Pharmacology Update By William T. Elliott
Paroxetine Capsules (Brisdelle)
By William T. Elliott, MD, FACP, and
James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved paroxetine for the treatment of hot flashes (vasomotor symptoms) in postmenopausal women — the first nonhormone product to be approved for this indication. Paroxetine is the same drug as the widely used serotonin reuptake inhibitor (SSRI) Paxil. It is dosed at 7.5 mg, which is lower than the initial dose for depression (20-25 mg). It will be marketed by Noven Therapeutics as Brisdelle.
Paroxetine (7.5 mg) is indicated for the treatment of moderate-to-severe vasomotor symptoms associated with menopause (VMS).1
The recommended dose is 7.5 mg taken at bedtime.1 It is available as 7.5 mg capsules.
Paroxetine provides a different mechanism of action for VMS and is the only FDA-approved, nonhormone treatment for this indication. It does not carry the same risk factors associated with hormonal treatment (e.g., thromboembolic events, breast cancer).
Paroxetine does not affect other problems associated with menopause such as vaginal atrophy and reduction in bone mineral density. It may actually increase the risk of fractures.1 Paroxetine may be less effective than hormonal treatment and reduces the effectiveness of tamoxifen.1 Paroxetine has a completely different safety profile compared to estrogens. It also carries the same boxed warning for suicide risk as the antidepressant form of the drug.
The safety and efficacy of paroxetine were evaluated in two randomized, double-blind, placebo-controlled studies. Subjects (n = 1174) with moderate-to-severe VMS (minimum of 7-8 per day at baseline, ≥ 50 per week, 30 days prior to treatment initiation) were randomized to paroxetine 7.5 mg at bedtime or placebo. One study was 12 weeks and the second was 24 weeks. The study population had an average age of 54-55 years, two-thirds to three-fourths were Caucasian, 81-82% were naturally menopausal, median VMS frequency was about 10 per day with a median severity of 2.5 (0-4 scale). The co-primary efficacy endpoints were the reduction from baseline in VMS frequency and severity at week 4 and 12. The persistence of benefit was assessed in the 24-week study. Analysis was by modified intent-to-treat requiring a valid baseline value and at least one dose taken. Paroxetine treatment showed a placebo-subtracted difference of -1.2 and -1.3 for median frequency reduction at week 4 and -0.9 and -1.7 at week 12. Severity was reduced by -0.05 and -0.03 at week 4 and -0.04 and -0.05 at week 12. This represents about an unadjusted 40% reduction in VMS and only a 12% reduction relative to placebo due to a high placebo effect (26-30% reduction). Reduction in severity is about 0.5 points on the severity scale. For subjects categorized as responders (≥ 50% reduction in frequency) at week 12, 48% of those randomized to paroxetine maintained this level of efficacy at week 24 compared to 36% for placebo. Common adverse reactions (compared to placebo) were headache (6.3% vs 4.8%), fatigue/malaise/lethargy (4.9% vs 2.8%), and nausea/vomiting (4.3% vs 2.3). There are currently no published comparative studies between paroxetine 7.5 mg vs hormonal treatment. The FDA only approved the 7.5 mg dose for VMS. Greater effectiveness has been previously reported with higher doses of paroxetine (12.5-25 mg); mean reduction of hot flash composite scores (frequency × severity) were 62.2% and 64.6% for the two doses of paroxetine, compared to 37.8% for placebo.2 These doses likely would be associated with a higher frequency of side effects. Low-dose estrogen appears to be more effective. It has been reported to reduce the number of VMS episodes by 65% compared to 35-40% for placebo.3
Hot flashes significantly affect quality of life of menopausal women. A recent survey by the North American Menopause Society (NAMS) reported that 89% of respondents reported experiencing hot flashes and about 50% were moderate and 34% were severe.4 Hormone therapy is still the most effective treatment.5 However, this may not be an option for certain patients (e.g., intolerance, increased breast cancer risk). Interestingly, in the same NAMS survey, 85% felt traditional hormone treatment was unsafe, suggesting a desire for nonhormone options. Antidepressants such as venlafaxine and paroxetine have been widely studied as nonhormonal alternatives and appear to be the most consistent in effectiveness.6,7 Paroxetine is the first to be approved and provides modest benefit in relieving VMS.
1. Brisdelle Prescribing Information. Miami, FL: Noven Therapeutics; June 2013.
2. Stearns V, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 2003;289:2827-2834.
3. Ettinger B. Vasomotor symptom relief versus unwanted effects: Role of estrogen dosage. Am J Med 2005; 118(Suppl 12b):S74-S78.
4. http://www.menopause.org/for-women/menopause-take-time-to-think-about-it/consumers/2013/05/14/results-of-our-survey-on-nonhormonal-treatment-for-menopause-symptoms. Accessed July 6, 2013.
5. http://www.menopause.org/for-women/menopauseflashes/the-experts-do-agree-about-hormone-therapy. Accessed July 6, 2013.
6. Pinkerton JV, et al. Advances in the treatment of menopausal symptoms. Womens Health 2009;5:361-384.
7. Carroll DG, Kelley KW. Use of antidepressants for management of hot flashes. Pharmacotherapy 2009;29: 1357-1374.