Safety of Topical Minoxidil

Solution: A One-Year, Prospective,

Observational Study DOI: 10.1007/s10227-002-0121-6
J Cutan Med Surg 2003; 322–329

Jerry Shapiro

Abstract
Background: Topical minoxidil solution (TMS) is widely used for androgenetic alo-
pecia (AGA), and this is the first report of a large safety trial.
Objectives: The aim of the study was to evaluate the safety profile of TMS by com-
paring hospitalization and death rates among subjects using TMS with controls. Car-
diovascular safety and pregnancy outcomes were evaluated, and usage patterns were
described.
Methods: All subjects were followed at baseline, 3, 6, 9, and 12 months. Usage pat-
terns, pregnancy status, overnight hospital stays, and cardiovascular risk factors were
evaluated. Subjects rated effectiveness of TMS in the treatment of AGA. Statistical
analyses were conducted to determine if TMS was associated with an increased risk of
death or hospitalization.
Results: TMS is a safe and effective treatment for AGA. There were no increases in
cardiovascular events and no apparent increased risk for adverse pregnancy outcomes.
Conclusions: This large, prospective study demonstrated the overall safety of TMS in
the treatment of AGA.

Sommaire
Ante´ce´dents: Le minoxidil en solution topique est fréquemment utilisé dans le trait-
ement de la pelade. Nous présentons ici le premier rapport d’innocuité à large échelle.
Objectifs: Évaluer le profil d’innocuité du minoxidil en solution topique en comparant
les taux d’hospitalisation et de mortalité des sujets qui reçoivent un traitement contrôlé
de la solution. L’innocuité cardiovasculaire a été évaluée, les grossesses ont été suivies et
les tendances d’utilisation décrites.
Me´thodes: Tous les sujets ont été suivis dès le début du traitement avec les évaluations
ayant lieu aux 3, 6, 9, et 12 mois. Les tendances d’utilisation, le statut des grossesses, les
hospitalisations et les facteurs de risques cardiovasculaires ont été évalués. Les sujets ont
évalué l’efficacité de la solution de minoxidil dans le traitement de la pelade. Des analyses
statistiques ont été effectuées en vue de déterminer si le minoxidil en solution topique
était associé à un risque plus élevé de décès ou d’hospitalisation.
Re´sultats: Le traitement au minoxidil en solution topique contre la pelade est sécur-
itaire et n’augmente pas le risque des accidents cardiovasculaires. Également il n’y a eu
aucune augmentation apparente des risques en cas de grossesse.
Conclusions: Cette étude prospective à large échelle a démontré l’innocuité générale
du traitement au minoxidil en solution topique centre la pelade.

A ndrogenetic alopecia (AGA), or hereditary hair

Division of Dermatology, Department of Medicine, The University of
British Columbia, Vancouver, British Columbia, Canada
Online publication: 28 July 2003
Correspondence to: Jerry Shapiro, Division of Dermatology, Department of
Medicine, The University of British Columbia, 835 West 10th Avenue,
Vancouver, British Columbia, Canada, V5Z 4E8, E-mail: shapiro@inter-
change.ubc.ca
thinning, is the most common cause of hair loss in
men and women and affects, to varying degrees, ap-
proximately 50% of adults older than age 40.1–3 Other
causes of hair loss are often secondary to pathologic
processes, such as drugs, autoimmune disease, endocrine
dysfunction, infection, trauma, or stress.2 Although hair
loss does not usually negatively affect physical health, it

322
J. Shapiro Safety of Topical Minoxidil Solution
can be profoundly distressing because of the stigma re-
lated to balding and the associated connotations of ill-
ness, premature aging, and loss of vitality.2,4 In a review
of the research literature, Cash5 reported that most men
suffer at least moderate stress from balding, and, for
some, hair loss may become a major focus of body dys-
morphic concern. In addition, women often respond to
hair loss with greater distress and impairment than men.
As a result, each year 60 million people in the United
States spend approximately $1.5 billion on hair regrowth
treatments,1,6 many of which are unproven.
Several treatment options have become available for
AGA in the past 15 years. One of the most widely used
and most rigorously studied therapies for AGA in men
and women is topical minoxidil solution (TMS), which is
now available in the United States without a prescription
as a 2% or 5% formulation for men and as a 2% for-
mulation for women. Although controlled data demon-
strate the efficacy of TMS in both men and women with
AGA,7,8 large-scale safety data have not been published.
Herein, the findings of one-year, prospective, observa-
tional study of TMS are reported, providing the largest
safety database yet available. The objectives of this study
were to describe the typical subject using TMS and his or
her pattern of use during one year. In addition, this study
compared one-year rates of hospitalizations and deaths
among subjects using TMS with periods of nonexposure
and with control subjects. Emphasis was placed on car-
diovascular safety and pregnancy outcomes.
Methods
Study Population
The protocol for this survey was submitted to the Insti-
tutional Review Board at Boston University Hospital,
which gave its approval of the study. At the time of the
study, TMS was available by prescription only. Subjects
were recruited and enrolled at the time when they had a
prescription for TMS filled at participating retail phar-
macies across the United States. Those pharmacies were
invited to participate in the study through their retail
chain management or through direct contact by the
Upjohn Company’s field staff. The participating phar-
macies received registry packets that included instruc-
tions on how to recruit subjects and an enrollment form
for each potential customer filling a prescription for
TMS. Subjects were considered eligible if they were old
enough to provide legal consent for release of medical
information, had a telephone, could speak English or had
access to a translator, and resided in the U.S. in order to
facilitate medical event confirmation. Each week, the
participating pharmacies mailed their completed enroll-
ment forms to the Upjohn Consumer Health Survey
Coordinating Center.
Control subjects were selected from members of a com-
mercial consumer panel maintained by NFO Research,
Incorporated, Toledo, Ohio. They were matched with the
323
TMS users by age, race, gender, education, and place of
residence. Control subjects received recruitment letters
that asked them to enroll in the study and provide written
consent to authorize release of medical information.
Study Design
In this prospective, observational study, data were col-
lected by computer-assisted telephone interviews at
baseline and at 3, 6, 9, and 12 months. The baseline
interview was conducted 4 weeks after enrollment and
focused on characterizing risk factors for adverse cardi-
ovascular outcomes. Subjects were asked to provide in-
formation on smoking history, height, weight, presence
of chronic or serious medical illness, prescription medi-
cations for diabetes, cholesterol, or high blood pressure,
and education level. Other questions sought information
about the number of overnight hospital admissions,
pattern of hair loss, pregnancy status, TMS use patterns,
and use of other hair regrowth products in combination
with TMS. To mask the cardiovascular focus of the in-
terview, subjects were also queried about a number of
broad-based, superficial topics (e.g., sleep habits, diet,
and dental history).
The four followup telephone interviews at 3, 6, 9, and
12 months were designed to obtain information on pri-
mary outcome measures: hospitalizations, deaths, and
pregnancy outcomes (i.e., infant status). Fewer masking
questions were asked during these intervals, and preg-
nancy status was confirmed. An interview was considered
complete when sufficient information was obtained to
confirm the continued willingness of the subject to par-
ticipate in the study, to confirm his/her hospitalization
status, and to allow for spontaneous reporting of medical
events. Subjects were allowed to withdraw from the study
at any point; subsequent events that occurred following
withdrawal were therefore not confirmed. However, at-
tempts were made to confirm the health of those subjects
who were lost to followup at 12 months after enrollment.
All medical event information reported during the
interviews and recorded on confirmation forms was
reviewed and coded by a blinded physician.
Attempts were made to confirm any hospitalizations,
deaths, or pregnancies reported. In the case of reported
hospitalizations, information requested from the hospi-
tals or the attending physicians included dates of the
event and diagnoses. In the case of reported deaths, a
letter requesting confirmation of death was sent to the
office responsible for death registration in each relevant
state. In the case of reported pregnancies the same con-
firmation procedures were followed as for hospitaliza-
tions two weeks following the subject’s projected delivery
date. Data reported during telephone interviews and re-
ceived on confirmation forms (i.e., reasons for hospitali-
zation, causes of death, discharge diagnoses, and infant
status at pregnancy termination) were reviewed and
classified by a blinded physician.
324 Journal of Cutaneous Medicine and Surgery Volume 7 Number 4 July 2003

TABLE I

Demographic characteristics of subjects in the TMSa and control groups

Chareteristics TMS group (%) Control group (%) Chi-squared significance

Gender
Male 10,085 (90.7) 9731 (87.1) <0.0005
Female 1037 (9.3) 1442 (12.9)
Age (years)
18–34 5408 (48.7) 5287 (47.3) 0.013
35–44 3602 (32.4) 3665 (32.8)
45–54 1407 (12.7) 1408 (12.6)
55–64 487 (4.4) 560 (5.0)
‡65 201 (1.8) 253 (2.3)
Race
White 10,087 (91.1) 10,141 (90.8) 0.437
Black and other 989 (8.9) 1031 (9.2)
Education (years)
<12 251 (2.3) 203 (1.9) 0.004
12–15 4475 (41.8) 4297 (40.3)
>15 5990 (55.9) 6162 (57.8)
Region of U.S.
North–Central 2234 (20.1) 2348 (21.0) 0.021
Northeast 2517 (22.7) 2492 (22.3)
South 3565 (32.1) 3695 (33.1)
West 2789 (25.1) 2631 (23.6)
Smoking history
Current smoker 1650 (14.8) 2111 (18.9) 0.003
Prior smoker 3242 (29.1) 2861 (25.6)
Overnight hospital
admissions in past year
None 10,115 (90.9) 10,003 (89.5) 0.939
1 episode 503 (4.5) 503 (4.5)
2 episodes 82 (0.7) 119 (1.1)
‡3 episodes 15 (0.1) 28 (0.3)

a
TMS = topical minoxidil solution.

During the interviews, subjects in the TMS group
were asked how often they used TMS. If they did not use
it twice daily, they were asked to specify start and stop
dates of treatment. This information was used to classify
confirmed adverse events relative to TMS use. Based on
the pharmacokinetic characteristics of TMS, subjects
reporting use of TMS within 4 days prior to a medical
event were classified as ‘‘exposed’’ at the time of the
event, whereas subjects reporting no TMS use for 4 or
more days prior to an event were classified as ‘‘not ex-
posed.’’ Subjects who were unable to specify start and
stop dates were classified as ‘‘possibly exposed’’ at the
time of the event.
Beginning with the 3-month interview, subjects in the
TMS group were asked to rate the effectiveness of TMS
in promoting new hair growth and in slowing or stopping
hair loss. Four responses were provided for answering
each question: excellent, good, fair, or poor.
Statistical Analysis
Chi-squared tests for homogeneity of distributions were
performed to compare the baseline characteristics of the
two groups on categorical variables. Two-sample t tests
were used to compare the groups with respect to baseline
characteristics on continuous variables.
For the primary end points, statistical analyses were
performed to determine whether exposure to TMS was
associated with an increased risk of death or hospitali-
zation from all causes or for cause-specific reasons within
each body system, with emphasis on the cardiovascular
system. All analyses were conducted on the intent-to-
treat population, with all subjects in the TMS group
considered exposed and all subjects in the control group
considered not exposed. Significance tests were two-sided
with an alpha level of 0.05, and only valid study regis-
trants were included in the analyses.
Relative risk estimates and 95% confidence intervals
were calculated to compare rates of deaths from all
causes, hospitalizations from all causes, and hospitaliza-
tions within each body system. Logistic regression anal-
yses were used to identify potential explanatory variables
associated with the risk of experiencing a hospitalization.
Potential explanatory variables included age, gender,
treatment group, cardiovascular risk, overall assessment
of health, overnight hospital stays in the past year, pattern
of hair loss, body mass index, and smoking history. Sur-
vival analysis techniques were used to compare the dis-
J. Shapiro Safety of Topical Minoxidil Solution 325

TABLE II

Self-rated effectiveness of TMSa for slowing or stopping hair loss

Responses Excellent Good Fair Poor Missing

from N (%) (%) (%) (%) (%)

Month 3 10,010 22.9 40.1 22.9 6.2 7.9

Month 6 9484 22.3 42.3 25.6 6.4 3.4
Month 9 8678 21.5 42.3 27.4 6.8 2.1
Month 12 8112 21.3 42.9 27.9 6.4 1.6
Month 12 by gender:
Male 7424 20.7 43.4 28.2 6.2 1.5
Female 688 27.2 37.8 24.3 8.7 2.0
Month 12 by baseline hair loss condition:
None/Slight 2625 23.4 43.8 25.7 5.4 1.7
Moderate 4009 20.2 43.8 28.7 5.9 1.4
Pronounced/Severe 1441 20.5 39.0 29.4 9.4 1.7

a
TMS = topical minoxidil solution.

tributions of time to first event for the two groups.
Survival distributions were estimated by the Kaplan–
Meier method and compared by log rank tests for time to
first hospitalization or death involving any body system
and involving the cardiovascular system. Chi-squared
tests for homogeneity of distributions were performed to
compare those subjects who were lost to followup with
subjects who completed the study.
Results
Demographics
A total of 11,122 subjects were enrolled in the TMS
group out of 12,738 subjects recruited, and 11,173 sub-
jects were enrolled in the control group out of 11,259
subjects recruited. Overall, followup data for one year
were obtained for more than 93% of subjects in both
groups, resulting in more than 3 million subject-days of
exposure to TMS observed. From the TMS group,
87.4% of subjects completed the study by completing
their month-12 interviews, and 6.5% of subjects achieved
12 months of study participation by responding to lost-
to-followup queries by telephone or mail contact. Simi-
larly, 88.6% of control subjects completed the study by
completing their 12-month interviews, and 8.2%
achieved 12 months of study participation by responding
to lost-to-followup procedures. A total of 1.1% of sub-
jects in the TMS group and 0.7% of control subjects
withdrew prematurely, and 4.9% (550 subjects) and 2.5%
(284 subjects) of subjects in the TMS and control groups,
respectively, remained lost to followup.
Most subjects were Caucasian men between the ages
of 18 and 44 (Table I). Chi-squared tests for between-
group homogeneity indicated that there were statistically
significant (P < 0.05) but clinically unimportant differ-
ences for all demographic variables, with the exception of
race. These differences were not clinically meaningful
because the actual differences in the proportions were so
small. Region of residence and education status at study
entry were similar; more than half of subjects graduated
from college. Data about smoking history were collected
for analytic intent from among the questions on lifestyle
and personal habits. Fifteen percent of subjects in the
TMS group and 19% of control subjects reported being
current smokers, and 29% and 26%, respectively, re-
ported a prior smoking history. All other questions re-
garding lifestyles and personal habits were used to
support the claim that this was a health survey, and to
provide descriptors of the study groups.
In addition, the number of hospital admissions that
resulted in at least one overnight stay during the year
prior to enrollment was collected for analytic purposes as
an indicator of health status and predisposition to hos-
pital admissions. A total of 91% of subjects in the TMS
group and 90% of control subjects reported no overnight
hospitalizations. Nearly 5% of subjects in both groups
reported one episode, and approximately 1% reported
two or more hospitalizations in both groups.
The extent of hair loss was determined during the
baseline interview. Hair loss was more prevalent and more
pronounced in the TMS group, and 67% of TMS subjects
reported moderate to severe hair loss versus 23% of
control subjects. Slight hair loss was reported by 31% of
subjects in the TMS group and 28% of control subjects. In
contrast, only 1% of subjects in the TMS group reported
no hair loss compared with 49% of control subjects.
Questions about indicators of cardiovascular disease,
such as diabetes, high blood pressure, heart attack, stroke,
and other heart conditions, were used as analytic variables
and to identify cardiovascular risk. Subjects who endorsed
one or more of these conditions were considered at risk for
cardiovascular disease. Fourteen percent of subjects in the
TMS group had cardiovascular risk factors compared with
20% of control subjects (P < 0.005).
Patterns of TMS Use
Overall, 96% of subjects in the TMS group used TMS
during the study compared with 1% of control subjects.
Use of TMS decreased from 95% in TMS subjects at
326 Journal of Cutaneous Medicine and Surgery
TABLE III
Pregnancy reports and confirmed outcomes
Pregnancy TMS Control
status groupa group
Reported 21 59
Confirmed 17 (81%) 49 (83%)
Outcomes:
Healthy infant 14 (82%) 46 (94%)
Healthy infant with
perinatal problem 4 7
Stillbirth 0 1
Elective abortion 1 0
Spontaneous/missed abortion 1 2
Congenital abnormality 1 0
a Overall, hospitalization rates from all cases were signifi-
TMS = topical minoxidil solution.
month 1 to 79% at month 12, and less than 1% of sub-
jects reported not using TMS at all during their partici-
pation in the study. Daily use of TMS was reported by
95% of subjects in the TMS group at month 1, but daily
use decreased to 82% by month 12. Daily use with oc-
casional interruptions was reported by 11% of subjects in
the TMS group at months 9 and 12, with 56% reporting
multiple episodes of discontinuation for more than 4
consecutive days in a single interview period. Twice-daily
application of TMS, the approved dosage regimen, was
reported by 89% of subjects at month 1 and 70% at
month 12. Less than 1% of subjects in the TMS group
reported using the product more frequently than twice
daily.
Effectiveness Ratings
New hair growth was rated as good or excellent by ap-
proximately 32% of subjects in the TMS group at each
interview. Women (51%) were more likely than men
(29%) to describe regrowth as good or excellent. Subjects
with less severe hair loss also reported excellent or good
outcomes compared with those with more severe hair loss
(37% vs. 25%, respectively) when questioned.
More striking results were found when subjects were
asked to rate the effectiveness of TMS in slowing or
stopping hair loss (Table II). By month 12, more than
92% of subjects described the effectiveness of TMS in
slowing or stopping hair loss as excellent, good, or fair. In
addition, men and women described similar effectiveness
ratings regardless of extent of hair loss.
Pregnancy Outcomes
A total of 80 pregnancies were reported, with 21 in the
TMS group and 59 in the control group. Confirmation of
pregnancy outcome (i.e., infant status) was obtained for
66 pregnancies (83%), and, of these, healthy infants were
delivered to 14 of the pregnant subjects in the TMS
group and 46 in the control group (Table III). Eleven of
these healthy infants, 4 in the TMS group and 7 in the
control group, experienced perinatal complications, in-
Volume 7 Number 4 July 2003
cluding obstetrical complications, during pregnancy or
labor and transient neonatal jaundice. Other pregnancy
outcomes included 1 stillbirth in the control group, 1
elective abortion in the TMS group, 1 spontaneous
abortion in each group, and 1 missed abortion in the
control group. One infant in the TMS group was born
with congenital heart disease. There were no patterns or
single reports of pregnancy outcomes, maternal compli-
cations, or neonatal abnormalities that suggested an as-
sociation with the use of TMS during pregnancy.
Hospitalizations and Deaths
Primary end points of the study were deaths and hos-
pitalizations that involved at least one overnight stay.
cantly lower for subjects in the TMS group compared
with subjects in the control group 95% confidence in-
terval (CI) = 0.70, 0.92. Five hundred twenty-six hospit-
alizations were reported by subjects in the TMS group
during the course of the study, and of the 386 confirmed
hospitalizations, 286 subjects continued to use TMS
during their hospitalization. A total of 61 of these hos-
pitalizations occurred at least 4 days after discontinuing
TMS, 12 subjects were never exposed to TMS, and in-
formation was missing on 27 subjects. Similarly, 711
hospitalizations were reported by control subjects. Out of
514 confirmed hospitalizations, 1 subject was currently
using TMS, and 4 had used it previously.
Cardiovascular hospitalizations were examined in
subjects with preexisting cardiovascular risk, in those
without preexisting cardiovascular risk, and in subjects
without preexisting cardiovascular risk or prior exposure
to TMS (Table IV). Relative risk was used to measure the
probability of hospitalization for subjects using TMS
compared with subjects not using TMS related to car-
diovascular risk at study entry. When the relative risk is
less than 1 with a wide confidence interval that extends
beyond 1 from either the upper or lower limit, the results
are not considered to be statistically significant (i.e., re-
sults cannot be interpreted with confidence). However,
when the relative risk is less than 1 with narrow confi-
dence intervals, the results are statistically significant and
there is a low risk (i.e., relative risk <1) associated with the
parameter under consideration. The data in the study
demonstrate that regardless of cardiovascular risk, rates
of hospitalization for all causes and cardiovascular causes
were not significantly different between subjects in the
TMS and control groups. In addition, by comparing
those subjects in the TMS group who had not received
TMS in the past with those in the control group who had
not previously received TMS, the hospitalization rates
were not significantly different (2.9% vs 3.0%; 95%
CI = 0.79, 1.18).
Logistic regression analysis was used to identify risk
factors for all-cause hospitalizations and cardiovascular
hospitalizations. Age, prior overnight hospital stays,
overall health, composite cardiovascular risk, gender,
J. Shapiro Safety of Topical Minoxidil Solution 327

TABLE IV
Relative risk estimates for subjects with prior exposure to TMS compared with those without prior exposure

Relative riska for

TMSc Controls TMS vs. controls

Event Event Risk 95%

Confirmed event Population Nc rateb N rateb estimate CIa

Hospitalization all causes CVa risk present at study entry 1585 6.1 2230 7.4 0.81 0.64, 1.04
CV risk absent at study entry 9123 2.6 8412 2.9 0.88 0.74, 1.05
CV risk absent and no
TMS exposure prior to study 5148 2.9 8317 3.0 0.97 0.79, 1.18
Cardiovascular hospitalization CV risk present at study entry 1585 1.6 2230 1.9 0.84 0.51, 1.37
CV risk absent at study entry 9123 0.2 8412 0.3 0.75 0.41, 1.41
CV risk absent and no
TMS exposure prior to study 5148 0.2 8317 0.3 0.73 1.35, 1.55

a
When the relative risk is less than 1 with a wide confidence interval that extends beyond 1 from either the upper or lower limit, the results are not
considered to be statistically significant. However, when the relative risk is less than 1 with narrow confidence intervals, the results are statistically
significant and there is a low risk associated with the parameter under consideration.
b
Calculated as percent of N experiencing the event.
c
CI = confidence interval; CV = cardiovascular; N = number of subjects fulfilling criteria; TMS = topical minoxidil solution.

TABLE V
Survival analyses of time to first event and number of events for hospitalizations and deaths involving any body system and for
cardiovascular reasons

Type of first event TMS groupa (N = 11,122) Control group (N = 11,173) P value

Hospitalization or death involving any body system

Mean time to event in days 177 173
Number of events 350 447 0.0013
Cardiovascular hospitalization or death
Mean time to event in days 167 168
Number of events 45 75 0.0082

a
TMS = topical minoxidil solution.

body mass index, and smoking history (P < 0.05) were risk
factors for all-cause hospitalizations. Risk factors for
cardiovascular hospitalizations were age, composite car-
diovascular risk, overall health, and smoking history (P <
0.05). TMS use was not a risk factor for either all-cause
hospitalizations or cardiovascular hospitalizations. Sur-
vival analysis of times to first-event hospitalization and
death revealed that TMS use did not adversely affect time
to first hospitalization or death overall or from cardio-
vascular causes (Table V). Interestingly, death rates from
all causes combined were significantly lower for subjects
in the TMS group (0.1%) compared with control subjects
(0.2%) (95% CI = 0.16, 0.82). These data demonstrate
that use of TMS is safe and presents no added risk
compared with control.
Medical Review of Hospitalizations and Deaths
Confirmed and unconfirmed reasons for hospitaliza-
tions and deaths were reviewed for each body system.
Special attention was paid to five body systems that could
be associated with either systemic absorption or topical
application of TMS, including dermatologic, cardiovas-
cular, neurologic, metabolic–nutritional, and allergic
events. For confirmed hospitalizations, there were no
hospitalizations in the TMS group that were associated
with contact allergic dermatitis or a contact irritant drug
reaction. However, 45 (0.41%) subjects in the TMS
group and 67 (0.60%) control subjects were hospitalized
at least once for a cardiovascular event. Similar to der-
matologic events, a review of cardiovascular reasons for
hospitalization did not suggest that use of TMS was as-
sociated with the observed cardiovascular events. Fifteen
subjects in each group were hospitalized for neurological
events, and although there were 2 more subjects in the
TMS group who experienced syncope, no neurological
events were considered to be related to TMS use. Two
subjects in the TMS group and 7 control subjects were
hospitalized because of metabolic–nutritional events, but
there was no evidence that exposure to TMS was a causal
or contributing factor. For events that were identified as
allergic-type reactions, 1 control subject required hospi-
talization for systemic lupus erythematosus, which is not
an allergic disorder, but was categorized in this body
system for purposes of coding. Hospitalization rates for
events related to all other body systems were similar
between the two groups.
328 Journal of Cutaneous Medicine and Surgery
Overall, the types of health events precipitating un-
confirmed hospitalizations were similar to those for the
confirmed hospitalizations. Of the 11 deaths reported in
the TMS group and 25 deaths reported in the control
group, three reports were found to be erroneous and no
reports were located for three other reported deaths.
Discussion
In controlled clinical trials, subjects must meet strict in-
clusion criteria, including rigid adherence to protocol
and lack of serious or chronic medical illness. Pregnant
women and women not using reliable methods of con-
traception also are generally excluded from a traditional
controlled trial. The information derived from most
controlled studies therefore does not necessarily reflect
the general population and may not translate well into
clinical practice. This study was designed to evaluate the
safety and use patterns of TMS in a general population of
adults, regardless of cardiovascular risk factors, history of
cardiovascular disease, or pregnancy status, and to pro-
vide relevant, naturalistic information to guide clinical
practice. More than 3 million subject-days of exposure to
TMS were observed in this large, one-year observational
study of more than 11,000 TMS users, for whom 12-
month data were obtained in 93%.
Subjects rated TMS as effective in slowing or stop-
ping hair loss, with an excellent, good, or fair response
reported by more than 90% of subjects at months 6, 9,
and 12. In addition, 89% of subjects at month 1 and 70%
at month 12 were applying TMS twice daily, as indicated
by the approved dosage regimen. Therefore, this study
demonstrates that subjects using TMS believe that the
medication is helping to slow or stop their hair loss and
that a large majority are complying with instructions for
use even after one year. The results of this study also
confirm the safety profile of TMS among a general adult
population with respect to pregnancy outcome and the
incidence of medical events resulting in hospitalization or
death. More than 80% of the 80 pregnancies reported
during the study were confirmed, and there was no in-
dication of increased risk of adverse pregnancy outcomes.
However, the pregnancy data reported in this study are
limited in that the study was not designed to determine
whether subjects continued using TMS after they became
pregnant or whether TMS was discontinued at that time.
Therefore, these findings cannot be interpreted to mean
that the use of TMS is safe during pregnancy, only that
there is no indication of increased risk of adverse preg-
nancy outcomes in the TMS group compared with the
control group.
Orally administered minoxidil was first marketed for
the treatment of severe hypertension. Systemic minoxidil
is a direct peripheral arteriolar vasodilator that reduces
peripheral vascular resistance.9 In patients taking sys-
temic minoxidil as an antihypertensive, peripheral vaso-
dilation causes predictable cardiovascular effects such as
Volume 7 Number 4 July 2003
lowered blood pressure, reflex tachycardia, and fluid re-
tention. However, subsequent clinical studies indicated
that when minoxidil was administered topically in the
treatment of pattern baldness, it was poorly absorbed
from normal intact skin and systemic-related cardiovas-
cular effects were absent.10 In bioavailability studies,
percutaneous absorption of 2% and 3% TMS in adults
has resulted in mean serum concentrations ranging from
0.6 to 2.0 ng/ml, falling well below the 20-ng/ml level at
which pulse rate begins to be affected.11,12
In this study, exposure to TMS was not found to be
an independent risk factor for hospitalization. Although
there are some data that suggest an increased risk of
cardiovascular events in bald men,13–18 an association
between TMS use and increased risk of hospitalization or
death was not observed in this study. Relative risk was
used to measure the probability of hospitalization for
subjects using TMS compared with subjects not using
TMS related to cardiovascular risk at study entry. The
results demonstrate that regardless of cardiovascular risk,
rates of hospitalization for all causes and cardiovascular
causes were not significantly different between subjects in
the TMS and control groups.
The difference in the incidence of hospitalizations
and deaths between the two groups may be attributed to
potential differences in subject characteristics between
the groups. Subjects using TMS may be healthier than
the average person because they are concerned enough
about their appearance to seek treatment. These subjects
also may be more diligent in exercising, maintaining a
healthy weight, and following a healthy lifestyle. As
demonstrated in the study, fewer subjects in the TMS
group were current smokers as compared with controls
(14.8% vs 18.9%, P < 0.003). In addition, the majority of
subjects in the TMS group had used the product pre-
viously and therefore may have skewed the results be-
cause less healthy subjects may have already discontinued
use of the product. This potential bias was addressed by
calculating the risk of adverse outcomes among subjects
who were first-time users at study entry and by ac-
counting for exposure differences between first-time
users and those who had been using TMS previously
through logistic regression analyses. Nonetheless, hos-
pitalization rates for first-time users of TMS were not
significantly different from rates of control subjects who
had no previous exposure to TMS.
Conclusions
This large, one-year observational study of more than 3
million subject-days of exposure to TMS demonstrated
the safety profile of TMS. Adults who use TMS for AGA
are no more likely to experience major medical events
than control subjects who have never been exposed to
TMS. In addition, no difference in the rates of cardio-
vascular events was demonstrated between the two
groups. There was no indication of increased risk of
J. Shapiro Safety of Topical Minoxidil Solution
adverse pregnancy outcomes among women who used
TMS during their pregnancy; however, the study was not
designed to determine whether subjects continued using
TMS after they became pregnant. In addition, the
majority of subjects perceived TMS as effective in slow-
ing or stopping hair loss as well as in promoting new hair
growth.
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