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Publication Date: September 2002
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HRT:
OPTIONS FOR MENOPAUSAL
VASOMOTOR SYMPTOMS


Crystal Capone, Pharm.D. Candidate


Introduction
The most common climacteric symptom
among post-menopausal women is the occurrence
of hot flashes, affecting approximately 80% of
women, and requiring 40% of those women to seek
medical attention.1 These symptoms last 1 to 5
years in 64% of women, with a median length of 4
years.2 Because the occurrence of these symptoms
is associated with decreased levels of estrogen,
logical treatment approaches have involved re-
placement of estrogen. Two types of estrogen have
been commonly prescribed, and include conjugated
equine estrogen (CEE) and a combination form of
CEE with medroxyprogesterone acetate (MPA),
with therapy depending on hysterectomy status. Re-
cent findings have redefined the role of hormone
replacement therapy (HRT), forcing practitioners to
seek other options for the primary prevention of
chronic diseases common in post-menopausal
women, and alternatives for the treatment of post-
menopausal symptoms. The purpose of this article
is to highlight the risk versus benefit of HRT, and
provide both pharmacological and non-
pharmacological alternatives for the management
of hot flashes in post-menopausal women.

Women's Health Initiative
The Women's Health Initiative (WHI) was


designed to assess the long-term risk/benefit ratio
of estrogen replacement therapy (ERT) and HRT in
disease prevention in healthy, post-menopausal
women. The study had two components: one which
randomized patients with a reported hysterectomy
to receive either CEE or placebo, and a second
component which randomized women with no his-
tory of hysterectomy to receive either placebo or a
combination of 0.625mg CEE and 5mg MPA
(Prempro). Coronary heart disease (CHD) was the
primary outcome measured, with a primary adverse
outcome of invasive breast cancer. A Global Index
was also compiled to assess other risk/benefits, and
included additional outcomes such as stroke, pul-
monary embolism, endometrial cancer, colorectal
cancer, hip fracture and death due to other causes.
The HRT component was terminated early, due to
statistically significant increases in the risk of cere-
bral vascular disease, stroke, pulmonary throm-
boembolism, and invasive breast cancer. These
risks outweighed the benefits of HRT, which in-
clude decreased incidences of hip fractures and co-
lon cancer.
Findings from the WHI created several
clinical dilemmas for practitioners. Cited benefits
of ERT/HRT include favorable effect on the lipid
profile, particularly increasing HDL, and the pre-
vention of osteoporosis. Lipid-lowering effects
were believed to be associated with stabilization or
prevention of CHD. It is now established that HRT
has no clinical role in the reversal of established
CHD, as determined by HERS II, or in the preven-
tion of CHD in health women as determined by the
WHI.3 Superior alternatives are available for pa-
tients using ERT/HRT for the prevention of osteo-
porosis. Patients requiring ERT or HRT for the
treatment of vasomotor symptoms associated with
menopause are still a challenge for clinicians. How-


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ever, other options are supported in scientific litera-
ture as being beneficial in hot flash reduction.

Non-pharmacological Options
Non-pharmacological options for the man-
agement of hot flashes revolve around lifestyle
changes and the addition of dietary supplements.
Lifestyle modifications target the avoidance of trig-
gers known to precipitate the hot flashes. Sugges-
tions include dressing appropriately so layers of
clothing can be removed should the patient begin to
experience warmth, and sleeping in a cool room for
patients who suffer from frequent night sweats. Pa-
tients should avoid getting too warm while indoors
by limiting hot beverages and foods such as soup.
Alcohol and spicy foods can cause vasodilatation,
triggering hot flashes in many patients, and there-
fore should be avoided whenever possible.1 Patients
should be instructed on diversion techniques such
as taking slow, deep breaths, to prevent the occur-
rence of hot flashes and lessen their severity.4
A diet high in soy or soy supplementation
may assist with management of hot flashes. Soy has
been advocated as an alternative to HRT in patients
with contraindications, or for patients searching for
natural alternatives. Soybeans are a rich source of
isoflavones, a class of phytoestrogens structurally
similar to estrogen derivatives and Selective Estro-
gen Receptor Modulators (SERMs).5
Several studies have compared the use of
soy versus placebo in reducing hot flash frequency
and severity. Both soy and placebo have demon-
strated statistically significant reductions in hot
flash frequency and severity, however, no statisti-
cally significant differences have been noted be-
tween the two.6,7 Decreases in frequency average
20% with soy products and placebo, although some
studies have demonstrated a 45% reduction with
soy products versus a 30% reduction with pla-
cebo.1'5 One studied noted patients on soy began
seeing relief of vasomotor symptoms within 2
weeks, while those on placebo did not experience
relief for an average of 4 weeks.' No recommended
doses of soy currently exist, however, the most
common dose in clinical studies was a product with
90 mg isoflavones given daily, which was well tol-
erated with no side effects.6
Black Cohosh, also known as Actaea ra-
cemosa, is an herb native to Eastern North Amer-


ica. Historical use has been for a variety of condi-
tions ranging from diarrhea to use as an antidote for
snake bites, while contemporary use focuses on the
treatment of menopausal symptoms.8 Clinical stud-
ies with Remifem (a standardized extract of black
cohosh) have demonstrated efficacy for alleviation
of menopausal complaints, specifically hot flashes.
One clinical study compared Remifem (40 mg
BID) to estriol (1 mg QD) and CEE (1.25 mg QD).
All treatment groups showed positive results, with
no significant difference between groups.8 In a sec-
ond study, Remifem 40 mg BID was compared to
CEE 0.625 mg and placebo for a duration of 12-
weeks. Significant improvements were seen in so-
matic parameters of those patients receiving the Re-
mifemin, compared to those treated with estrogen
or placebo.8 A third clinical study assessed the ef-
fective dose of black cohosh. Patients were ran-
domized to receive either 20 mg or 40mg BID of
Remifemin. Decreases in symptom scores were
seen with each dose, but no statistical difference
was noted between groups, leading to a recom-
mended dose 20 mg BID.8 The most common side
effect experienced by patients was gastric discom-
fort. A lack of toxicology studies led the German
Commission E to the recommendation not to ex-
ceed 6 months of use.
The use of soy and black cohosh have been
associated with a 20% reduction in hot flashes,
which is not comparable to the 70% reduction of
symptoms seen with HRT.5 This limits their use to
those patients who are highly susceptible to experi-
encing a placebo effect or those patients experienc-
ing mild hot flashes. Other limitations regarding
these products, include; limited knowledge of the
precise active ingredients, the minimal effective
dose, and lack of standardization.5 Other therapeu-
tic options are indicated for patients who do not ex-
perience relief with these products.

Pharmacological Options
Pharmacological options for the treatment
of hot flashes are based on proposed pathophysiol-
ogy theories regarding their etiology. Estrogen is
believed to play a role in hot flashes, but poor cor-
relation between blood estrogen levels and the fre-
quency and severity of hot flashes exists, suggest-
ing other mechanisms are involved.1 Two proposed
mechanisms frequently discussed in the literature


Pha rma Note Volume 17, Issue 11 September 2002


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involve the neurotransmitters norepinephrine (NE)
and serotonin (5-HT).

Clonidine
Evidence suggests that NE plays a signifi-
cant role in the prevalence of hot flashes. Studies
show increased brain NE levels in symptomatic
women, which rise when a hot flash occurs.2 NE
results in peripheral vasodilatation, heat loss and a
subsequent decrease in core body temperature. This
effect is provoked with central injection of yo-
himbine (an a2-adrenergic antagonist), and relieved
with injection of clonidine (Catapress), (an a2-
adrenergic agonist), suggesting that NE plays a role
in thermoregulation mediated through alpha-2
adrenergic receptors.2
The effects of clonidine on hot flashes are
believed to be mediated by a reduction in NE re-
lease, subsequently raising the sweating threshold
while lowering the shivering threshold.2 Clinical
trials demonstrate that clonidine significantly in-
creases the length of heating time required to in-
duce a hot flash, while decreasing the total number
of hot flashes.2 Two dosage forms have demon-
strated success in decreasing hot flash frequency,
severity and duration: transdermal patches and oral
tablets. One clinical trial compared transdermal ad-
ministration of clonidine 0.1mg to placebo. Clo-
nidine was associated with decreased patient re-
ports of hot flash frequency (80% vs 36% placebo),
decreased severity (73% vs 29% with placebo) and
decreased duration of hot flashes (67% vs 21%)
with p-values of <0.04, <0.04, and <0.03, respec-
tively.9 A second trial compared oral clonidine 0.05
mg twice daily to placebo, and 4 separate studies
were carried out. Since no statistically significant
differences were observed between studies, results
were averaged. The frequency, severity and dura-
tion of attacks were decreased in 78%, 89%, and
88% of patients, respectively, compared to 50%,
53%, and 50% decreases with placebo (p<0.05,
paired t-test).10 Both studies demonstrated no sig-
nificant effects on blood pressure, and determined
the required dose for post-menopausal symptoms to
be lower than the dose needed for the treatment of
hypertension.9,10
Caution should be exercised when adminis-
tering clonidine to patients with severe coronary
disease, recent MI, cerebrovascular disease or im-


paired hepatic or renal function. Because clonidine
is classically used as an anti-hypertensive, patient
blood pressure and pulse should be monitored.
Common adverse events include drowsiness, dizzi-
ness, dry mouth, constipation, and orthostatic hy-
potension. Patients should be advised not to
abruptly discontinue therapy, because rebound hy-
pertension may occur.

Antidepressants
Some antidepressants have been evaluated
for treatment of hot flashes in women post-breast
cancer treatment, with a history of breast cancer or
a concern regarding the use of estrogen because of
their risk for developing breast cancer. Antidepres-
sants have demonstrated more significant reduc-
tions in hot flash frequency and severity compared
to other options such as isoflavones, black cohosh
or clonidine. Anti-depressants are believed to work
via their effects on serotonin (5-HT), a neurotrans-
mitter associated with hot flashes.
Two Selective Serotonin Reuptake Inhibi-
tors (SSRIs) have shown benefit in post-
menopausal women in reducing hot flashes,
fluoxetine (Prozac) and paroxetine (Paxil ).
Fluoxetine 20 mg has been compared with placebo
in a double-blind randomized cross-over study. Hot
flash scores, defined as frequency x average sever-
ity, were decreased by 50% compared to a 36% re-
duction in the placebo arm (p=0.35)11 The superior-
ity of fluoxetine was verified by cross-over analy-
sis. Paroxetine has also demonstrated effectiveness
in reducing hot flash frequency and severity. Pa-
tients received paroxetine 10 mg daily for one
week, followed by four weeks at 20 mg daily.
Treatment with 20mg paroxetine reduced hot flash
frequency 56%-79%, with a mean reduction of
67%, and reduced the hot flash severity score by
66%-85%, with a mean reduction of 75%.12 Both
SSRIs were well tolerated, with somnolence being
the main adverse event.
The largest published study assessing the
use of an antidepressant for the management of hot
flashes involves the use of venlafaxine (Effexor).
In the venlafaxine dose-seeking trial, venlafaxine
was evaluated at doses of 37.5, 75 and 150 mg/day
compared to placebo. Overall, the median decrease
in hot flash scores was significantly greater in all
three venlafaxine groups vs placebo (p<0.0001).13


Pha rma Note Volume 17, Issue 11 September 2002


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Volume 17, Issue 11 September 2002







The study found a 27% reduction in the average
daily hot flash score in patients receiving placebo,
and a 37% reduction in patients receiving 37.5 mg
daily (p=0.008).13 Patients receiving 75 mg demon-
strated a 61% reduction, a statistically significant
difference when compared to the 37.5 mg group
(p=0.03), and no significant difference existed be-
tween the 75 mg and 150 mg groups.13 The use of
venlafaxine was associated with dry mouth and ap-
petite suppression. Dosing recommendations for
the treatment of hot flashes have been made based
on the findings of this study. Therapy should be ini-
tiated at a dose of 37.5 mg daily for 1 week.13 If
symptom control is not optimal, the dose may be
increased to 75 mg daily. Doses greater than this
are not recommended since they provide no addi-
tional benefit, and increase the occurrence of side
effects.

Conclusion
Before prescribing HRT, patients should
demonstrate a clear and strong indication for ther-
apy and the risk versus benefits should be evalu-
ated. In patients prescribed HRT for the manage-
ment of postmenopausal symptoms, several safer
alternatives exist. The most studied and effective
non-hormonal therapy for hot flashes is venlafaxine
at a dose of 75 mg daily, in an extended-release
form.13 Patients who are currently on HRT should
be tapered off therapy to lessen the chance of re-
bound hot flashes. The clinical implications for
women on ERT have not yet been defined, how-
ever, practitioners may chose to err on the side of
caution. Patients who can not tolerate other options
and require HRT should be carefully monitored
short term. Long-term use over 2 years should be
rigorously monitored, and the risk-benefit ratio re-
assessed often.

References
1. Berendsen, H. Hypothesis: The role of sero-
tonin in hot flushes. Maturitas 2000;36:155-
164.
2. Freedman R. Physiology of hot flashes. Am j of
Hum Bio 2001;13:453-464.
3. Utian, WH. Managing menopause after HERS
II and WHI: Coping with the aftermath. Meno-
pause Management 2002 Jul-Aug. Available
from: URL: http://www.menopause.org/pr.
html.


4. Alternatives to Hormone Replacement Therapy:
Suggestions from the North American Meno-
pause Society. July 11, 2002. Available from:
URL: http://www.menopause.org/
alteratives hrt.html.
5. Vincent A, Fitzpatrick LA. Soy isoflavones: are
they useful in menopause? Mayo Clin Proc
2000 Nov; 75(11): 1174-84.
6. Van Patten CL, Olivotto IA, Chambers GK,
Gelmon KA, Hislop TG, Templeton E, et al.
Effect of soy phytoestrogens on hot flashes in
postmenopausal women with breast cancer: a
randomized, controlled clinical trial. J Clin On-
col. 2002 Mar; 20(6):1436-8.
7. Upmalis DH, Lobo R, Bradley L, Warren M,
Cone FL, Lamia CA. Vasomotor symptom re-
lief by soy isoflavone extract tablets in post-
menopausal women: a multicenter, double-
blind, randomized, placebo-controlled study.
Menopause 2000 Jul-Aug; 7(4):236-42.
8. Mckenna, Dennis J., Kenneth, Humphrey,
Sheila, et al. Black Cohosh: efficacy, safety,
and use in clinical and preclinical applications.
Alt Ther in Health & Med 2001 May-Jun; 7(3):
[15 screens]. Available from URL: http://www.
webbackup.epnet.com/citation.
9. Nagamani M, Kelver ME, Smith ER. Treatment
of menopausal hot flashes with transdermal ad-
ministration of clonidine. Am J Obstet Gynecol
1987 Mar; 156(3):561-5.
10. Edington RF, Chagnon JP, Steinberg WM. Clo-
nidine (Dixarit) for menopausal flushing. CMA
J 1980 Jul; 123(4):23-6.
11. Loprinzi C, Sloan J, Perez E, Quella S, Stella P,
Mailliard J, et al. Phase III evaluation of
fluoxetine for treatment of hot flashes. Joum
Clin Oncol 2002 Mar; 20(6):1578-1583.
12. Steams C, Isaccs C, Rowland J, Crawford J,
Ellis M, Kramer J, et al. A pilot trial assessing
the efficacy of paroxetine hydrochloride (Paxil)
in controlling hot flashes in breast cancer survi-
vors. Annal Oncol 2000; 11:17-22.
13. Loprinzi C, Kugler JW, Sloan JA, Mailliard JA,
LaVasseur BI, Barton DL, et al. Venlafaxine in
the management of hot flashes in survivors of
breast cancer: a randomised controlled trial.
Lancet 2000 Dec;356:2059-63.
14. Writing Group for the Women's Health Initia-
tive Investigators. risks and benefits of estrogen


-
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Volume 17, Issue 11 September 2002







plus progestin in health postmenopausal
women: principal results from the Women's
Health Initiative Randomized Controlled Trial.
2002 Jul; 288(3):321-333.


ACCUTANE
UPDATE



Jenny McCabe, Pharm.D. Candidate
Introduction



Acne vulgaris affects 80% of the population
between the ages of 12 and 25.1 There are various
over-the-counter (OTC) and prescription medica-
tions available to treat acne, but only one has
shown significant effects in treating severe acne.
The FDA approved Accutane isotretinoinn) in May


1982, for the treatment of severe recalcitrant nodu-
lar acne.23 In the last 8 years, there has been a
250% increase in the number of dispensed prescrip-
tions for isotretinoin in the United States.4 This
data also reveals an increase in the use of isotreti-
noin for mild to moderate acne.
Acne vulgaris is an inflammation of the
pilosebaceous unit. Acne is capable of producing
psychological and physical scarring. A prospective
clinical study examined the early use of isotretinoin
in acne treatment and demonstrated the beneficial
effect in minimizing acne scarring.5 This article will
discuss the pharmacology, dosing, adverse effects,
clinical trials, and new prescribing guidelines for
isotretinoin.

Pharmacology/Pharmacokinetics
Isotretinoin (13-cis-retinoic acid) is an oral
retinoid that mediates intracrine and paracrine cell
differentiation, proliferation, apoptosis, and repro-
duction. The primary action of isotretinoin is a re-
versible inhibition of sebum production through a
reduction in the size of sebaceous glands and possi-
ble inhibition of follicular keratinization.2 Only
isotretinoin exerts such an effect on sebum produc-
tion. Isotretinoin is an effective compound capable
of treating severe acne because it is the only one


rhcrmainte


that affects all etiological factors of acne: sebum
production, comedogenesis and colonization with
Propionibacterium acnes.6
The pharmacokinetics of isotretinoin do
not seem to differ with gender. Absorption of isot-
retinoin is incomplete; however, bioavailability can
be enhanced by taking it with food or milk. Peak
plasma concentrations are attained within 3 hours.
Unlike vitamin A, isotretinoin does not accumulate
in the liver. Isotretinoin is 99.9% bound to plasma
proteins, and is metabolized in the liver to 4-oxo-
isotretinoin. It is unknown whether this metabolite
has pharmacologic activity. The half-life of isotreti-
noin is 10-20 hours. The metabolites are eliminated
via renal pathways, while unchanged drug appears
to be excreted in the feces through biliary elimina-
tion.2

Dosing
The recommended dosage range for isotreti-
noin is 0.5-1.0mg/kg/day, by mouth, given in two
divided doses for 15-20 weeks. Maximum recom-
mended daily dose is 2mg/kg. A safe dosage has
not been established in children. The age in which
isotretinoin can be safely given is unclear. Specific
guidelines for dosage adjustments in hepatic and
renal impairments are not available; it appears that
no dosage adjustments are needed.2

Adverse Effects
The use of isotretinoin has been associated
with reports of adverse events. Two trials examined
the difference in adverse events in once daily dos-
ing verses twice daily dosing of isotretinoin. Demo-
graphics are summarized in Table 1. In the first
trial, 67 patients received isotretinoin at 1mg/kg in
a single dose with food for 16-20 weeks. The pa-
tients were asked to evaluate adverse effects at
weekly visits. The patients rated the severity of
each event on a 10cm visual analog scale (VAS)
with 0 being not present and 10 being extremely
noticeable. In the second trial, 300 patients received
isotretinoin at 1mg/kg in 2 equally divided doses
with meals. The incidence of adverse effects, in
both trials, is seen in Table 2. Chelitis persisted for
up to 95.8% of the therapy period and was the big-
gest concern among patients.7
Liver function tests and cholesterol levels
should be evaluated on a monthly basis during isot-
retinoin therapy. As many as 5% to 25% of patients

Volume 17, Issue 11 September 2002


1


I I I I I I IP I W







Table 1. Summary of Demographic Data7
Trial 1 Trial 2
Characteristic
(n=69) (n=300)
Sex
Male (%) 31(45) 174(58)
Female (%) 38(39) 126(42)
Age (y)
Mean 22.9 21.6
Median 21 20
SD 7.6 6.8
Range 13-43 13-50
Height (cm)
Mean 171.2 172.7
Median 172 172
SD 9.7 9.4
Range 152-192 144-203
Weight (kg)
Mean 69.4 71.6
Median 67 69.3
SD 15.6 14.5
Range 41-120 41-125



show abnormalities in liver function tests, but most
of these cases present with no histologic liver
change.1l Elevations in triglyceride levels occur in
25% to 45% of patients.l In both trials, serum
triglyceride values increased by 0.99 to 1.441
mmol/L over baseline to 2.11-1.670 mmol/L at
week 20. In both groups the mean variation was
within the normal range. Both treatment groups
were not associated with increased risk of cardio-
vascular problems or pancreatitis.7
Between the years 1982 and 2000, 37 cases
of suicide have been reported while taking isotreti-
noin.1 The population most commonly treated with
isotretinoin (12-18 year olds) are at increased risk
for depression and suicide. The number of suicides
reported does not exceed what is expected, given
the suicide rate in the United States." A prospective
and retrospective study of isotretinoin concludes
that there is not an increased risk for depression,
suicide, or other psychiatric problems associated
with isotretinoin use.10 Because there are few trials
that have evaluated at the psychiatric effect of isot-
retinoin, a conservative approach has been adopted,
including FDA warnings. Also it is important that
physicians advise patients, especially those with a
history of depression, to report changes in mood or
behavior."1


Table 2. Incidence of adverse events by body systems7
Percentage of patients with
adverse events
Body System Trial 1 Trial 2
(n=69) (n=300)
All body systems 100 97.6
Skin and subcutaneous disorders 100 92
Gastrointestinal 100 93
Respiratoryb, thoracic, and
62 70.7
mediastinal disorders
Disorders of eye' 73 57
Infections and infestations 9 26
Neurologic disorderSd 29 16.3
Musculoskeletal, connective 2 .
20 14.3
tissue, and bone disorders
General disorder 3 4.7
Injury and poisoning 1 10.7
Psychiatric disorders 0 0.3
Reproductive system and breast 3
disorders
Disorders of immune system 0 2.3
Disorders of metabolism and
nutrition
Cysts 0.7 0.3
Cardiac disorders 0 1
Disorders of ear and labyrinth 0 0.7
SIncludes cheilitis, b Includes dry nose and epistaxis, c Includes dry and irritated
eyes, d Includes headaches


The most serious adverse event associated
with isotretinoin is congenital abnormalities. When
a pregnant woman exposes a fetus to isotretinoin,
25% to 30% of pregnancies will show malforma-
tions.1 The most commonly reported malforma-
tions include craniofacial, cardiac, thymic and cen-
tral nervous system structures."l The severity of fe-
tal malformation has led to new prescribing proce-
dures for isotretinoin, including the System to Man-
age Accutane Related Teratogenicity (S.M.A.R.T).

Clinical Trials
A randomized, double blind, placebo con-
trolled trial examined 33 patients with treatment re-
sistant cystic and conglobate acne. This study
tested the efficacy of isotretinoin versus placebo.
Criteria for inclusion into the study required at least
10 inflamed deep dermal or subcutaneous acne
cysts of at least 4mm diameter. All patients had dis-
continued their conventional acne treatment for at
least one month before entry into the study. No
other acne therapy was allowed during the 4-month
treatment period. The number of cysts present de-


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Volume 17, Issue 11 September 2002







Table 3. Grading of facial acne scars according to scar type
Ice-pick macular atrophic Hypertrophic keloid
number scar grade number scar grade
(1-5) 1 (1-3) 2
(6-10) 2 (4-7) 4
(11-25) 3 (>7) 6
(26-50) 4
(51-100) 5
(>100) 6


termined efficacy of treatment. Patients assigned to
the placebo group were comparable in age, sex, and
number and distribution of lesions to those patients
who received isotretinoin.14
At the 1-month observation period, the mean
number of cystic lesions in the 17 patients receiv-
ing the placebo had increased by 33%. Eight pa-
tients receiving placebo had a mean increase of
61% in their lesion count, and were switched to
isotretinoin. The remaining 9 patients had a mean
increase in lesions of 58%. Five of the 9 patients
were dropped from the study and were switched to
isotretinoin. Two patients had slightly fewer lesions
after 2 months. Of these 2 patients, one received
isotretinoin by mistake. During placebo therapy,
there was an overall 57% increase in the number of
lesions. Sixteen of the 17 patients receiving placebo
were subsequently treated with isotretinoin.14
Sixteen patients received isotretinoin ther-
apy beginning at 0.5mg/kg/day. Six patients had
their dosage increased when no improvement in
their acne was noted at the 1-month follow-up.
Acne became worse in 2 patients treated with isot-
retinoin and they subsequently received treatment
at a higher dose. The mean daily dose of isotreti-
noin at month 2 of the study was 0.65mg/kg/day.
After one month, cystic lesions in patients treated
with isotretinoin decreased by 17% from baseline.
After 2 months, the lesions decreased by 32%. 14
This study concluded that there was a 95% im-
provement in the 16 patients who were randomly
selected to receive isotretinoin. Sixteen of the 17
patients receiving placebo were switched to isot-
retinoin, which resulted in a 98% improvement
from baseline. Twenty-seven of the 32 patients
treated with isotretinoin cleared completely. Eight-
een patients received only one 4-month course of


isotretinoin. Fifteen patients received 2 courses. Of
these fifteen patients, twelve responded with the
first course of treatment but had mild relapse after
six months off treatment. All patients are now in
remission averaging 38 months in duration. Contin-
ued healing and prolonged remission after discon-
tinuation of therapy with isotretinoin was observed
in these patients. 14
A prospective trial was designed to assess
the effect of early therapy on the outcome of acne
scarring. This trial included 107 patients with facial
acne, treated with isotretinoin 1mg/kg/day for 4
months (Table 3). At the end of treatment, the de-
gree of acne scarring was scored. This study found
that patients given treatment after 3 years of acne
received a mean scar score of 4.34. Patients with
acne for less than 3 years had a mean score of 1.11.
The study concluded that less scaring resulted in
patients who received isotretinoin early in their dis-
ease process.

New Prescribing Guidelines
Effective April 10, 2002, all prescribers,
pharmacists, and patients must comply with the
conditions of the S.M.A.R.T. program.13 Prescrib-
ers must sign and return to Roche the Letter of Un-
derstanding certifying their knowledge in minimiz-
ing fetal exposure to isotretinoin. Prescribers will
receive Accutane Qualification stickers that must
be attached to all prescription forms. The stickers
indicate to the pharmacist that the patient is quali-
fied to receive isotretinoin. Females of childbearing
potential must have 2 negative pregnancy tests
prior to beginning isotretinoin and then monthly
during treatment. Sexually active patients must use
two forms of contraception for a least one-month
prior to initiation of treatment, during treatment,
and one month after discontinuing treatment. Pa-
tients must sign a consent form prior to beginning
therapy.
Pharmacists may only dispense isotretinoin
upon presentation of a prescription with a special
Accutane Qualification sticker, and will dispense a
maximum of a 1-month supply. Prescriptions must
be filled within 7 days from the date written on the
yellow qualification sticker. Pharmacists must pro-
vide a Medication Guide for patients with each
isotretinoin prescription. Requests for refills and
phone-in prescriptions will not be filled.2'13


Ph ra ot Vlue 7,Isue11Setebe 20


PharmaNote


Volume 17, Issue 11 September 2002








Summary
Acne is both psychologically and physically
scarring. With proper training and knowledge, phy-
sicians can safely prescribe isotretinoin for patients
with acne. Isotretinoin has severe adverse events
but with the S.M.A.R.T. program in place, these
adverse events can be prevented. The S.M.A.R.T.
program requires patients, physicians and pharma-
cists to work as a team to reduce acne, the scarring
from acne, and adverse events.

References
1. Leyden JJ. Therapy for acne vulgaris. N Engl J
Med 1997; 336: 1156-1162.
2. Reents S, Seymour J. Clinical Pharmacology
2000. Version 2.0. Gold Standard Multimedia;
2002
3. Accutane Product Information. Roche Labora-
tories Inc, February 2002
4. Wysowski DK, Swann J, Vega A. Use of isot-
retinoin (Accutane) in the United States: Rapid
increase from 1992 through 2000. J Am Acad
Dermatol 2002; 46: 505-9.
5. Layton AM, Seukeran D, Cunliffe WJ. Scarred
for Life? Dermatology 1997; 195 supplyl 1): 15-
21.
6. Ortonne JP. Oral Isotretinoin Treatment Policy:
Do We All Agree? Dermatology 1997; 195
supplyl 1): 34-37.
7. McLane J. Analysis of common side effects of
isotretinoin. J Am Acad Dermatol 2001; 45:
Suppl 1:188-94.
8. Wysowski DK, Pitts M, Beitz J. Depression and
suicide in patients treated with isotretinoin. N
Engl J Med 2001; 344:460.
9. Thiboutot DM. Acne and rosacea: New and
emerging therapies. Dermatol Clin 2000; 18:63-
71.
10. Jick ss, Kremers HM, Vasilakis-Scaramozza C.
Isotretinoin use and risk of depression, psy-
chotic symptoms, suicide, and attempted sui-
cide. Arch Dermatol 2000 136:1231-36.
11. Hanson N, Leachman S. Safety Issues in Isot-
retinoin Therapy. Seminars in Cutaneous Medi-
cine and Surgery September 2000; 20(3): 166-
83.
12. Ishijima K, Sando I. Multiple temporal bone
anomalies in isotretinoin syndrome: A temporal


bone histopathologic case report. Arch Oto-
laryngol Head Neck Surg 1999; 125: 1385-88.
13. Hoffmann-La Roche Inc. Current News Re-
lease: Roche initiates S.M.A.R.T.TM, an en-
hanced pregnancy prevention program to pre-
vent Accutane-exposed pregnancies. Jan. 2002:
Nutley, N.J. Available from: URL: http://www.
rocheusa.com/newsroom/current/2002/
pr2002010701.html.
14. Peck GP, Olsen TG, Butka, D, Pandya M, Ar-
naud-Battandier J, Gross EG, Windhorst DB,
Cheripko J. Isotretinoin versus placebo in the
treatment of cystic acne. J Am Acad Dermatol
1982; 6: 73-745.


Pha rma Note Volume 17, Issue 11 September 2002


The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.

v'^yyyyyyyyyyyyyyyyyyyyyyy111


PharmaNote


Volume 17, Issue 11 September 2002




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