Menopause: The Journal of The North American Menopause Society

Vol. 20, No. 10, pp. 1027/1035

DOI: 10.1097/gme.0b013e3182a66aa7
* 2013 by The North American Menopause Society

Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms:

two randomized controlled trials
James A. Simon, MD, CCD, NCMP, IF, FACOG,1 David J. Portman, MD,2 Andrew M. Kaunitz, MD,3
Hana Mekonnen, MA,4 Kazem Kazempour, PhD,4 Sailaja Bhaskar, PhD,5 and Joel Lippman, MD5
Abstract
Objective: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor
symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks
duration.
Methods: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once
daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe
vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24.
Results: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and
593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week
study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P G 0.0001 for
both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in
the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of
treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or
moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no shortterm discontinuation of symptoms followed treatment cessation.
Conclusions: Paroxetine 7.5 mg is well-tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment.
Key Words: Hot flashes Y Menopause Y Nonhormonal Y Paroxetine mesylate Y Selective serotonin reuptake
inhibitor Y Vasomotor symptoms.

Received May 30, 2013; revised and accepted July 23, 2013.
From the 1George Washington University School of Medicine and
Womens Health and Research Consultants, Washington, DC; 2Columbus
Center for Womens Health Research, Columbus, OH; 3University of
Florida College of Medicine, Jacksonville, FL; 4Amarex Clinical Research,
Germantown, MD; and 5Noven Pharmaceuticals Inc, New York, NY.
Funding/support: These studies (ClinicalTrials.gov identifiers NCT01361308
and NCT01101841) were funded by Noven Pharmaceuticals Inc (New
York, NY). Editorial assistance was likewise funded by Noven Pharmaceuticals Inc.
Financial disclosure/conflicts of interest: J.A.S. has served (in the last year) or
is currently serving as consultant to or on the advisory boards of Abbott
Laboratories/AbbVie Inc (North Chicago, IL), Agile Therapeutics Inc
(Princeton, NJ), Amgen Inc (Thousand Oaks, CA), Apotex Inc (Toronto,
Canada), Ascend Therapeutics (Herndon, VA), BioSante (Lincolnshire, IL),
Depomed Inc (Menlo Park, CA), Everett Laboratories Inc (West Orange, NJ),
Intimina by Lelo Inc (San Jose, CA), Lupin Pharmaceuticals (Baltimore,
MD), MD Therapeutics (Boca Raton, FL), Meda Pharmaceuticals Inc
(Somerset, NJ), Merck (Whitehouse Station, NJ), Noven Pharmaceuticals
Inc, Novo Nordisk (Bagsv&rd, Denmark), Novogyne (East Hanover, NJ),
Pfizer Inc (New York, NY), Shionogi Inc (Florham Park, NJ), Shippan Point
Advisors LLC (Upper Saddle River, NJ), Slate Pharmaceuticals Inc (Durham,
NC), Sprout Pharmaceuticals (Raleigh, NC), Teva Pharmaceutical Industries
Ltd (Jerusalem, Israel), Warner Chilcott (Rockaway, NJ), and Watson
Pharmaceutical Inc (Corona, CA). He has received or is currently receiving
grant/research support from Abbott Laboratories/AbbVie Inc, BioSante,
EndoCeutics Inc (Quebec, Canada), Novo Nordisk, Novogyne, Palatin

Technologies (Cranbury, NJ), Teva Pharmaceutical Industries Ltd, and

Warner Chilcott. He has also served or is currently serving on speakers
bureaus for Amgen Inc, Eisai Inc (Woodcliff Lake, NJ), Merck, Novartis
(Basel, Switzerland), Noven Pharmaceuticals Inc, Novo Nordisk, Novogyne,
Shionogi Inc, Teva Pharmaceutical Industries Ltd, and Warner Chilcott.
J.A.S. served as chief medical officer at Sprout Pharmaceuticals.
D.J.P. has served on the speakers bureau for Noven Pharmaceuticals Inc,
from which he has also received research grant support and consulting
fees. He has served on the advisory board of and the speakers bureau for
Teva Pharmaceutical Industries Ltd, from which he has also received
research grant support and payment for educational presentations and
travel expenses. D.J.P. has received research support from Depomed Inc
and Pfizer Inc and has served on the speakers bureau for Warner
Chilcott. He has also served as consultant to Meda Pharmaceuticals Inc.
A.M.K. has served on the board of The North American Menopause
Society (Mayfield Heights, OH) and has received consultancy fees from
Bayer AG (Leverkusen, Germany), Depomed Inc, Merck, and Noven
Pharmaceuticals Inc. The Department of Obstetrics and Gynecology at
the University of Florida College of Medicine (Jacksonville, FL) has
received grants from EndoCeutics Inc, Bayer AG, Teva Pharmaceutical
Industries Ltd, and Noven Pharmaceuticals Inc. H.M. and K.K. have no
conflicts of interest to disclose. S.B. and J.L. are employees of Noven
Pharmaceuticals Inc.
Address correspondence to: James A. Simon, MD, CCD, NCMP, IF, FACOG,
Department of Obstetrics and Gynecology, George Washington University,
and Womens Health and Research Consultants, Suite 450, 1850 M Street,
NW, Washington, DC 20036. E-mail: jsimon@jamesasimonmd.com
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SIMON ET AL

asomotor symptoms (VMS), encompassing hot flashes

and night sweats,1 affect up to 80% of menopausal
women in the United States.2,3 VMS are the most
bothersome aspects of menopause,4 significantly affecting
quality of life.5,6 To date, hormone therapy (HT) has been the
only approved treatment for moderate to severe VMS due to
menopause.7 However, women seeking treatment need safe
and effective non-HT options. In the past few years, several
clinical trials have demonstrated that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake
inhibitors (SNRIs) may be efficacious in treating VMS due to
menopause among nondepressed women,8 although tolerability
of such agents may be a concern at doses indicated for psychiatric disorders.
Brisdelle (paroxetine 7.5 mg; previously called low-dose
mesylate salt of paroxetine [LDMP]) is the first and only
US Food and Drug Administration (FDA)Yapproved nonhormonal option for the treatment of moderate to severe VMS
associated with menopause. This medication was specifically
developed for the treatment of menopausal VMS at a dose
lower than that indicated for psychiatric disorders. Paroxetine
mesylate is an orally administered psychotropic drug similar
to paroxetine hydrochloride, which contains mesylate salt instead of hydrochloride salt.9 Results of an 8-week phase 2
study in postmenopausal women (N = 102)10 showed that
paroxetine 7.5 mg was efficacious in treating moderate to severe VMS and was well-tolerated. The mean difference in hot
flash frequency reduction between paroxetine 7.5 mg and placebo was j1.4 hot flashes per day (P = 0.0177), with a mean
reduction of 6.5 hot flashes per day for paroxetine 7.5 mgtreated women and 5.1 hot flashes per day for placebo-treated
women. The discontinuation rate in the paroxetine 7.5 mg arm
in the phase 2 study and the safety profile of paroxetine 7.5 mg
were comparable with those of placebo.10
Reduced estrogen levels in menopause are hypothesized
to modulate endorphin concentrations in the hypothalamus,
leading to changes in norepinephrine and serotonin levels.11<13
These neurotransmitters lower the thermoregulatory set point
in the hypothalamic neuroregulatory nucleus, triggering inappropriate heat loss.11<13 Paroxetines mechanism of action
in reducing hot flashes is not clearly understood but is probably mediated by the activation of hypothalamic serotonin
receptors.13
Herein, we report the results of two similarly designed,
multicenter, double-blind, randomized, placebo-controlled,
phase 3 studies of 12 and 24 weeks duration, respectively,
conducted to evaluate the safety and efficacy of paroxetine
7.5 mg (once daily at bedtime) in postmenopausal women with
moderate to severe VMS due to menopause.
METHODS
Study participants
Both studies included postmenopausal women 40 years or
older who were required to meet one of the following criteria
for menopause: spontaneous amenorrhea for 12 consecutive
months or longer; amenorrhea for 6 months or more with

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follicle-stimulating hormone levels higher than 40 mIU/mL;

or bilateral salpingo-oophorectomy, with or without hysterectomy, 6 weeks or more before screening. A key eligibility
criterion was an average of more than 7 to 8 moderate to severe hot flashes per day, or 50 to 60 moderate to severe hot
flashes per week, before screening. Moderate hot flashes were
defined as a sensation of heat with sweating and ability to
continue with activity, whereas severe hot flashes were defined as a sensation of heat with sweating causing cessation of
activity. No concomitant estrogen/progestinYcontaining products were permitted during the study, and participants who were
taking such products at the screening visit had to undergo
washout periods: 1 week before the run-in visit for vaginal
hormone products (rings, creams, and gels), 4 weeks for transdermal estrogen or estrogen/progestin products, and 8 weeks
for oral estrogen or estrogen/progestin therapy.
The inclusion and exclusion criteria for these studies were
consistent with the 2003 FDA guidance for the clinical evaluation of HT for VMS due to menopause.14 Concomitant use
of psychotropic drugs during the study was limited. Participants who were taking such medications at the screening visit
had to undergo washout periods: 2 weeks before the run-in visit
for thioridazine, pimozide, tricyclic antidepressants, SSRIs
(except for fluoxetine), SNRIs, lithium and oral neuroleptics,
and all sedatives and hypnotics (except for zolpidem, zaleplon,
eszopiclone, and diphenhydramine); 4 weeks before the run-in
visit for fluoxetine, St Johns wort, and monoamine oxidase
inhibitors; and 12 weeks before the run-in visit for depot neuroleptics. During the entire duration of the study, participants were not permitted to take the following: tamoxifen,
select psychotropic drugs, thioridazine, pimozide, monoamine
oxidase inhibitors, estrogen or estrogen/progestinYcontaining
products, gabapentin and pregabalin, soy and soy-based products, isoflavone-containing substances, and alternative therapies for the treatment of VMS.
Key exclusion criteria were as follows: hypersensitivity to
paroxetine; known nonresponse to previous SSRI or SNRI
treatment of VMS; untreated hypertension; impaired liver or
kidney function; unstable cardiac disease; pregnancy; a history
of self-injurious behavior; a history of clinical diagnosis or
treatment of any psychiatric disorder; and any other medical
condition. Participants with any clinically significant abnormality at screening (physical examination, electrocardiogram
[ECG], laboratory tests, or urine drug screening) were not
eligible for inclusion. Use of an investigational study medication within 30 days before screening or during the study
was also prohibited.
Study design
These multicenter, double-blind, randomized, placebocontrolled, phase 3 studies were conducted from June 2011
to January 2012 (12-wk study) and from March 2010 to
September 2011 (24-wk study). Both studies were designed to
meet the FDA guidance for VMS, which specifies that studies
should be of 12 weeks duration.14 However, because VMS
may persist for months or years after the onset of menopause,
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PAROXETINE 7.5 MG FOR TREATING MENOPAUSAL VMS

the 24-week study was designed to examine whether efficacy

and safety outcomes were maintained for a longer duration.
The studies were conducted according to the guidelines of
Good Clinical Practice, the Declaration of Helsinki, and
all applicable local regulations and were approved by each
study centers local or central institutional review board.
Seventy research sites across the United States contributed to
the 12-week study, and 65 US investigative sites contributed
to the 24-week study. A written informed consent form for
study participation was obtained from all participants.
After an initial screening period, eligible participants entered a single-blind, run-in period of up to 12 days, during
which they received placebo once daily at bedtime and
recorded the number and severity of hot flashes in electronic
daily diaries (Fig. 1). This run-in period allowed participants
to learn the definitions of mild, moderate, and severe hot
flashes and to be trained on using the electronic diary system
as they familiarized themselves with protocol requirements.
At the end of the run-in period, participants who no longer met
the eligibility criterion of more than 7 to 8 moderate to severe
hot flashes per day or 50 to 60 moderate to severe hot flashes
per week or who were noncompliant with dosing or daily diary recording of hot flashes were excluded from the study.
This ensured that participants met the eligibility criteria and
screened out high placebo responders who may not have
benefited from pharmacological intervention while eliminating those who were unwilling or unable to complete the
electronic diary. Participants compliant with electronic diary
entry and dosing and met hot flash eligibility criteria were
randomly assigned 1:1 to receive paroxetine 7.5 mg or an
identical capsule of placebo once daily at bedtime. Randomization was applied centrally across all sites using an interactive voice response system. All personnel were blinded to
medication until study completion and database lock. Treatment began at bedtime on the day of randomization (day 1)
and continued until day 84 (end of 12-wk study) or day 168
(end of 24-wk study) or until early discontinuation. During

the double-blind treatment period, participants in both

studies were required to return to the clinic for assessment
on days 14 and 28. Participants were also required to come
to the clinic on day 85 (12-wk study) or day 169 (24-wk
study) for all scheduled end-of-study evaluations. For participants who discontinued prematurely from the study, all
scheduled end-of-study evaluations were performed at the
time of early discontinuation.
Study endpoints
The coprimary efficacy endpoints in this study were mean
change from baseline in the frequency of moderate to severe
hot flashes on weeks 4 and 12 and mean change from baseline
in the severity of moderate to severe hot flashes on weeks 4
and 12.14 Persistence of treatment benefit, an additional efficacy endpoint, was also included in the 24-week study.
Study assessments
Treatment compliance was assessed by counting the number of capsules dispensed and the number of capsules
returned. Compliance percentage was calculated and dichotomized into two groups: those taking 80% or more of the
study drug (compliance) and those taking less than 80% of the
study drug (noncompliance).
Daily hot flash data were collected using the electronic hot
flash diary, which was completed daily by study participants.
This validated, interactive, real-time system was available for
use 24 hours per day for data entry, and daily compliance
reports were generated for each participant.
Safety assessments included treatment-emergent adverse
events (TEAEs), vital signs, ECG, and clinical laboratory
abnormalities. TEAEs were summarized by preferred term
according to the Medical Dictionary for Regulatory Activities
(MedDRA), as is standard procedure for this type of investigation. Because the studies were not designed to detect
statistical differences in adverse events between treatments,
results are shown quantitatively by treatment arm. Adverse
events of special interest (ie, linked to reports from studies

FIG. 1. Study design. SAQ, Symptom Assessment Questionnaire; DESS, Discontinuation-Emergent Signs and Symptoms.
Menopause, Vol. 20, No. 10, 2013

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SIMON ET AL

using higher doses of paroxetine), including suicidality, abnormal bleeding, and bone fractures, were also assessed.
For assessment of potential discontinuation symptoms,
participants were asked to complete a 27-symptom surveyV
the Discontinuation-Emergent Signs and Symptoms (DESS)
scaleVwithin 7 (3) [mean (SD)] days of the last dose of study
medication, regardless of when they exited the study. The
DESS scale has been shown to provide an accurate assessment
of discontinuation symptoms when used in trials of antidepressants used to treat depression and anxiety disorders.15
Statistical analyses
Five hundred thirty-four participants (267 per treatment
arm) were planned to be randomly assigned in each study; this
included a conservative dropout rate of approximately 15%
(based on the phase 2 trial, which had a dropout rate of 6%10).
Sample size estimation using nQuery Advisor 6.01 (Statistical
Solutions LLC, Overland Park, KS) indicated that, for VMS
severity, 155 participants per treatment arm were required for
95% power based on a type I error rate of 0.05 (> = 0.05, twosided), a clinically meaningful reduction in severity higher
than 50% (mean difference, 0.17 j 0.08), and a common SD
of 0.22. For the coprimary endpoint of VMS frequency, 227
participants per treatment arm were required to provide 85%
statistical power to detect a mean difference between treatments of 1.41 hot flashes per day based on a type I error rate of
0.05 (> = 0.05, two-sided) and a common SD of 5. The aim,
therefore, was to have 454 participants complete each study.
Prespecified analysis populations included modified intentto-treat (mITT), per-protocol (PP), and safety populations.
The mITT group, which served as the primary population for
analysis, comprised all randomly assigned participants with
valid baseline daily hot flash diary data who had taken one or
more doses of study medication and had one or more days of
on-treatment daily hot flash diary data. The PP population
included all participants in the mITT population who were
treated according to the protocol and fulfilled the following:
(1) satisfied all inclusion and exclusion criteria without compromise of the blind; (2) had no significant protocol violations; and (3) demonstrated 80% or more compliance with
assigned study treatment. The PP population was identified
before database lock and was used to conduct supportive
analysis. The safety population included all participants who
had received one or more doses of study medication and had
undergone one or more postdose safety measurements.
All analyses were performed using SAS for Windows, version 9.2 (SAS Institute Inc, Cary, NC). Descriptive statistics (n,
mean, SD, median, and range) were calculated by treatment
arm for continuous variables. Frequencies and percentages are
presented by treatment arm for categorical variables.
Primary efficacy variables were measured at multiple time
points during the study. Because the data were not normally
distributed, treatment arms were compared using ranktransformed analysis of covariance with baseline values as
covariates. For categorical variables, a logit model was used,
with baseline as covariate. In the event of missing diary data,

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Menopause, Vol. 20, No. 10, 2013

the average of hot flash diary data across entries in the previous 7 days was imputed. Sensitivity analysis was performed
using the last observation carried forward (LOCF) principle
for all missing data.
Total weekly moderate and severe hot flashes at baseline for
each participant were calculated by a standard method as follows: [(x on day 1 + x on day 2 + I + x on day n) / (n j 1)]  7,
where x is the number of moderate and severe hot flashes,
and n is the number of days in the run-in period. This number
was used for all analyses requiring a baseline hot flash count.
Total weekly moderate and severe hot flashes during the
double-blind treatment period were calculated as the sum of
moderate and severe hot flashes recorded in the daily hot
flash diary for seven calendar days in the specific treatment
week. Weekly hot flash severity score was determined by
(2Fm + 3Fs) / (Fm + Fs), where Fm and Fs are the frequencies
of moderate and severe hot flashes, respectively, during the
study week.
To calculate the persistence of treatment benefit (24-wk
study only), we compared the paroxetine 7.5 mg and placebo
arms on proportions of responders (defined as those participants who achieved a 50% or more reduction in moderate to
severe hot flash frequency from baseline to week 24). Persistence of treatment benefit was demonstrated by a statistically
significant difference in the proportion of responders on week
24 versus baseline between the paroxetine 7.5 mg arm and the
placebo arm. For this analysis, a logit model was used, with
the baseline number of hot flashes as covariate. Participants
who discontinued from the study before week 24 were considered treatment failures.
In pooled analysis, data from both studies from baseline to
week 12 were used to calculate the primary efficacy endpoints. Rank-transformed analysis of covariance was used to
compare treatment arms for pooled results.
RESULTS
Participant disposition
Six hundred fourteen postmenopausal women were randomly assigned to the 12-week study, and 570 postmenopausal
women were randomly assigned to the 24-week study. In the
12-week study, the paroxetine 7.5 mg arm comprised 306 participants, and the placebo arm included 308 participants
(Fig. 2A). Five participants randomly assigned to the paroxetine 7.5 mg arm and three participants randomly assigned to
the placebo arm did not receive the study drug and were accordingly excluded from the mITT and safety populations
(paroxetine 7.5 mg, 301; placebo, 305). The mITT population
in this study was identical to the safety population. In the
24-week study, 285 women were randomly assigned to each
treatment arm (Fig. 2B). One participant in the placebo arm
did not receive the study medication and was excluded from
the mITT and safety populations (paroxetine 7.5 mg, 285;
placebo, 284). One additional participant in the paroxetine
7.5 mg arm did not have complete diary entries and was excluded from the mITT population (paroxetine 7.5 mg, 284;
placebo, 284) but was included in the safety population.
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PAROXETINE 7.5 MG FOR TREATING MENOPAUSAL VMS

FIG. 2. Disposition of study participants. A: Twelve-week study. B: Twenty-four-week study. AE, adverse event; SAE, serious adverse event.

Most study discontinuations occurred upon the participants

request (12-wk study: paroxetine 7.5 mg, 2.6%; placebo, 3.9%;
24-wk study: paroxetine 7.5 mg, 5.3%; placebo, 12.3%). Twelve
participants (2.0%) in the 12-week study and 30 participants
(5.3%) in the 24-week study discontinued the study early because
of an adverse event (Fig. 2). Most participants were 80% or
more compliant with their assigned study drug (12-wk study:
paroxetine 7.5 mg, 91.7%; placebo, 91.8%; 24-wk study: paroxetine 7.5 mg, 84.2%; placebo, 78.9%).

than for placebo on week 4 (j33.0 and j23.5, respectively;

P G 0.0001) and week 12 (j43.5 and j37.3, respectively;
P = 0.0090; Fig. 3A). In the 24-week study, the mean weekly
reductions in VMS frequency were significantly greater for
paroxetine 7.5 mg than for placebo on week 4 (j28.9 and
j19.0, respectively; P G 0.0001) and week 12 (j37.2 and
j27.6, respectively; P = 0.0001; Fig. 3B). In the pooled
analysis, paroxetine 7.5 mg significantly reduced the frequency
of VMS versus placebo on weeks 4 and 12 (P G 0.0001; Fig. 3C).

Baseline demographics and characteristics

Baseline demographics were similar between treatment
arms (Table 1). All participants were postmenopausal women;
most were white (70%) or black (27%), and 3% were of other
races. The median age was 54 years. At baseline, the mean
daily frequency of hot flashes was 11.3, and the mean hot
flash severity score was 2.53.

Effect of treatment on VMS severity

In the 12-week study, the mean weekly reductions from
baseline in VMS severity were significantly greater for paroxetine 7.5 mg than for placebo on week 4 (j0.09 and
j0.05, respectively; P = 0.0048) but not on week 12 (j0.10
and j0.09, respectively; P = 0.2893; Fig. 3D). In the 24-week
study, the mean weekly reductions in VMS severity were significantly greater for paroxetine 7.5 mg than for placebo on
week 4 (j0.09 and j0.06, respectively; P = 0.0452) and week
12 (j0.12 and j0.07, respectively; P = 0.0114; Fig. 3E). In the
pooled analysis, paroxetine 7.5 mg significantly reduced the

Effect of treatment on VMS frequency

In the 12-week study, the mean weekly reductions in VMS
frequency were significantly greater for paroxetine 7.5 mg

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SIMON ET AL
TABLE 1. Demographics and baseline characteristics (mITT population)
Study 1 (12 wk)
Characteristic

Paroxetine 7.5 mg
(n = 301)

Placebo
(n = 305)

Study 2 (24 wk)

Paroxetine 7.5 mg
(n = 284)

Placebo
(n = 284)

Pooled analysis
Paroxetine 7.5 mg
(n = 585)

Placebo
(n = 589)

Age, median (range), y

54 (40-73)
53 (40-79)
54 (41-70)
54 (40-74)
54 (40-73)
54 (40-79)
Age category, n (%), y
Q40 to G50
45 (15.0)
55 (18.0)
50 (17.6)
55 (19.4)
95 (16.2)
110 (18.7)
Q50 to G60
194 (64.5)
195 (63.9)
189 (66.5)
179 (63.0)
383 (65.5)
374 (63.5)
Q60 to G70
55 (18.3)
49 (16.1)
44 (15.5)
47 (16.5)
99 (16.9)
96 (16.3)
Q70
7 (2.3)
6 (2.0)
1 (0.4)
3 (1.1)
8 (1.4)
9 (1.5)
Ethnicity, n (%)
Hispanic/Latino
27 (9.0)
37 (12.1)
16 (5.6)
21 (7.4)
43 (7.4)
58 (9.8)
Other
274 (91.0)
268 (87.9)
268 (94.4)
263 (92.6)
542 (92.6)
531 (90.2)
Race, n (%)
Asian
1 (0.3)
1 (0.3)
3 (1.1)
6 (2.1)
4 (0.7)
7 (1.2)
Black
106 (35.2)
93 (30.5)
69 (24.3)
53 (18.7)
175 (29.9)
146 (24.8)
White
190 (63.1)
202 (66.2)
205 (72.2)
224 (78.9)
395 (67.5)
426 (72.3)
Other
4 (1.3)
9 (3.0)
7 (2.5)
1 (0.4)
11 (1.8)
10 (1.7)
28.3 (16.8-60.7)
29.0 (19.0-56.5)
27.4 (18.3-40.6)
27.7 (18.7-39.7)
27.9 (16.8-60.7)
28.2 (18.7-56.5)
BMI, median (range),
kg/m2
Menopause type, n (%)
Natural
242 (80.4)
253 (83.0)
227 (79.9)
230 (81.0)
469 (80.2)
483 (82.0)
Surgical
59 (19.6)
52 (17.0)
57 (20.1)
54 (19.0)
116 (19.8)
106 (18.0)
Daily VMS frequency,
11.79 (4.87)
11.65 (4.39)
10.83 (3.86)
10.90 (3.96)
11.32 (4.43)
11.29 (4.21)
mean (SD)
Daily VMS severity,
2.53 (0.30)
2.53 (0.31)
2.53 (0.30)
2.53 (0.32)
2.53 (0.30)
2.53 (0.31)
mean (SD)
Daily awakenings due to
3.55 (1.94)
3.72 (2.36)
3.58 (1.98)
3.56 (1.93)
3.56 (1.96)
3.64 (2.16)
VMS, mean (SD)
mITT, modified intent-to-treat (received one or more doses of study medication and had completed diary entries); BMI, body mass index; VMS, vasomotor symptoms.

severity of VMS versus placebo on week 4 (P = 0.0006) and

week 12 (P = 0.0110; Fig. 3F).
Persistence of treatment benefit
Significantly more participants treated with paroxetine 7.5 mg
than with placebo were responders on week 24 (47.5% vs 36.3%,
respectively; P = 0.0066; Fig. 3G), thus demonstrating persistence of treatment benefit.
Additional analyses
Results of sensitivity analyses that used the LOCF principle
in handling missing data were similar to the results calculated
without LOCF imputation (data not shown). Results of efficacy analyses using the PP population were supportive of data
calculated using the mITT population (data not shown).
Safety
Overall, 295 of 586 (50.3%) participants in the paroxetine
7.5 mg arm and 275 of 589 (46.7%) participants in the placebo
arm experienced one or more TEAEs; most were mild or
moderate in severity (Table 2). Twenty-three participants
(3.9%) in the paroxetine 7.5 mg arm and 18 participants
(3.1%) in the placebo arm reported a severe TEAE.
Study drug discontinuations caused by TEAEs were reported for 26 of 586 (4.4%) participants in the paroxetine
7.5 mg arm and for 21 of 589 (3.6%) participants in the placebo arm. Twelve participants had study drug interruption
because of an adverse event (paroxetine 7.5 mg, 6 of 586
[1.0%]; placebo, 6 of 589 [1.0%]). Twenty-two participants
reported treatment-emergent serious adverse events (paroxe-

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tine 7.5 mg, 14 of 586 [2.4%] participants; placebo, 8 of 589

[1.4%] participants). One death was reported (12-wk study:
acute respiratory failure with evidence of hypertensionmediated pulmonary edema and hypertensive cardiovascular
disease) and was not considered by the investigator to be related to the study drug.
The TEAEs reported in 2% or more of participants in the
paroxetine 7.5 mg arm and with twofold (or more) higher
frequency than in the placebo arm were nausea (paroxetine
7.5 mg, 3.8%; placebo, 1.4%), fatigue (paroxetine 7.5 mg,
3.4%; placebo, 1.5%), and dizziness (paroxetine 7.5 mg, 2.0%;
placebo, 0.8%; Table 2). No clinically significant changes in
laboratory values, vital signs, or ECG were observed in either
treatment arm during the course of the study.
A suicide attempt was spontaneously reported in the 24-week
study. One participant in the paroxetine 7.5 mg arm took an
overdose of nonstudy medications 1 week after receiving a
prescription for clonazepam for newly reported anxiety. Investigators determined that the event was unrelated to paroxetine 7.5 mg treatment.
The incidences of gastrointestinal or other bleeding adverse
events between treatment arms were similar. Vaginal or postmenopausal hemorrhage was the most commonly reported
bleeding adverse event (six participants in each arm). No
clinically important findings on gastrointestinal or bleeding
adverse events were evident in the paroxetine 7.5 mg arm.
Five bone fractures were reported: four events in three
participants in the placebo arm and one event in the paroxetine
7.5 mg arm. Three of the fractures in the placebo arm were
reported as serious adverse events.
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PAROXETINE 7.5 MG FOR TREATING MENOPAUSAL VMS

FIG. 3. Primary outcome measures: mITT population. A: Mean weekly change in the frequency of VMS, 12-week study. B: Mean weekly change in the
frequency of VMS, 24-week study. C: Mean weekly change in the frequency of VMS, pooled analysis. D: Mean weekly change in the severity of VMS,
12-week study. E: Mean weekly change in the severity of VMS, 24-week study. F: Mean weekly change in the severity of VMS, pooled analysis. G:
Persistence of treatment benefit on week 24, 24-week study. aResponders: participants who achieved a 50% or more reduction in hot flashes. P values
for (A) through (F), based on medians, were calculated by rank-transformed ANCOVA. Standard error bars are shown for primary outcome data (weeks
4 and 12) and week 24 time points. P values for (G) were calculated using a logistic model incorporating baseline as a covariate. HF, hot flash; mITT,
modified intent-to-treat (received one or more doses of study medication and had completed diary entries); VMS, vasomotor symptoms; ANCOVA,
analysis of covariance.
Menopause, Vol. 20, No. 10, 2013

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SIMON ET AL
TABLE 2. Adverse events (safety population, pooled analysis)
Paroxetine 7.5 mg
(n = 586)

Placebo
(n = 589)

Participants with TEAE, n (%)

Any TEAE
295 (50.3)
275 (46.7)
116 (19.8)
101 (17.1)
Any related TEAEa
Any severe TEAE
23 (3.9)
18 (3.1)
5 (0.9)
6 (1.0)
Any related severe TEAEa
Discontinuation because of TEAE
26 (4.4)
21 (3.6)
Deaths, n (%)
Any death
1 (0.2)
0
Any related death
0
0
SAE, n (%)
Any SAE
14 (2.4)
8 (1.4)
3 (0.5)
0
Any drug-related SAEa
Adverse events occurring in Q2% of the LDMP group and at twofold
(or more) higher incidence than in the placebo group, n (%)
Nausea
22 (3.8)
8 (1.4)
Fatigue
20 (3.4)
9 (1.5)
Dizziness
12 (2.0)
5 (0.8)
Participants were counted once within each category. For participants with
more than one event per category, the worst-case assessment was tabulated.
TEAE, treatment-emergent adverse event (any adverse event that started or
worsened on or after the day of the first dose); SAE, serious adverse event.
a
Any relationship to the study drug.

Finally, DESS scale results did not demonstrate any meaningful differences between the paroxetine 7.5 mg arm and the
placebo arm. After treatment discontinuation without tapering,
17.2% of paroxetine 7.5 mg-treated participants and 13.6%
of placebo-treated participants experienced one or more new
symptoms, and 25.3% and 17.7%, respectively, reported worsening of a previously reported symptom. The new symptoms
described in 2% or more of participants in the paroxetine 7.5 mg
arm and with twofold (or more) higher frequency than in the
placebo arm were muscle cramps, spasms, and twitching (paroxetine 7.5 mg, 3.4%; placebo, 1.5%); a restless feeling in the
legs (paroxetine 7.5 mg, 2.6%; placebo, 1.2%); and insomnia
(paroxetine 7.5 mg, 2.6%; placebo, 1.2%). No worsening of a
previously reported symptom occurred in 2% or more of participants in the LDMP arm or with twofold (or more) higher
frequency than in the placebo arm.
DISCUSSION
Paroxetine 7.5 mg, a once-daily nonhormonal agent specifically developed for the treatment of moderate to severe
menopausal VMS, has been shown in these two phase 3
studies to be effective in reducing symptoms. In both studies,
paroxetine 7.5 mg administration reduced the frequency and
severity of moderate to severe VMS compared with placebo.
The observed reduction in the frequency of moderate to severe
VMS among participants treated with paroxetine 7.5 mg
remained statistically significant versus placebo throughout
the studies; in the 24-week study, the proportion of responders
(defined as Q50% reduction from baseline) was significantly
greater in the paroxetine 7.5 mg arm than in the placebo arm,
thereby demonstrating persistence of treatment benefit with
paroxetine 7.5 mg up to 24 weeks.
Paroxetine 7.5 mg was also safe and well-tolerated in this
population; most TEAEs were mild to moderate. The fre-

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Menopause, Vol. 20, No. 10, 2013

quency of adverse events and the rate of discontinuations

associated with adverse events were low, and the compliance
rate was high. No clinically important findings on abnormal
bleeding, bone fractures, or suicidality were evident in the paroxetine 7.5 mg arm. Moreover, no meaningful differences in
discontinuation symptoms were observed between the paroxetine 7.5 mg arm and the placebo arm upon cessation of the
study drug without down-titration. Results of the DESS scale
indicate that paroxetine 7.5 mg does not cause an increase
in discontinuation symptoms after treatment discontinuation.
Tapering of higher-dose SSRI therapy, as opposed to abrupt
discontinuation, has been recommended by prescribing information and several guidelines in the literature to diminish the
occurrence of discontinuation symptoms (which may include
flu-like symptoms, dizziness, fatigue, nausea, sensory disturbances, and paresthesias).16,17 In the present studies, participants
did not report discontinuation symptoms typically observed with
higher doses of SSRIs,16,17 and no discontinuation-emergent
symptom was reported in 5% or more of paroxetine 7.5 mgtreated participants and at twice the incidence observed in the
placebo arm. Collectively, these reassuring observations may be
attributable to the low dose of paroxetine used in these studies.
The results of these studies are timely and important because, to date, there is an unmet need for FDA-approved
nonhormonal treatments of VMS due to menopause. After the
publication of the Womens Health Initiative in 2002,18 many
clinicians became reluctant to prescribe HT for symptomatic
women, and many women discontinued or chose not to initiate HT because of risk concerns. HT prescriptions rapidly
declined by 44% between 2001 and 2003.19 The National
Health and Nutrition Examination Survey (1999-2010) reported
a continued decline in HT use to the current level of 4.7% across
a wide range of participant subgroups.20 It is clear that many
women with symptoms do not seek treatment, and others desire
treatment but prefer not to initiate or continue HT.4,21<23 Complementary and alternative therapies are often used to selfmanage symptoms,21 but none has shown significant benefit in
randomized controlled trials.7,23,24 Previously, no nonhormonal
treatments were approved for the treatment of VMS due to
menopause, and clinicians consequently may have prescribed
antidepressants off-label.21 However, tolerability may be an issue if doses commonly used for psychiatric disorders are used to
manage VMS, as is often the case. According to an estimate
from IMS Health, more than 2.4 million SSRI prescriptions
for the treatment of VMS were filled in 2012; in prescriptions
for paroxetine, the most commonly prescribed doses were
20 and 40 mg.25
The mechanism of action for VMS improvement with
SSRIs is complex and probably differs from the mechanisms involved in the treatment of psychiatric disorders.
Two 5-HT receptor subtypes, 5-HT1a and 5-HT2a, have
been associated with thermoregulation in mammals and
seem to have opposite regulatory effects; a balance between
the two probably maintains temperature homeostasis.26<28
Higher doses of SSRIs used for treating major depression,
anxiety, and other indications may be unnecessary for treating
* 2013 The North American Menopause Society

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PAROXETINE 7.5 MG FOR TREATING MENOPAUSAL VMS

menopausal VMS. Current off-label use of these medications

for VMS is not supported by safety and efficacy data from
adequate and well-controlled trials. Until more data are available, only agents specifically tested in randomized controlled
studies at doses and formulations for postmenopausal women
with VMS due to menopause should be considered as safe
and effective treatments to relieve symptoms.
Some limitations of the current studies should be noted.
First, consistent with guidance from the FDA, the studies had
no HT arm serving as an active comparator, and the duration
of the studies was limited to 12 or 24 weeks. Most participants (80%) had naturally occurring menopause. To date,
only combined estrogen/progestin therapy has been approved
for treating VMS in women with intact uterus and spontaneous menopause. Because the Womens Health Initiative
estrogen/progestin study demonstrated greater risks with combined therapy than with estrogen alone,18,29,30 alternative nonhormonal treatments are needed for this population of women.
By using a low-dose paroxetine regimen that has not been
used or indicated for psychiatric conditions, clinicians will be
able to offer women a nonhormonal treatment specifically
geared toward menopausal VMS and will avoid possible concerns about mental health stigmatization or minimization of
VMS. Untoward adverse effects and withdrawal symptoms
associated with higher paroxetine doses seem to be avoided
with paroxetine 7.5 mg.
CONCLUSIONS
Paroxetine 7.5 mg is safe, well-tolerated, and efficacious
in reducing the frequency and severity of moderate to severe VMS due to menopause and demonstrates persistence of
treatment benefit throughout a 24-week treatment duration.
Paroxetine 7.5 mg is a nonhormonal option for women seeking an alternative to estrogen-containing therapies for VMS
due to menopause.
Acknowledgments: We acknowledge the editorial assistance provided by Maribeth Bogush, PhD, Lynn Brown, PhD, and Sally
Mitchell, PhD, of ApotheCom LLC.

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