Non-Hormonal Pharmacologic Options to Treat Postmenopausal

Vasomotor Symptoms

Presented by Dave Porter

March 5th, 2014

Outline

Question

Background

Article IObjectives, methods, results, weaknesses

Article IIObjectives, methods, results, weaknesses

Summary of Recommendations

References

Questions (and hopefully answers)

The Big Question

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

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

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 serotonergicprojections 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

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

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.

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

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

Figure 1: Patient Entry, Random Assignment and Assessability3

Figure 1: Patient Entry, Random Assignment and Assessability3

4 weeks paroxetine4 weeks placebo

4 weeks paroxetine4 weeks placebo

4 weeks placebo4 weeks paroxetine

4 weeks placebo4 weeks paroxetine

Stratified, randomized, double-blind, placebo-controlled, cross-over trial

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

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

Figure 2A: Average Percentage Reduction in Hot Flash Frequency3

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

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?

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 = constipationB = headache E = fatigue/weaknessC = weight gain

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 drynessG = blurred visionH = nausea

The paroxetine 20mg group has a large percentageof patients experience worsening nausea at thatdose, compared to nausea remaining equal to thatwhich they felt at the start of the study

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

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

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

Objectives2

• Primary Objective– Compare efficacies and side effect profiles of

two regimens (TDD 300mg and TDD 900mg) of gabapentin with placebo

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)

Figure 1:Trial Profile2

• Used intention-to-treat principle

• Patients wereincluded 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

Table 1: Demographic and Baseline Characteristics2

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)

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

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

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

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

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.