit. positories by the FIRST-Progesterone VGS
Suppository Preparation Time 50 kit (8.2 ± 1.68 minutes) was significantly
Suppositories Weight Variation Test The time spent preparing the supposito- shorter than the average time needed to com-
The individual weights of ten suppositories ries by the FIRST-Progesterone VGS 50 kits pound suppositories by the traditional method
per batch were measured, and the average was recorded and compared to the time spent (41 ± 10.72 minutes; P <0.05), as shown in Fig-
weight of each batch and the standard devia- preparing suppositories by the traditional ure 2. Saving time in compounding is a great
tion (SD) were calculated. compounding method. advantage for extremely busy pharmacists. It is
also crucial for the patient, who could receive
Suppositories Content Uniformity her kit-compounded prescription within an
RESULTS AND hour, while she might have to wait a few hours
Test
The content uniformity test was performed DISCUSSION or even until the next day to receive supposito-
on ten suppositories from each batch, a total of Suppository Content Uniformity ries prepared by the traditional compounding
100 suppositories. Each suppository was trans- Test method.
ferred to a 200-mL volumetric flask, dissolved The results of weight variation and content
in 100 mL of methanol at 45°C, subjected to uniformity tests are shown in the table that Number of Compounded
sonication, and then allowed to cool to room accompanies this article. The USP content Suppositories
temperature before being diluted to 200 mL by uniformity standard for 50-mg progesterone Each of the ten batches of suppositories
methanol. One milliliter of the diluted solution suppositories is 50 mg ± 5 mg. All tested sup- compounded by using the FIRST-Progester-
was then transferred to a 10-mL volumetric positories, prepared by either method, met the one VGS 50 kit numbered 30 suppositories.
flask and further diluted with methanol to USP requirements for weight variation and This yield was consistent across all five partici-
10 mL. A sample from the final solution was content uniformity. pating students. When the traditional method
filtered through a syringe filter (0.45 mcm) and was used, on the other hand, three students
then analyzed by HPLC.4 pH of Progesterone Suppositories were not able to fill 30 suppositories and ended
The vagina is normally acidic, and thus with fewer suppositories than required, even
HPLC Conditions the pH of vaginal suppositories should be in though all participants were advised to count
An HPLC system (Hewlett Packard 1100) the acidic range to minimize irritation of the for 10% extra. The reasons for this defi-
and an Alltima C18, 4.4 × 150-mm, 5-mcm vagina.13 The average pH of 15 supposito- ciency were mold leakage or spilling during
column were used to analyze the samples. ries (three suppositories from five different mold filling. It is thus recommended that the
The ultraviolet detector was set at a wave- batches) prepared by the FIRST-Progesterone compounder use 15% extra, rather than 10%,
length of 275 nm, and the USP-recommended VGS 50 kit was 5.3 ± 0.2 SD, which was when using the traditional method.

Peer Reviewed
4. Mahaguna V, McDermott JM, Zhang F

Figure 1. pH of suppositories prepared by the traditional method and by the et al. Investigation of product quality
suppository kit. between extemporaneously compounded
progesterone vaginal suppositories and an
7 approved progesterone vaginal gel. Drug
7
Dev Ind Pharm 2004; 30(10): 1069–1078.
È
6 5. Choavaratana R, Manoch D. Efficacy of
Kit’s suppositories oral micronized progesterone when ap-
5
5
Traditional suppositories plied via vaginal route. J Med Assoc Thai
4
4 2004; 87(5): 455–457.
pH
6. Bolaji II, Mortimer G, Grimes H et al.

3
3 Clinical evaluation of near-continuous
2
2 oral micronized progesterone therapy
in estrogenized postmenopausal women.
1
1 Gynecol Endocrinol 1996; 10(1): 41–47.
7. Nahoul K, Dehennin L, Jondet M et al.
0
0
Profiles of plasma estrogens, progesterone
Compounding Method and their metabolites after oral or vaginal
administration of estradiol or progester-
one. Maturitas 1993; 16(3): 185–202.
8. von Eye Corleta H, Capp E, Ferreira MB.
Figure 2. Comparison of compounding time of suppositories using the Pharmacokinetics of natural progesterone
traditional method and kits. vaginal suppository. Gynecol Obstet Invest
2004; 58(2): 105–108.
9. [No author listed.] 2006 Limited FDA
ÈäÊÊ
Survey of Compounded Drug Products.
50 - Available at: http://www.fda.gov/Cder/
Time (minutes)
pharmcomp/survey_2006.htm. Accessed
40 - January 2008.
10. Huffman DC, Holmes ER. Specialty
30 - compounding for improved patient care:
2006 national survey of compounding
20 - pharmacists. IJPC 2008; 12(1): 74–82.
11. United States Pharmacopeial Convention,
10 -
Inc. United States Pharmacopeia 32–National
0 - Formulary 27. Rockville, MD: US Pharma-
Kit’s suppositories Traditional suppositories copeial Convention, Inc.; 2008: 317.
12. Azechi Y, Ishikawa K, Mizuno N et al.
Sustained release of diclofenac from
polymer-containing suppository and the
mechanism involved. Drug Dev Ind Pharm
CONCLUSION pharmacists, time constraint is a major obstacle 2000; 26(11): 1177–1183.
It is clear that the FIRST-Progesterone in compounding. Using kits as a compounding 13. Caillouette JC, Sharp CF Jr, Zimmer-
VGS 50 kit is a convenient method for success- tool may help promote the re-emergence of man GJ et al. Vaginal pH as a marker
ful compounding of progesterone supposito- pharmacy compounding. for bacterial pathogens and menopausal
ries in a timely manner. By following Good status. Am J Obstet Gynecol 1997; 176(6):
Laboratory Practices, however, the traditional REFERENCES 1270–1277.
compounding process may be used effectively 1. Meis PJ, Connors N. Progesterone treat-
for preparing progesterone suppositories. The ment to prevent preterm birth. Clin Obstet
only drawbacks of traditional compounding Gynecol 2004; 47(4): 784–795.
are the time consumed and the risk of insuffi- 2. Justin-Temu M, Damain F, Kinget R et al. Address correspondence to Eman Atef, PhD, As-
cient yield. To overcome such problems, some Intravaginal gels as drug delivery systems. sistant Professor of Pharmaceutics, Department of
pharmacies create a directory of frequently J Womens Health 2004; 13(7): 834–844. Pharmaceutical Sciences, Massachusetts College of
compounded prescriptions with all required 3. Valenta C. The use of mucoadhesive Pharmacy and Health Sciences, School of Phar-
calculations including 15% extra, and they polymers in vaginal delivery. Adv Drug macy-Boston, 179 Longwood Avenue, Boston, MA
use disposable tools as much as possible. For Deliv Rev 2005; 57(11): 1692–1712. 02115-5896. E-mail: eman.atef@mcphs.edu

Peer Reviewed
Women’s Perspective on Progesterone: A Qualitative
Study Conducted in Australia
M. Joy Spark, MPharm ABSTRACT
School of Pharmacy and Applied Science This study explored the perspective of women using compounded pro-
La Trobe University gesterone preparations. Semi-structured interviews were conducted in
Bendigo, Victoria, Australia Victoria, Australia with eight self-selected women who were dispensed a
progesterone-only preparation. Participating women gained symptom relief
Rebecca A. Dunn, BPharm (Hons) for migraine, painful breasts, mood swings, bloating, hot flushes, and oth-
Northeast Health er conditions. The participants also experienced unexpected benefits such
Wangaratta, Victoria, Australia as improvement in irregular and painful periods, relief from cystitis, or in-
creased libido, without any reported negative side effects. The participants
Kelli L. Houlahan, BASc Dip Ed appreciated the ability to adjust the dose and dosage form to their individual
BPharm (Hons) requirements and held a positive perception of progesterone as a “natural”
Strathdale Pharmacy product. Accessibility of progesterone treatment is limited due to the limited
Bendigo, Victoria, Australia number of doctors that have knowledge about the treatment, little informa-
tion available for lay people, and cost. Participants who had been treated
with progesterone were willing to share their experience with others, and
many heard about progesterone therapy from their social contacts. The cost
INTRODUCTION of progesterone therapy, which was often more expensive than traditional
The human body makes one progestational
hormone replacement therapy, was outweighed by the benefits received.
agent—progesterone. Synthetic hormones
These women found that progesterone treatment, although hard to access,
with some of the progestational effects of
progesterone are called progestins and have a was beneficial over conventional therapy.
different side effect profile to progesterone.1-2
For example, the adverse effects on cholesterol
A purposeful sample of women using a
and lipoproteins caused by progestins are not FINDINGS AND
compounded progesterone preparation was
seen with progesterone.3 Yet progesterone is DISCUSSION
used. Four pharmacies in Victoria, Australia
often classed as a progestin.4 Progestins can The eight self-selected participants had a
agreed that at the time of dispensing the pa-
be patented and have been widely researched, variety of occupations and were aged between
tients’ prescriptions of progesterone prepara-
but progesterone, which originally had poor 37 and 67 years (Table 1). It was expected that
tions they would include an information leaflet
oral absorption, has not been widely studied they would be treating symptoms of meno-
about the study. Women willing to participate
despite minimal side effects5 and a micronized pause or perimenopause,17 but progesterone
either posted a reply slip in a reply-paid enve-
form that shows good oral bioavailability.6 was also being used for other conditions
lope or called the phone number provided, and
In Australia, progesterone therapy is not (Table 1).
an interview was arranged at a time and place
recognized as evidence-based medicine7 for Seven themes emerged from the data and
to suit them. Women were recruited until
applications other than infertility,8 yet women these were divided into two broad areas; (1)
theme saturation (no new emerging themes)
are using progesterone for other conditions. product acceptability (symptom relief, posi-
occurred.14 Semi-structured interviews were
Choice in treatment is one of the advantages tive side effects, individuality of treatment,
conducted. The initial interview guide
of modern medicine,9 and women like to have “naturalness”), and (2) accessibility (doctors,
(See the figure that accompanies this article.)
control over their treatment.10 information sources, cost).
was based on two previous studies11-12 and dis-
Other studies have investigated why women
cussion by the research team. Participants were
use traditional hormone replacement therapy
allowed to direct the interview. The interview
(HRT)11-12 but not progesterone. This study
guide was used flexibly and adapted after each
PRODUCT
sought to explore and understand the user’s ACCEPTABILITY
interview. Interviews were audio-taped and
perspective of progesterone preparations. Symptom Relief
their comments transcribed verbatim. The
transcripts were analyzed for emerging themes Effective relief of symptoms is the main
METHODS using open coding followed by axial coding.14 reason women use HRT,18 and this, rather
A qualitative descriptive methodology was Analysis of the data was inductive, with the than long-term disease prevention, was the
chosen to provide a conceptual view of the categories or themes being derived from the main motivation for the participants’ use of
issues and allow the data collected to reflect data which ensured important themes were not progesterone. Various degrees of symptom
the thoughts and concerns of the participants missed, something that could occur if prede- relief were experienced for conditions includ-
rather than of the researchers.13 termined categories were used.15-16 ing menopause, migraines, osteoporosis, and

Peer Reviewed
pounded progesterone products, particularly

Table 1. Participant Characteristics.
transdermal creams, allow the dose to be
Participant Age Occupation Principal Reason for Taking Progesterone
adjusted according to symptoms and/or results
W1 50 Office and house work Post-menopausal hormone replacement
from endogenous hormone level tests. The
W2 48 Technical officer Painful breasts
ability to titrate dosage enables the correct
W3 67 Psychologist and family Migraines, bloating, insomnia, and other
oestrogen/progesterone ratio to be main-
therapist menopausal symptoms
tained, which is more important than attaining
W4 37 Home duties Mood swings, bloatedness, cravings
set levels of either hormone in isolation.26
W5 61 Home duties Post-menopausal hormone replacement therapy,
mainly hot flushes
W6 49 Manager Perimenopause
Naturalness
The perceived “naturalness” of progester-
W7 56 Garden designer Osteoporosis
one was an important issue for the women,
W8 45 Manager Fibroids
who associated this with fewer side effects
than HRT. Some of the women had looked for
fibroids. For some it was life changing and for Table 2. Dosage Forms Used by an alternative to HRT because of the publi-
others normalizing (see participants W1’s and cized risks involved with taking it, as well as
Participants.
W2’s comments in the product acceptability/ stories they had heard from other women (see
Current Other
symptom relief section of the Specific Com- participant W6’s comments in the product ac-
ments from Study Participants form). Dosage Dosage
Participant Form Forms Tried ceptability/naturalness section of the Specific
The symptom relief obtained is unlikely to Comments from Study Participants form).
be a placebo effect as other treatments had not W1 Cream NA
W2 Cream NA Other studies have shown that women were
been effective, and some of the conditions such concerned about the side effects and safety of
as fibroids and osteoporosis are assessed objec- W3 Suppositories Cream and
troches conventional therapy,18 or preferred to treat
tively and, therefore, are less likely to be influ- menopause with natural remedies.10 Women
enced by the placebo effect. Studies involving W4 Cream Troches
W5 Cream Troches using complementary medicines have been
patients using progesterone have reported high found to equate “natural” with safe and be
degrees of symptom relief.19-21 W6 Troches NA
W7 Cream NA unconcerned about potential side effects or
W8 Sublingual Cream long-term hazards of their treatment.10 Proges-
Positive Side Effects terone has been shown in both studies and
Progesterone also relieved symptoms that drops and
pessaries clinical experience to have fewer side effects
participants had not originally considered as than conventional HRT.19,27-28
related to progesterone deficiency, including
improvement in cystitis or irregular and painful Individuality of Treatment
periods, clearing the side effects of traditional Compounded progesterone therapy is avail- ACCESSIBILITY
HRT, and increased libido (see participant able in a range of dosage forms and strengths Doctors
W8’s comments in the product acceptability/ and allows adjustment according to individual The main restriction on progesterone ac-
positive side effects section of the Specific requirements. Most participants were using a cessibility was doctors’ knowledge. Women
Comments from Study Participants form). topical cream (Table 2) and were happy with were prepared to switch doctors to one who
Participants were asked if they had any the dosage form they were currently using. knew about progesterone if their usual doc-
problems with progesterone, and many were Some women had changed dosage forms until tor did not (see participant W7’s comments
emphatic about there being no problems (see they found one that suited them (see partici- in the accessibility/doctors section of the
participants W3’s and W5’s comments in the pant W3’s comments in the product accept- Specific Comments from Study Participants
product acceptability/positive side effects ability/individuality of treatment section of form). Doctors who were prepared to listen
section of the Specific Comments from Study the Specific Comments from Study Partici- to the women and examine them as a whole
Participants form). pants form). person were preferred to those who didn’t
A participant was concerned that unab- Saliva or plasma progesterone levels were make time to understand (see participant W4’s
sorbed progesterone left on her skin would be used to monitor and adjust some participants’ comments in the accessibility/doctors relief
transferred to her partner following topical progesterone therapy. Knowing that their section of the Specific Comments from Study
application of a cream at bedtime. This was treatment was individualized taking into ac- Participants form). Some women discovered
overcome by changing the time of application count their hormone levels was important to they had to do their own research to find out
(see participant W2’s comments in the product the women (see participant W8’s comments about alternative treatments (see participant
acceptability/positive side effects section of in the product acceptability/individuality of W2’s comments in the accessibility/doctors
the Specific Comments from Study Partici- treatment section of the Specific Comments section of the Specific Comments from Study
pants form). from Study Participants form). Participants form).
Some studies of menopausal women have Adjustment of hormone therapy to match Women who knew the difference between
shown that progesterone improves quality of women’s individual metabolic balance is a progestins and progesterone preferred to be
life,19 vasomotor symptoms,22 and libido23 with desirable feature, not usually feasible with the treated with progesterone (see participant
minimal side effects. tablets and patches used for HRT.24-25 Com- W5’s comments in the accessibility/doctors

Peer Reviewed
section of the Specific Comments from Study comments in the accessibility/cost section of REFERENCES
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Menopausal hormone replacement therapy with
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Limitations of the study include the re- 389–397.
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population of women using progesterone BMJ 2006; 332(7547): 981.
this study to increase their knowledge about 10. Seidl MM, Stewart DE. Alternative treatments
progesterone treatment (see participant W1’s products.
for menopausal symptoms. Qualitative study of
comments in the accessibility/information More research is required to assess the ef- women's experiences. Can Fam Physician 1998; 44:
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pants reported that they shared stories with in the body. Maintaining this balance appears Women's beliefs and decisions about hormone
important to reduce the risk of breast and replacement therapy. J Womens Health 1997; 6(4):
relatives and friends about their progesterone
459–465.
treatment (see participants W2’s, W4’s (com- endometrial cancer, osteoporosis, and other
12. Hunter MS, O'Dea I, Britten N. Decision-making
ment 2), and W6’s (comment 2) comments in conditions associated with the years following and hormone replacement therapy: A qualitative
the accessibility/information sources section menopause.26 However, the dilemma remains analysis. Soc Sci Med 1997; 45(10): 1541–1548.
of the Specific Comments from Study Partici- as to who will fund this research when there 13. Green J, Britten N. Qualitative research and
pants form). are no gains to be made through patent protec- evidence based medicine. BMJ 1998; 316(7139):
tion. 1230–1232.
Participants had difficulty understand-
Women interviewed found progesterone 14. Ezzy D. Qualitative analysis - Practice and innovation.
ing the limited available information about Sydney, NSW: Allen & Unwin; 2002.
progesterone products that are most generally preparations relieved both their symptoms 15. Pope C, Ziebland S, Mays N. Qualitative research
written in professional (non-lay-person’s) attributable to progesterone deficiency and in health care. Analysing qualitative data. BMJ
language. As with HRT,31 women were more other symptoms they had not associated 2000; 320(7227): 114–116.
likely to find out about progesterone therapy with progesterone deficiency. The fact that 16. Sandelowski M. Focus on Research Methods:
from their social contacts and then find a treatment could be individualized was seen as Whatever happened to qualitative description? Res
beneficial. They found progesterone products Nurs Health 2000; 23: 334–340.
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not tell you about premenopause: Balance your hormones
people, few prescribing doctors, and higher and your life from thirty to fifty. New York, NY:
cost than HRT. Warner Books; 1999.
Cost
18. Travers C, O'Neill SM, Khoo SK et al. Hormones
The cost of progesterone treatment for
down under: Hormone therapy use after the
most participants was more than that of the
government subsidized conventional treat-
ACKNOWLEDGMENTS Women's Health Initiative. Aust N Z J Obstet
Gynaecol 2006; 46(4): 330–335.
The authors appreciate the valuable com-
ment, but the improvement in the symptoms 19. Fitzpatrick LA, Pace C, Wiita B. Comparison of
ments and review of research material of Shir- regimens containing oral micronized progester-
outweighed the increased cost (see participants
W2’s and W8’s comments in the accessibility/ ley James and the support and encouragement one or medroxyprogesterone acetate on quality of
cost section of the Specific Comments from of pharmacies and pharmacists. life in postmenopausal women: A cross-sectional
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osteoporosis commented that while the cost to This study was approved by the Human 20. Santoro F. Satisfaction of patients using bioiden-
her was the same as her subsidized medication, Research Ethics Committee at La Trobe Uni- tical hormones for hormone replacement therapy.
the overall cost was less (see participant W7’s versity, Bendigo HREC No.: A049/03. IJPC 2002; 6(5): 377–378.

Peer Reviewed
21. Warren A, Listecki RE. Bioidentical topical pro- 25. McPherson K. Where are we now with hormone ing women's concerns about the menopause and
gesterone: A survey of patients. IJPC 2001; 5(5): replacement therapy? Reprod Health Matters 2004; HRT. Maturitas 1999; 33(Suppl 1): S15–S23.
354–355. 12(24): 200–203. 30. Britten N. Patients' ideas about medicines: A
22. Leonetti HB, Longo S, Anasti JN. Transdermal 26. Zava DT. The hormonal link to breast cancer: qualitative study in a general practice population.
progesterone cream for vasomotor symptoms and The estrogen matrix. IJPC 2002; 6(4): 250–254. Br J Gen Pract 1994; 44(387): 465–468.
postmenopausal bone loss. Obstet Gynecol 1999; 27. Taylor EB, Bell-Taylor A. Are Your Hormones 31. Griffiths F. Women's control and choice regarding
94(2): 225–228. Making You Sick? A Woman's Guide to Better Health HRT. Soc Sci Med 1999; 49(4): 469–481.
23. Lee JR. Osteoporosis reversal: The role of pro- through Hormone Balance. 3rd ed. U.S.: Physicians
gesterone. Intern Clin Nutr Rev 1990; 10: 384–391. Natural Medicine Inc.; 2003.
24. Hargrove JT, Osteen KG. An alternative method 28. Lee JR. Natural Progesterone: The Multiple Roles Address Correspondence to M. Joy Spark, MPharm,
of hormone replacement therapy using the natu- of a Remarkable Hormone. Sebastopol, CA: BLL School of Pharmacy and Applied Science, LaTrobe
ral sex steroids. Infert Repro Med Clin N Am 1995; Publishing; 1993. University, PO Box 199, Bendigo, Victoria, Australia,
6(4): 653–674. 29. Graziottin A. Strategies for effectively address- 3552. Email: j.spark@latrobe.edu.au
Figure. Initial Interview Guide.
Age________
Occupation ________________________________________________
For what condition are you taking progesterone? _______________________________________
Expand on condition (e.g., symptoms, which symptoms are worst, length of time had condition) __________________________________________
______________________________________________________________________________________________________________________
In what dosage form are you taking progesterone? (e.g., cream, tablet) ______________________
Are there any benefits to taking it in this dosage form? __________________________________________________________________________
______________________________________________________________________________________________________________________
Why did you choose progesterone over conventional hormone replacement therapy (or conventional treatment for their condition if different than
hormone replacement therapy)? ___________________________________________________________________________________________
Expound on this topic ____________________________________________________________________________________________________
______________________________________________________________________________________________________________________
What are the positives (perceived positives) of progesterone treatment over conventional hormone replacement therapy? ______________________
______________________________________________________________________________________________________________________
What are the negatives (perceived negatives) of progesterone treatment over conventional hormone replacement therapy? ______________________
______________________________________________________________________________________________________________________
What was tried (if anything) before using progesterone treatment? _________________________________________________________________
What where the positives and negatives of this treatment? ________________________________________________________________________
Why was another treatment sought? _________________________________________________________________________________________
What else do you know about progesterone treatment or conventional hormone replacement therapy? _____________________________________
______________________________________________________________________________________________________________________

Peer Reviewed
Specific Comments from Study Participants

Theme Participant Participant Response
Product Acceptability
Symptom Relief W1 Since I’ve been on this [progesterone treatment] I certainly feel better. Progesterone makes me
feel more like myself.
W2 It’s [progesterone treatment] wonderful. It means, you can have a normal life.
Positive Side Effects W2 The only thing that concerns me is how long it takes [progesterone cream] to absorb into your
body and if there is any transfer [of progesterone] to your partner when you’re laying together at
night. So I decided just to use it in the morning.
W3 No, not at all. I have had no negative side effects [from progesterone treatment] whatsoever.
W5 No [side effects from progesterone treatment].
W8 Even if it [progesterone treatment] wasn’t shrinking the fibroids, which is my main aim, I’d still
continue with progesterone without a doubt because I’ve seen so many benefits, and I wouldn’t
go off it [progesterone treatment] now.
Individuality of W3 I’ve tried [progesterone] creams and troches and there’s no doubt that the suppositories work
Treatment best.
W8 When she [the doctor] undertook a test [of hormone levels] for me, she said, ‘Look, this
[hormone level] is perfectly balanced now for you.’
Naturalness W6 So when I went to my doctor I was trying to ask if there was something I could take that doesn’t
have a lot of side effects but perhaps is a bit more natural.
Accessibility
Doctor W2 Their [the hospital’s] solution for painful periods, was ‘we’ll just give you a hysterectomy.’ That
wasn’t what I wanted to do.
W4 She’s [doctor] very regimented as regard to time, so I didn’t feel like my questions were being
answered. I’d go away thinking, ‘oh, I’m none the wiser.’ I had a prescription but I had no answers.
W5 I didn’t realize that the synthetic progesterone that you get from the doctor wasn’t real pro-
gesterone.
W7 [Comments made to the testing laboratory.] I’m getting nowhere with my general practitioner.
He doesn’t know what I’m talking about. They [testing laboratory] gave me a name of a doctor
who is into the natural remedies and things, and, yes, she knew what I was talking about.
Information Sources W1 It would be good to have more information about the topic [of progesterone treatment] to help
other people.
W2 I’ve seen my sister-in-law try HRT for years and still be really frustrated by the whole process
[trials of different hormone replacement therapy treatments], and at the end of it feel like she
hadn’t been helped at all.
W4 [Comment 1] The pharmacists are great, they give you lots of information; they’re excellent.
W4 [Comment 2] I had heard about it [progesterone] from the sister of a girlfriend, so it wasn’t
anything I found on the Internet; it was more word of mouth. And that’s how other women that I
know have since started [progesterone treatment], by word of mouth.
W6 [Comment 1] I suppose like a lot of those things [information] it is hard to find things in
layman’s terms.
W6 [Comment 2] I’ve talked to my girlfriends about it [progesterone treatment].
Cost W2 If we do something to actually keep ourselves healthy, out of the hospital systems, and out of the
doctor’s office less regularly, we pay more. But I figure I want to keep my health.
W3 Women who haven’t got any money at all, they can’t afford to do this [progesterone treatment].
And, if they’re receiving a pension, they can’t get it [progesterone]. It’s wrong, it’s politically
wrong that people can’t have this as an option.
W7 Well, the cost to me is even, but the cost to the nation is minimal.
W8 Obviously, I don’t like paying $45 every six weeks, but I wouldn’t even consider that an issue.

Postscription
COMPOUNDING PHARMACY IN
Puerto Rico
Marisol López, RPh, MPH t 1512 — The first Spanish pharmacist Sterile compounding began to gain impor-
RCMI-Clinical Research Center arrived in PR and established the first phar- tance in PR at the end of the 1990s because
macy in America, as described in the Royal of the proliferation of infusion and specialty
School of Pharmacy
Decree of Graces, a legal order approved by pharmacies. This boom attracted the attention
Medical Sciences Campus of regulatory agencies, requiring that phar-
the Spanish Crown, of February 23, 1512.1
University of Puerto Rico macists who wanted to engage in this practice
Puerto Rico t 1767 — Hospital de la Concepcion El must have training and established policies to
Grande had the first hospital pharmacy comply with safety standards. The pharmacist’s
with “Boticario Mayor.” professional development and importance in
HISTORY AND EVOLUTION t 1841 — Pharmacists in PR received Puerto Rican’s society have contributed to
formal compounding education. making compounding an essential function of
OF COMPOUNDING IN pharmacy and to its continued acceptance.
t 1898 — PR became a U.S. territory; as a
PUERTO RICO territory of the U.S., the U.S. Food & Drug
Compounding is part of Puerto Rico’s (PR) Administration (FDA) observes the practice OVERVIEW
historic development. The chronological his- of compounding to make sure that drug Currently, there are two Pharmacy Schools
tory of pharmacy in PR is as follows: manufacturing is not exercised. in PR: the School of Pharmacy of the Univer-

Postscription
sity of Puerto Rico (UPR), and Nova South- the formulation of

eastern University (NOVA). During 2008, 46 suspensions and
new pharmacists graduated from UPR and ap- topical preparations.
proximately the same number graduated from Pharmacies that com-
NOVA. These new students mainly will be pound these prepara-
involved in retail pharmacy, and some of them tions, which include
will be recruited by pharmacy chains in the community pharma-
U.S. and will migrate to the U.S. Recent gradu- cies and some local
ates and Puerto Rican pharmacists are eligible and national chains,
for licensure reciprocity in the U.S. Similar to use basic equipment,
the U.S., PR has a shortage of pharmacists. such as mortars,
scales, and graduated
cylinders. Very few
REGULATORY AGENCY of these pharmacies
Compounding is regulated by the Depart-
are engaged in some
ment of Health of Puerto Rico, through the San Juan, Puerto Rico
form of nonsterile
Division of Drugs and Pharmacies in the
compounding that
Assistant Ministry of Regulation and Accredi-
requires complex calculations or procedures
tation of Health Facilities. The Pharmacy Act
using commercial products or bulk materials.
of Puerto Rico (Act No. 247; approved on Sep-
tember 3, 2004) created the Division of Drugs
and Pharmacies, as an administrative unit of Category 2
the Department of Health, for a more effective Pharmacies Engaged in the
monitoring of the stages of manufacturing, Formulation of Low- or
distribution, and dispensing of medicines and
Medium-risk Sterile Preparations
generic drugs exchange in PR.
These pharmacies are called “infusion
The new Department of Health of PR
pharmacies” or “specialty pharmacies.” Infu-
Regulation No. 133, Department of State of
sion or specialty pharmacies prepare sterile
Puerto Rico No. 7568, became effective on
formulations for hospitals, nursing homes, and
December 31, 2008. This regulation stipulates
other facilities that do not meet the require-
that any licensed pharmacy may compound
ments of USP Chapter <797>.
medications if it is compliant with all appli-
Pharmacists in PR are allowed by the FDA
cable federal and local regulations, includ- Example of a sterile compounding
to only compound medications that are not
ing United States Pharmacopeia (USP) Chapter
commercially available. A prescription is
area in an infusion pharmacy in
<795> for nonsterile formulations and USP Puerto Rico.
required for the formulation of medications.
Chapter <797> for sterile formulations. Other Source: Courtesy of Baxter Pharmacy,
Common dosage forms compounded by phar-
USP chapters included in the regulation that Guaynabo, PR.
macists in PR are:
need to be followed are USP <1075> Good
Compounding Practices and USP <1160>
Pharmaceutical Calculations in Prescription Nonsterile government is promoting the development of
Compounding. In PR, pharmacists also must t Oral liquids: solutions, suspensions the biotechnology industry. Faced with the
follow the regulations of compounding prac- t Topical liquids: solutions, suspensions new challenges and changes in technology and
tices established by the government of the U.S. emulsions pharmaceutical therapy through pharmaco-
t Suppositories genetics, pharmacists in PR and around the
t Ointments, creams, lotions world will require training in compounding as
ALLOWABLE COMPOUNDING well as in advanced techniques.
Sterile
FOR PHARMACIES AND t Ophthalmic preparations
PHARMACISTS IN PR t Nasal preparations REFERENCE
Compounding pharmacies in PR can be t Intravenous admixtures 1. Fábregas, Troche SM. La Institucionalización
divided into two categories, as described below. de la Farmacia en Puerto Rico. San Juan,
Puerto Rico: Centro de Estudios Avanzados
Category 1 CONCLUSION de Puerto Rico y el Caribe; 2003.
Pharmacists in PR are increasingly real-
Pharmacies that Prepare Simple
izing the importance of compounding and
Nonsterile Formulations in Limited are seeking training to be compliant with Address correspondence to Marisol López, RPh,
Quantities USP standards. The new pharmacy regula- MPH, Paseo Herradura #115, Parque del Rio,
This practice consists of mixing one or tions will give guidance and uniformity to the Trujillo Alto, Puerto Rico 00976.
two commercially available products for compounding practice in PR. Currently, PR’s E-mail: mlopezrx@gmail.com

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july/august 2009

276 Hormone Treatment Options for Males:

280 Saliva Tests, Part 1: Clinical Use, Elements

290 Preventing Nonmicrobiologic Airborne

276 296 Compounding Naltrexone for the

280 300 Preparing Nonsterile and Sterile Hazardous

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Applied PHA RMACEUTICAL

322 Basics of Gigi Davidson, BSPh, RPh, FSVHP, DICVP

CLAUDIA C. OKEKE, PHD, RPH;

314 Poster Presentation Peer Reviewed EMAIL: cburr@ijpc.com

MASC; DAVID ZAVA, PHD; DANIEL

333 Benzoyl Peroxide 10% Gel

337 Moxifloxacin 20-mg/mL Oral Liquid Progesterone: ( W EBSI TE )

340 Selegiline Hydrocholoride Australia SUBSCRIPTION AND ADVERTISING

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Jim E. Paoletti, RPh, FAARFM

International Journal of Pharmaceutical Compounding www.IJPC.com

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contain the same amount of the much stronger

International Journal of Pharmaceutical Compounding www.IJPC.com

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Hormone Treatment Options for Males:

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Treatment Options without

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24. Wittie J. Male hormonal contraceptives. Student paper. 2007 Feb.

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SALIVA TESTS, PART 1:

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t The collection time for saliva testing is more

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CONSUMER-DIRECT ORDERING OF SALIVA TESTING

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In general, increasing or decreasing the hormone dose will result in a

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The variations in hormone levels in men

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Tired of losing money, risking

Extra Personal Service in supplying pharmacy

PHARMACY SUPPLIES HOTLINE: 1-800-523-8966

in the Compounding Pharmacy: Ensuring a Safe Environment for

Gary Ille, MSIH

Editor’s Note: The safety of employees involved in the

Abstract Preventing and minimizing exposure to nonmicrobiologic airborne contaminants in a com-

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all workers are repeatedly exposed day after

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in this report is sound and accurate, and elimi-

Free Weekly contamination. IJPC 2006; 10(6): 446–448.

Newsletter pressures, evaporation behavior and airborne

For additional information, contact Bill Mixon, RPh,

International Journal of Pharmaceutical Compounding www.IJPC.com

Tom Wynn, RPh

International Journal of Pharmaceutical Compounding www.IJPC.com

for cytotoxic and hazardous drug prepara-

should be labeled as “chemotherapy gloves”

the proper equipment or environment, ﬁne