1. Non-Hormonal Pharmacologic
Options to Treat Postmenopausal
Vasomotor Symptoms
Presented by Dave Porter
March 5th, 2014

2. Outline
Question
Background
Article I
Objectives, methods, results, weaknesses
Article II
Objectives, methods, results, weaknesses
Summary of Recommendations
References
Questions (and hopefully answers)

3. The Big Question
• “What are possible drug-therapy
alternatives to hormone replacement
therapy in women with post-
menopausal vasomotor symptoms?”

4. Background1,2,3
• Vasomotor symptoms (VMS)
–Hot flashes, night sweats
–Most commonly reported symptoms
during the transition to menopause and
early post-menopausal period
• May be worse in breast cancer patients
–Affect 60–90% of women!
–May lead to significant physical
discomfort and functional impairment.
• Psychological symptoms, too

5. Hot Flashes1,2,3
• Begin with sudden onset of heat sensation in the
upper body, chest and face
– May be followed by sweating, palpitations, chills, shivering
• Caused by disruption within thermoregulatory
circuits
– Core temperature is regulated by the preoptic nucleus in
the hypothalamus, which is innervated by serotonergic
projections and estrogen receptors
• Small increases in body temperature can trigger
hot flashes
– Women experiencing hot flashes have a narrower
thermoregulatory zone than asymptomatic women
– Small changes in symptomatic women are sufficient to
cross the upper/lower normal thresholds, thereby
provoking either sweating and shivering
• Severity varies

6. Treatment Options1
• Hormonal
– Estrogen-based therapy is 1st line
• History of breast cancer – don’t use estrogen!
– Long-term therapy not recommended
• Steroids
• Long-term safety? (Controversial)
• Non-Hormonal
– That’s what this presentation is about!
• Paroxetine (FDA approved as Brisdelle) and
gabapentin
• Other SSRIs, venlafaxine, clonidine
• Black kohosh, vitamin E

7. Article I
• “Paroxetine is an effective treatment
for hot flashes: results from a
prospective randomized clinical trial.”
– Stearns V, Slack R, Greep N, Henry-Tilman R,
Osborne M, et al.
– J Clin Oncol. 2005 Oct 1;23(28):6919-30.

8. Study Objectives3
• Primary objective
– Evaluate efficacy of paroxetine in reducing hot
flash frequency and composite score compared to
placebo
– Compare effectiveness of the standard paroxetine
starting dose for depression/other psychiatric
illnesses (20 mg paroxetine) and low-dose (10 mg
paroxetine) for the treatment of hot flashes.
• Secondary objective - FYI
– Evaluate change in depression and anxiety scores,
sleep, sexual function, and overall quality of life in
women treated with paroxetine compared with
placebo

9. Methods3
• Inclusion Criteria
– 18+ years old
– With or without a history of breast cancer
– Hot flashes at least 14 times per week
• Lasted 1 month or longer
– Creatinine and bilirubin not more than twice normal
limit
• Exclusion Criteria
– No other hot flash treatments (besides vitamin E, if
used for 1 month or more and continued)
– No cytotoxic chemotherapy, radiation therapy,
hormone therapy, antidepressants, or MAOIs
• DC’ed at least 1 month prior to starting in the trial
• Anti-estrogen therapy allowed, if used at least 1 month prior
and continued

10. Figure 1: Patient Entry, Random
Assignment and Assessability3

11. Figure 1: Patient Entry, Random
Assignment and Assessability3
4 weeks paroxetine
4 weeks placebo
4 weeks paroxetine
4 weeks placebo
4 weeks placebo
4 weeks paroxetine
4 weeks placebo
4 weeks paroxetine
Stratified, randomized, double-blind, placebo-controlled, cross-over trial

12. Table 1: Patient Characteristics of Randomly
Assigned Patients by Treatment Arm3

13. Table 1: Patient Characteristics of Randomly
Assigned Patients by Treatment Arm3

14. Figure 2A: Average Percentage Reduction
in Hot Flash Frequency3

15. Figure 2B: Average Percentage Reduction
in Hot Flash Composite Score3

16. Comparison of Paroxetine 10mg vs. 20mg3
• The average reductions in the frequency of hot
flashes (compared to placebo) for paroxetine
10mg and 20mg were 27.0% and 25.2%,
respectively
– Relative to placebo
– Difference of only 1.8%!
• Both doses were similar in efficacy in reducing
hot flash frequency.
– Side effects?
– ADRs?

17. Figure 4: Changes in Symptoms Reported
Subjectively by Patients at Baseline and Week 5 for
Eight Symptoms that may be Related to Paroxetine3
A = fatigue/drowsiness D = constipation
B = headache E = fatigue/weakness
C = weight gain

18. Figure 4: Changes in Symptoms Reported
Subjectively by Patients at Baseline and Week 5 for
Eight Symptoms that may be Related to Paroxetine3
F = mouth dryness
G = blurred vision
H = nausea
The paroxetine 20mg group has a large percentage
of patients experience worsening nausea at that
dose, compared to nausea remaining equal to that
which they felt at the start of the study

19. Weaknesses of Article I
• Compliance and loss to follow-up
– 39 women (26%) did not complete the 9 weeks of
therapy required for crossover analysis.
• “The positive effects of paroxetine were similar when
the 9 weeks of study were included or when only the
first 5 weeks were analyzed.”
– 26 women (17%) did not return symptom diaries.
– Patient reported information!
• CYP2D6 inhibitors and tamoxifen
– Breast cancer patients taking this?
– Tamoxifen needs to be activated!
• Placebo controlled
– Not head-to-head with a
comparator drug

20. Conclusions from Article I
• Paroxetine 10mg is effective in
reducing the frequency of hot flashes
• Both doses of paroxetine were similar
in effectiveness for reducing hot flash
frequency.
– Use lower dose, to minimize adverse effects
such as fatigue, nausea and weight gain

21. Article II
• Gabapentin for hot flashes in 420
women with breast cancer: a
randomised double-blind placebo-
controlled trial.
– Kishan J Pandya, Gary R Morrow, Joseph A
Roscoe, Hongwei Zhao, Jane T Hickok,
Eduardo Pajon, Thomas J Sweeney, Tarit K
Banerjee, Patrick J Flynn
– Lancet 2005; 366: 818–24

22. Objectives2
• Primary Objective
– Compare efficacies and side effect profiles of
two regimens (TDD 300mg and TDD 900mg)
of gabapentin with placebo

23. Inclusion/Exclusion Criteria2
• Inclusion
– 18 years or older with breast cancer
• May be on nonsteroidal contraception
– Two or more hot flashes per day
– Written informed consent
• Exclusion
– Chemotherapy other than tamoxifen
– Patients taking venlafaxine, clonidine or
anticonvulsants
• SSRIs/SNRIs allowed, though
– Breastfeeding mothers, recent MI, stroke,
hypotension, liver dysfunction (AST >2x ULN, or
bilirubin > normal)
– Hormonal contraception
– Renal dysfunction (SCr >1.25 ULN)

24. Figure 1:
Trial Profile2
• Used intention-to-
treat principle
• Patients were
included in the
analysis of the group
they were assigned,
regardless of any
subsequent changes
to the treatment,
such as dropping out
of the clinical trial

25. Table 1: Demographic and Baseline
Characteristics2

26. Table 2: Estimated Effect of
Gabapentin vs. Placebo2
• Data not robust for the 300mg TDD group
• Data significant in the 900mg TDD group
• Reductions of 26% in frequency and 30% in
severity (compared to placebo)

27. Table 4: Changes in Symptoms Between
Baseline and Week 4 or Week 82
• Only significant differences were the 4 week appetite
and pain symptoms
– Pain lessened, no loss of appetite at week 4 only

28. Weaknesses of Article II
• No P-values given for baseline
characteristics
• No short term side effect/ADR
analysis/data collection
• Study only 8 weeks long
– What about more long term use > 8 weeks?
• Power of study was only 80%
– To detect a 15% difference
• Placebo controlled
– Not head-to head with a
comparator drug

29. Conclusions from Article II
• Gabapentin can effectively control hot
flashes in patients with breast cancer
– In a TDD of 900mg or greater
• 26% in frequency and 30% in severity
– 300mg TDD was not significantly different
from placebo
• Safety analyses don’t show major concerns
with gabapentin use in this patient
population
– Pain lessened, sleep increased

30. Putting it All Together
• Q: What are possible drug-therapy
alternatives to hormone replacement
therapy in women with post-
menopausal vasomotor symptoms?
• A: Paroxetine and gabapentin

31. References
1. Hall, Elise, Benicio N. Frey, and Claudio N.
Soares. Non-hormonal treatment strategies for
vasomotor symptoms. Drugs 71.3 (2011): 287-
304.
2. Pandya, Kishan J., et al. Gabapentin for hot
flashes in 420 women with breast cancer: a
randomised double-blind placebo-controlled
trial. The Lancet 366.9488 (2005): 818-824.
3. Stearns, Vered, et al. Paroxetine is an effective
treatment for hot flashes: results from a
prospective randomized clinical trial. Journal of
Clinical Oncology 23.28 (2005): 6919-6930.