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A Review of Paroxetine for the Treatment of Vasomotor Symptoms Rachel M. Slaton, Megan N. Champion and Kayla B. Palmore Journal of Pharmacy Practice published online 8 August 2014 DOI: 10.1177/0897190014544785 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/08/07/0897190014544785

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New York State Council of Health-system Pharmacists

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Review

A Review of Paroxetine for the Treatment of Vasomotor Symptoms

Journal of Pharmacy Practice 1-9 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014544785 jpp.sagepub.com

Rachel M. Slaton, PharmD, BCPS1, Megan N. Champion, PharmD1, and Kayla B. Palmore, PharmD1

Abstract Background: Studies in recent years have exposed concerns about the safety of hormone replacement therapy (HRT) in the treatment of vasomotor symptoms (VMS) in menopausal women. Numerous studies have examined the use of antidepressants for relief of VMS. Despite recommendations to deny approval of paroxetine mesylate (Brisdelle™) for the treatment of VMS, the Food and Drug Administration (FDA) recently granted it approval for this indication. Objective: To evaluate all published literature examining use of paroxetine salts (mesylate and hydrochloride) in the treatment of menopausal VMS. Methods: Both PubMed and International Pharmaceutical Abstracts (IPA) were searched using the keywords hot flashes, vasomotor symptoms, menopause, and paroxetine. In PubMed, MeSH terms were used for paroxetine, menopause, and hot flashes. Searches were limited to humans, English language, and clinical trial design. The references for each study identified in this search process were examined in order to locate any additional relevant articles. Results: Compared with placebo, paroxetine salts offer a modest benefit in the treatment of menopausal VMS reducing the frequency and severity of weekly hot flashes. Conclusion: Paroxetine (mesylate or hydrochloride) is an effective alternative to HRT for the reduction in VMS in menopausal women. Future head-to-head studies with active medications are needed in order to identify the best algorithm of treatment for this condition. Keywords paroxetine, hot flashes, vasomotor symptoms, menopause

Introduction Menopause is a term used to describe a permanent lack of ovarian function that results in amenorrhea and a drop in estrogen and progesterone levels.1 In most cases, menopause is diagnosed after 12 consecutive months of amenorrhea.2 Although menopause is a natural part of female aging, it may also result from interventions such as hysterectomies, bilateral oophorectomies, or cancer treatments.1,2 Historically, menopause has been associated with a variety of symptoms, but only vasomotor symptoms (VMS) and vaginal dryness have been definitively linked to menopause.2 The vasomotor symptoms that include hot flashes and night sweats appear to be the most frequently reported and debilitating for patients.2 In fact, 70% of women have menopausal VMS and 20% of menopausal women perceive these symptoms to be unbearable, revealing that menopausal VMS can have a significant impact upon quality of life and daily functioning.3 Intervention is required in women who experience impaired daily functioning as a result of menopausal VMS. Estrogen, either alone or in combination with a progestin, has long been the standard therapy for relief of VMS and other menopausal symptoms.2-4 However, the long-term risks of hormone replacement therapy (HRT) have been brought to light in the recent years. Most notably in the Women’s Health Initiative

(WHI) study, an increased risk of breast cancer resulted in the early discontinuation of combination equine estrogen and medroxyprogesterone acetate in menopausal women with an intact uterus.5 Two years later, the estrogen-only treatment arm for hysterectomized women was also discontinued early due to an increased risk of stroke.6 These findings raised serious concerns about the risk of breast cancer and cardiovascular disease in menopausal women receiving HRT, causing a decrease in utilization of these agents.6 Despite these concerns, HRT remains the most effective agent for the treatment of menopausal VMS, and current guidelines recommend that it may be used as long as practitioners and patients carefully consider both the risks and the benefits.7,8 Nonetheless, the risks associated with the use of HRT are especially severe in certain patient populations, including those with a personal history or strong family history of breast, ovarian, or endometrial cancer and

1

McWhorter School of Pharmacy, Department of Pharmacy Practice, Samford University, Birmingham, AL, USA Corresponding Author: Rachel M. Slaton, Samford University, 800 lakeshore drive, Birmingham, AL 35229, USA. Email: [email protected]

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women who are at increased risk of thrombotic events.2,7 Because of this, an alternative to HRT is greatly needed, particularly in those patients who are at highest risk of developing adverse outcomes. In response to this need, several studies have examined the efficacy of nonhormonal agents in the treatment of menopausal VMS. In terms of nonprescription products, soy supplements have shown some benefit in reducing hot flashes, but the long-term safety of these products is unknown, particularly in women with a history of breast cancer.2,3 St John’s Wort and omega 3 fatty acids have also shown some benefit in alleviating hot flashes and night sweats, but more definitive data are needed.4 In addition to these over-the-counter products, several prescription medications have been studied as alternative treatments for menopausal VMS. Gabapentin has been shown to decrease hot flashes in women with and without a history of breast cancer but not without significant adverse effects.3,4 The use of clonidine has also been assessed, with studies producing conflicting results.2-4 Besides clonidine and gabapentin, other prescription alternatives include a variety of selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). The use of these agents for the management of VMS is supported by the role of both serotonin and norepinephrine in thermoregulation.4 Although the exact mechanism by which serotonin and norepinephrine reuptake improve VMS is unclear, many SSRIs and SNRIs have demonstrated efficacy in reducing hot flashes and night sweats. Agents that have shown benefit include citalopram, escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine, desvenlafaxine, and fluvoxamine.3,4 Although paroxetine hydrochloride (HCl) has been used for many years off-label, Brisdelle™ (paroxetine mesylate) is the first to be approved by the Food and Drug Administration (FDA) for the treatment of menopausal hot flashes and night sweats (moderate to severe menopausal VMS)9,10 This article reviews all available data regarding the safety and efficacy of Brisdelle and paroxetine HCl for this indication.

Pharmacology/Pharmacokinetics In general, paroxetine is an SSRI that primarily inhibits the serotonin transporter (SERT) in presynaptic neurons. This allows for an increased concentration of serotonin, or 5-HT, to be present in the synapse.11 SSRIs also work by desensitizing 5-HT1A autoreceptors. This blocks the regulation of serotonin by negative feedback and consequently results in the neuron having no means of internal regulation of the production and transmission of 5-HT to the synapse. In general, SSRIs have fewer side effects than other centrally acting agents like tricyclic antidepressants because they were formulated to have little affinity for histaminergic, cholinergic, or adrenergic receptors. However, paroxetine exhibits minor anticholinergic affinity when compared to other SSRIs, potentially causing increased adverse effects in comparison.12 In relation to SSRIs, paroxetine also has the highest affinity for the norepinephrine transporter (NET), although it is minimal.11

The pharmacokinetic profile of Brisdelle (paroxetine mesylate) was defined in a Phase 1, open-label, single-center trial (N ¼ 24) in postmenopausal women who were at least 40 years old and had spontaneous amenorrhea for at least 12 consecutive months, amenorrhea for at least 6 months, follicle-stimulating hormone (FSH) > 40 mIU/mL for at least 6 months, or documented bilateral salpingooophorectomy for at least 6 weeks with or without hysterectomy.13 Patients were given Brisdelle 7.5 mg daily for 19 days with blood samples being drawn multiple times daily. It was found that the mesylate salt is completely absorbed upon oral administration with peak concentrations occurring at around 6 hours, steady state concentrations at 12 days with a half-life of roughly 17.3 hours. Similar to other formulations of paroxetine, Brisdelle follows nonlinear pharmacokinetics. This nonlinearity allows for saturation of the 2D6 enzyme thus causing inhibition of metabolism of medications dependent on this pathway. Thus, at any dose, it could act as a strong 2D6 inhibitor. The pharmacokinetics of Brisdelle was similar to all strengths of the mesylate salt. Paroxetine is readily dispersed throughout the body, and it is about 94% protein bound.13

Efficacy Six controlled clinical trials and two open-label studies have evaluated the use of paroxetine (7.5-25 mg) for the reduction in the frequency and severity of VMS over a 4- to 24-week period.14-19 Two of the studies were used to gain FDA approval for Brisdelle for the treatment of VMS.14 In general, to be included, subjects had to be postmenopausal women greater than 40 years of age who had amenorrhea occur spontaneously (>12 months ago); amenorrhea for 6 months with follicle-stimulating hormone levels >40 mIU/mL; or bilateral salpingo-oophorectomy (with or without hysterectomy) greater than 6 weeks before the study period. Subjects had to have greater than 7 moderate to severe hot flashes/week defined as a sensation of heat with sweating and ability to continue activities (moderate) or sweating without ability to continue activities (severe). Concomitant psychotropic or hormonal drug use was restricted, and washout periods for specific products were required.14-19 In addition, 3 studies evaluated subjects who were breast cancer survivors.17-19 In general, subjects with uncontrolled comorbidities (eg, hypertension, cardiovascular disease, and psychiatric disorders) or with previous nonresponse to SSRI or SNRI therapy or hypersensitivity to paroxetine were excluded.14-19 End points were evaluated using various tools. Most studies required that subjects maintain daily diaries to record frequency and severity of hot flashes as well as adverse effects in a systematic manner. Composite scores for VMS symptoms were developed by assigning a value to the severity of hot flashes (mild ¼ 1, moderate ¼ 2, severe ¼ 3, and very severe ¼ 4) and multiplying this by the number of hot flashes at that level per week; thus, higher numbers were indicative of more severe symptoms. VMS were evaluated using selfassessment tools such as the Green Climateric Scale (GCS;

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Drug regimen (n)

PCR12.5-25 (n ¼ 27) PBO (n ¼ 23)

PCR 12.5 (n ¼ 51) PCR 25 (n ¼ 58) PBO (n ¼ 56)

Soares et al. (2007); DB, PC, PG; 6 weeks

Stearns et al. (2003); R, DB, PC, PG; 6 weeks

Simon et al (2013); Two R, 12 week: PM 7.5 (n ¼ 306) DB, PC, MC, PG; 12 PBO once daily weeks and 24 weeks, (n ¼ 308) Phase 3 24 week: PM 7.5 (n ¼ 285) PBO once daily (n ¼ 285)

Author; study design; duration Secondary end points (SE) results

Comments

(continued)

PEs: Mean changes in the frequency and severity of  Clinically meaningful reduction in severity  AEs were mild or moderate in severity was considered 0.08 + 0.22; for VMS at 4 and 12 weeks; persistence of with 50.3% (P7.5) and 46.7% (PBO) frequency was 1.41 + 5 hot flashes/day treatment benefit at week 24 reporting events 12-week study:  P7.5 was well tolerated and reduced the  AEs most common with P7.5 were nausea frequency and severity of menopausal (3.8% vs 1.4%), fatigue (3.4% vs 1.5%), and  P7.5 reduced the mean weekly VMS VMS. Treatment benefit lasts through 24 frequency compared with PBO at week 4 dizziness (2% vs 0.8%). No clinically weeks (33 vs 23.5; P < .0001) and week 12 important changes in laboratory values or (43.5 vs 37.3; P ¼ .0090) vital signs were identified  P7.5 reduced the mean weekly VMS  Discontinuation symptoms were reported severity compared with PBO at week 4 in 17.2% (P7.5) and 13.6% (PBO) and (0.09 vs 0.05; P < .0048) but not at included muscle cramps, spasms, twitching, week 12 (0.10 vs 0.09; P ¼ .2893) restless legs, and insomnia 24 week:  P7.5 reduced the mean weekly VMS frequency compared with PBO at week 4 (28.9 vs 19; P < .0001 for both studies), week 12 (37.2 vs 27.6; P ¼ .0001)  Mean weekly reduction in VMS severity was greater for P7.5 mg than for PBO at week 4 (0.09 vs 0.06; P ¼ .0045), week 12 (0.12 vs 0.07; P ¼ .0114)  Persistence of treatment benefit was found at 24 weeks (47.5% vs 36.3%; P ¼ .0066). PE: Change from baseline in vasomotor symptoms SE: Change in MADRS and GCS scores at study PCR 12.5 could be increased to PCR 25 after 2 weeks of therapy based upon clinician’s end after six weeks of therapy impression of patient response. 17 (63%)  Reduction in MADRS: PCR 12.5-25 ¼ 3.6  Median reduction in weekly hot flashes: patients in the paroxetine group were placed points, PBO ¼ 0.4 points (P ¼ .01) PCR 12.5-25 ¼ 6.1, PBO ¼ 2.8 (P ¼ .03) on the higher dose  Between group differences in GCS scores: vasomotor symptoms, P ¼ .04, psychological, somatic, or sexual dysfunction scores, P > .05 for all PE: Mean change from baseline hot flash SE: Mean change from baseline in daily hot flash Hot flash responders were defined as those participants who had at least a 50% reduction composite score at 6 weeks with the 12.5-mg composite score at 6 weeks in the 25-mg group in baseline hot flash score at study end group, proportion of hot flash score responversus placebo CGI responders were defined as those ders, proportion of CGI responders, mean  Percentage reduction in mean baseline hot participants achieving a score of 1 or 2 on the change from baseline in BDI-II and BAI-II flash composite score: PCR25 ¼ 64.6%, clinician-rated CGI improvement item scores, safety, and tolerability PBO ¼ 37.8%  Hot flash composite score after 6 weeks:  PBO-adjusted reduction in hot flash comPCR 12.5: 62.2%, PBO-adjusted reduction posite score at 6 weeks with PCR 25 ¼ ¼ 4.7 (95% CI, 8.1 to 1.3; P ¼ .007) 3.6 (95% CI 6.8 to 0.4; P ¼ .03)

Primary end point (PE) results

Table 1. Studies Evaluating the Efficacy of Paroxetine Salts for the Treatment of VMS.14-19

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Drug regimen (n)

Primary end point (PE) results

Secondary end points (SE) results

Comments

Abbreviations: R, randomized; DB, double blind; PC, placebo controlled; PG, parallel group; P7.5, paroxetine mesylate 7.5 mg daily; PCR12.5, paroxetine CR 12.5 mg daily; PCR 25, paroxetine CR 25 mg daily; PBO, placebo; CGI, Clinical Global Impression; BDI-II, Beck Depression Inventory; BAI-II, Beck Anxiety Inventory; MADRS, Montgomery-Asberg Depression Rating Scale; GCS, Greene Climacteric Scale; DCO, double crossover; PLT, pilot trial; OL, open label; BCS, breast cancer survivor; BCP, breast cancer patient; P10, paroxetine 10 mg daily; P20, paroxetine 20 mg daily; PE, primary end point; SE, secondary end point; EuroQOL, linear quality-of-life rating scale; sleep score, the Medical Outcomes Study 9-item sleep scale; AEs, adverse effects; PSQI, Pittsburgh Sleep Quality Index; MFSI, Multidimensional Fatigue Symptom Inventory.

 Proportion of hot flash responders in paroxetine groups at study end: 60.5%  Proportion of CGI responders in paroxetine groups at study end: >50%  There was no statistically significant difference between the paroxetine groups and placebo in change from baseline BDI-II and BAI-II scores (P > .05 for all)  Percentage of patients reporting AEs: PCR12.5 to PCR25 ¼ 58.3%, PBO ¼ 53.6%  53.6%, PBOf patients reporting AEs:roxetine groups and placebo in change from baseline BDI-II and B Patient preference to continue medication: Stearns et al (2000); OL, P10  1 week, then P20 PE: Mean reduction in hot flash frequency severity SE: Improvement in quality-of-life parameters Paroxetine 83%, not dose specific PLT, BCS; 4 weeks  4 weeks (n ¼ 30) score  Depression: P ¼ .02  Sleep score: P ¼ .0002  P20 67% (95% CI: 56%-79%) reduction in frequency  Anxiety: P ¼ .0005  EuroQOL: P ¼ .004  P20 75% (95% CI: 66%-85%) reduction in severity score  ADEs: 66% of women noted worsening of symptoms that could be contributed to paroxetine (somnolence, dry mouth, nausea, constipation, decreased appetite) SE: Improvement in quality-of-life parameters Weitzner et al (2002); P10  3 days, then P20 PE: Mean reduction in hot flash severity Clinical depression improvement: pretreatment OL, PLT, BCP; 4 weeks  4 weeks (n ¼ 13) 39% met criteria versus posttreatment 8%,  Mean sleep quality ¼ 1.85 vs 0.77, P ¼ .003  Pretreatment mean, 3.62 versus (PSQI) posttreatment mean, 2.08 (P ¼ .002) P ¼ .13  Mean quality of life ¼ 35.7 vs 20.2, P ¼ .01 (MFSI) Patient preference to continue medication PE: Change (% reduction) in hot flash frequency SE: Improvement in quality-of-life parameters P10-PBO (n ¼ 37) Stearns et al (2005); R, better with lowest dose (P10 ¼ 81% vs P20 ¼ and composite score at study conclusion P20-PBO (n ¼ 39) DB, PC, DCO;  Sleep score: P ¼ .003 65%) PBO-P10 (n ¼ 39) 63 days  EuroQOL: P ¼ .05  Hot flash frequency: P10 40.6% versus PBO 13.7% (P ¼ .0006) PBO-P20 (n ¼ 37)  ADEs: fatigue, headaches, weight gain, constipation, weakness, increased appetite,  P20 51.7% versus PBO 26.6% (P ¼ .002) vaginal discharge, mouth dryness, blurred  Composite score: P10 45.6% versus PBO vision, and dizziness. Nausea was 13.7% (P ¼ .0008) significantly worse in P20 group (P < .001).  P20 56.1% versus PBO 28.5% (P < .001) Toxicity led to withdrawal more in P20 than P10 (17% vs 5%; P ¼ .02)

Author; study design; duration

Table 1. (continued)

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VMS subscore >3 suggests moderate to severe symptoms) and the Discontinuation-Emergent Signs and Symptoms (DESS) scale. The DESS scale was used to evaluate the association of adverse effects with treatment based on the time frame of occurrence (within 7 days of discontinuation). Selfassessments of anxiety and depression associated with menopause were evaluated with the Beck Anxiety Inventory II (BAI-II) and Beck Depression Inventory II (BDI-II) scales, where higher scores are indicative of moderate to severe anxiety and depression, respectively. Similarly, higher scores (>19 and >16, respectively) on the clinician-administered evaluations of depression (ie, Montgomery-Asberg Depression Rating Scale [MADRS], Center for Epidemiological Study—Depression [CES-D] scale) were indicative of more severe symptoms. The Eastern Cooperative Oncology Group performance status rating (ECOG-PSR) was used to evaluate general well-being and activities of daily living (scores of 0-2 suggest patients are in perfect health to moderate health status).14-19 End points were evaluated by analyzing the change from baseline in scores on assessments at defined study periods. Patients who show improvements in scores on these scales are considered responders to treatment, while patients who do not score well are considered poor responders to treatment. Two randomized, double-blind, placebo-controlled clinical trials (N ¼ 534 and N ¼ 614) evaluated the efficacy and safety of Brisdelle 7.5 mg once daily versus placebo for the treatment of VMS over a period of 12 and 24 weeks, respectively.14 The studies had co-primary end points that included the mean changes in the frequency and severity of moderate to severe VMS at weeks 4 and 12. The 24-week study also evaluated the duration of the treatment benefit at 24 weeks. Clinically meaningful changes in the end points included a reduction in symptom severity of 0.08 + 0.22 and a change in frequency of 1.41 + 5 hot flashes/d.14 Overall, the demographics were well balanced between treatment groups in both studies.14 The mean frequency of hot flashes was 11.3 per week, and the mean severity score was 2.53 per hot flash. Both the 12- and 24-week studies subjects taking Brisdelle 7.5 mg daily noted significant reductions in the severity and mean number of weekly hot flashes after 4 weeks of treatment. The Brisdelle group experienced 33 less hot flashes per week compared to 23.5 less in the placebo group (P < .0001). At 12 weeks, the frequency of hot flashes was further reduced in both studies (12 weeks: 43.5 vs 37.3; P ¼ .0090 and 24 weeks: 37.2 vs 27.6; P ¼.0001). Severity of VMS was also significantly improved in both studies at 4 weeks but in only 1 study at 12 weeks compared to placebo. Hot flash severity was reduced by 0.09 points (P < .0048) at 4 weeks and by 0.12 points (P ¼ .0114) at 12 weeks. The benefits of treatment with Brisdelle were found to last through 24 weeks in 47.5% and 36.3% of subjects, respectively (P ¼ .0066).14 Two double-blind, placebo-controlled, parallel-group studies (N ¼ 215) examined the efficacy of paroxetine HCl controlled-release (CR) tablets (12.5-25 mg) versus placebo for the treatment of menopausal VMS over a 6-week period.15,16

The primary end points included change from baseline in hot flash composite score in the paroxetine HCl CR 25 mg group versus placebo and mean change in hot flash frequency at the end of the treatment period. Secondary end points included the change from baseline in the MADRS (depressive symptoms) and GCS (menopause-related symptoms) scores after 6 weeks of treatment. Menopausal women with at least 14 hot flashes per week were included. Although the first study included patients regardless of prior HRT use, the second only included those women who had received prior HRT.15,16 The first study evaluated subjects who had previously been treated with HRT.15 In these patients, there was a significant reduction in median number hot flashes per week with paroxetine HCl CR 25 mg when compared to placebo (median, 6.1 vs 2.8 [interquartile range, 0.1-4.5]; P ¼ .03).15 Although over half of the patients were titrated to the 25-mg dose, the reductions in VMS were similar between patients receiving the 12.5 mg CR tablet and those receiving the higher dose.15 A significant reduction in MADRS scores was also noted (3.6 vs 0.4 points; P ¼ .01). Although there was no difference in total GCS scores between the groups, a reduction in VMS subsection (P ¼ .04) of the GCS evaluation was noted. No improvements were noted in the other subsections (psychological, somatic, and sexual dysfunction scores) on the GCS.15 In the second study, the mean change from baseline in hot flash composite score at 6 weeks was significant for both doses of paroxetine HCl CR versus placebo (12.5 mg ¼ 62.2%, 25mg ¼ 64.6% vs placebo ¼ 37.8%; P < .05 for both).16 Hot flash frequency was also reduced by a mean of 3.3 per week (12.5 mg group) and 3.2 (25 mg group) versus 1.8 for placebo (P < .01 for both). Although subjects in both paroxetine HCl groups responded well, the odds of responding to the 25 mg dose were significantly better (odds ratio [OR] ¼ 2.56 [95% confidence interval, CI, 1.15-5.68; P ¼ .02]). Similar to the first study, changes in GCS scores were only significant for the vasomotor subsection indicating that paroxetine HCl has no appreciable effects on other menopausal symptoms. Anxiety and depression were assessed using the BAI-II and BDI-II scales, respectively. Using these scales, investigators found no significant difference in mood symptoms between the paroxetine CR and placebo groups and also failed to find a correlation between improved VMS and mood (P > .05 for both). Paroxetine HCl CR was well tolerated, with only headache, nausea, and insomnia reported.16 With an increasing population affected by breast cancer, many studies have also been conducted concerning alternative therapies in patients with active or remissive breast cancer who wish to avoid HRT. There are currently 3 studies that evaluated the use of paroxetine HCl in a population that includes patients with breast cancer and breast cancer survivors.17-19 Two of the studies were open-label pilot trials conducted in a single institution, while the other is a randomized, double-blind, placebo-controlled, double-crossover trial. All 3 of these studies evaluated the effects of paroxetine HCl on hot flash frequency, hot flash severity, and quality of life. All trials utilized either paroxetine 10 mg or 20 mg in either an

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open-label fashion or compared with placebo. In general, the patients had to be at least 18 years of age, have a life expectancy of at least 6 months, and have an ECOG-PSR score of < 2. Concurrent tamoxifen use was allowed provided the patient had been receiving therapy for at least 1 month prior to screening. Patients could also continue to supplement with vitamin E provided they were receiving the medication 6 weeks prior to screening. The exclusion criteria consisted of patients actively receiving chemotherapy, taking antidepressants, or patients using other medications to control hot flashes.17-19 The first open-label pilot study (N ¼ 30) was conducted in breast cancer survivors who complained of at least 2 hot flashes per day for at least 1 month.17 During the first week, no drug was given, but patients were instructed to record in their diary about the frequency and severity of hot flashes. In week 2, patients were given a dose of paroxetine HCl 10 mg daily. If well tolerated, the dose was titrated to 20 mg daily for 4 weeks. Of the 30 participants, 27 (90%) completed the trial. Of these, 80% were taking concurrent tamoxifen and 73% were taking vitamin E. Patients were allowed to continue stable (>6 weeks) vitamin E therapy since it is a nonhormonal therapy with minimal risk of toxicity and is more effective than placebo at reducing hot flashes. The mean number of hot flashes daily was 8 (range: 2.1-21).17 Overall, 67% of women reported greater than 50% reduction in the mean number of daily hot flashes (95% CI, 56%-79%). In addition, 73% of women reported a greater than 50% reduction in hot flash severity score. The mean hot flash severity score was 75% (95% CI, 66%-85%) at the end of the study period. With regard to quality of life, paroxetine HCl treatment led to significant improvements in mean depression (P ¼ .02), anxiety (P ¼ .0005), and sleep (P ¼ .0002) scores. Adverse effects were mild with somnolence most reported. Also notable, the study found that 25 (83%) of the women requested to continue paroxetine therapy upon completion of the study.17 A second open-label pilot study (n ¼ 13) was conducted in women who complained of moderate to severe hot flashes who were either actively receiving or had received chemotherapy in the 6 months prior to enrollment and who were at any stage in the menopausal cycle.18 Patients received paroxetine HCl 10 mg at night for 3 nights with a dose increase to 20 mg at night for 1 month.18 In general, 70% of the women had stage 0 to II hormone receptor positive breast cancer, and 69% were taking antiestrogen therapy.18 The study found that paroxetine HCl reduced the baseline hot flash severity (3.62 on a 5-point scale) significantly to 2.08 (P ¼ .002); only 38% of women rated their hot flashes as severe at study conclusion. This was a 62% reduction from a mean of 134 (range 29-361; P ¼ .008). Other significant results to note are the improvement in sleep quality from an average rating of ‘‘fairly bad’’ at 1.85 on the Pittsburgh Sleep Quality Index (PSQI) to an average rating of ‘‘very good’’ at 0.77 (P ¼ .003). Depressive symptomology assessed by the CES-D scale was also improved (P ¼ .0009). Prior to the administration of paroxetine in the study, 30% of the enrolled

women fell under the criteria for diagnosis of clinical depression; however, only 8% of women still met the criteria at study conclusion.18 The third study was a stratified, randomized, double-blind, placebo-controlled, double-crossover clinical trial (N ¼ 151) that looked at the efficacy of paroxetine HCl 10 mg and 20 mg versus placebo in hot flashes over a 9-week period.19 The primary end point was the percentage of reduction in the number and composite scores of weekly hot flashes from week 1 to the end of phase 1 at week 5 and the end of phase 2 at week 9. Data collected at the end of phase 2 was the primary point of analysis. There were 4 arms to this double-crossover study. Arms 1 and 2 consisted of 4 weeks of active treatment (paroxetine HCl 10 mg and 20 mg) followed by 4 weeks of placebo. Arms 3 and 4 consisted of 4 weeks of placebo followed by 4 weeks of active treatment. Arms 1 and 3 were compared, and arms 2 and 4 were compared over a span of 9 weeks. Women were allowed to continue treatment with vitamin E as long as it had been used at least 1 month prior to enrollment, and antiestrogen use was allowed in the study provided the patient had been on it at least 1 month and would continue to be on it for the duration of the study. Overall, 59% to 68% of women were taking antiestrogen therapy and 41% to 54% were taking vitamin E. After 5 weeks of paroxetine HCl treatment, mean number of daily hot flashes was reduced from 6.83 to 3.42 (51%) in the 10-mg group and from 6.42 to 3.14 (50%) in the 20-mg group (P ¼ .0001 for both). The mean difference in hot flash frequency between the 10 mg and 20 mg groups was insignificant (1.8% [95% CI, 18.9% to 22.5%]). Mean reductions in composite scores were 53.9% and 54.3% in the paroxetine HCl 10 mg and 20 mg groups, respectively (P ¼ .0001 for both). The difference in composite scores between groups was also insignificant (3.3% (95% CI, 22.1% to 29%).These reductions were consistent with the findings at week 9. Adverse effects were similar between treatment arms and included fatigue, headaches, weight gain, constipation, weakness, increased appetite, vaginal discharge, mouth dryness, blurred vision, and dizziness. Also noted in the study was that in the paroxetine HCl 10-mg group, 81% of the women wished to continue medication therapy upon completion of the trial.19

Avalability and Cost Considerations Although Brisdelle is the first formulation of paroxetine approved for the treatment of VMS, several other formulations of paroxetine are available. These formulations include generic and branded (Paxil™) paroxetine HCl immediate-release and CR tablets and suspension and paroxetine mesylate tablets (Pexeva™).20 All of these products are intended for oncedaily use and are usually administered in the morning.9,20 Although the currently available solid dosage forms of paroxetine salts range in strength from 10 to 40 mg, each capsule of Brisdelle contains 9.69 mg of paroxetine mesylate in order to provide 7.5 mg of paroxetine per dose.9 This dose of Brisdelle was identified to cause less adverse effects. The adverse

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effect profile is further improved with administration of Brisdelle at bedtime.9 A 30-day supply of Brisdelle 7.5 mg capsules is competitively priced at US$161.64.21 Paroxetine mesylate is also available as the branded product Pexeva (Noven Therapeutics, LLC) in 10 to 40 mg tablets that costs approximately US$220 for a 1-month supply. Comparatively, a similar supply of generic paroxetine HCl tablets (10-40 mg) is US$84 while the suspension (10 mg/5 mL, 250 mL bottle) is US$268.35.21 The generic paroxetine HCl 10-mg tablet is the closest dosage form to Brisdelle and the least expensive. For patients who need financial assistance, it may be prudent to try the lowest dose (10 mg) of the generic product (dosed at bedtime before) and monitor for improvements in VMS and adverse effects. If the adverse effects are intolerable, the patient may benefit from the lower dose available in Brisdelle. The manufacturer of Brisdelle also offers a copayment assistance program. Brisdelle is formulated with a different salt (mesylate) than paroxetine HCl. Pharmacokinetic data that compared single doses of paroxetine mesylate and paroxetine HCl 10-mg tablets suggest that paroxetine mesylate has slightly higher values for maximum concentration (Cmax; 6.4 vs 5.9 ng/mL), time to maximum concentration (Tmax; 6.2 vs 5.8 hours), half-life (t1/2; 13.4 vs 12.7 hours), and area under the curve (AUC; 158.3 vs 144.9 ng  h/mL), respectively.22 However, these data were derived from single-dose studies, and it is unclear how or whether these minor differences transition clinically. Other than the lower dose, Brisdelle offers no unique pharmacological advantage over generic paroxetine HCl. Because biopharmaceutical guidelines do not mandate testing for bioequivalence at the lowest doses, there is little data to suggest that minor pharmacokinetic differences would result in clinically significant effects for the patient.

Safety Paroxetine has been available in the United States as the HCl salt since 1992, and it has been available as the mesylate salt since 2003.10 Distinct adverse effects associated with paroxetine range from minor effects like weight gain, somnolence, insomnia, headache, nausea/vomiting, decreased libido, and constipation to more severe effects including atrial fibrillation, aggression, anxiety, blood dyscrasias, and serotonin syndrome. Although Brisdelle has a black-box warning for suicidal thoughts and behaviors, the low-dose formulation utilized in the menopausal population carries little risk. Similar to other paroxetine formulations, a medication guide is to be supplied to every patient who receives treatment with Brisdelle.9 In general, when higher doses of paroxetine are used to treat hot flashes, a similar adverse effect profile ensues as seen in the treatment of depression and psychological disorders. These adverse effects include somnolence, dry mouth, nausea, constipation, anxiety, and sexual dysfunction.23 Withdrawal symptoms have been noted in patients who are abruptly discontinued (vs tapered slowly) from the treatment.15,16 This adverse effect is not

expected to be experienced with Brisdelle due to a lower dose of paroxetine being utilized. In a pilot trial of paroxetine HCl in breast cancer survivors, the adverse effect most duly noted was somnolence. In all, 2 patients discontinued drug therapy, and 2 patients decreased the dose due to the excessiveness of the somnolence.17 However, in another study with similar sample size, the treatment was well tolerated without any outstanding adverse effects.18 A dose-dependent adverse effect profile was identified with paroxetine 20 mg having significantly worse adverse effects compared with the 10 mg dose and placebo. Also noted was the 17% dropout rate in the paroxetine 20 mg group due to drowsiness and nausea.19

Drug Interactions In general, the drug interaction profile as well as the precautions and contraindications of therapy with Brisdelle are similar to other paroxetine formulations. Because paroxetine salts are cytochrome P (CYP)-450 isoenzyme 2D6 inhibitors, increased levels of other drugs metabolized via this enzyme can occur which may potentiate the adverse effect profile of those medications.9 In contrast, paroxetine may actually decrease the antiestrogen activity of tamoxifen by preventing the conversion of the drug to endoxifen (N-desmethyl tamoxifen), the active metabolite. In fact, paroxetine has been shown to decrease endoxifen levels by as much as 56% in women with the wild-type CYP2D6 allele.24 The clinical implications of this interaction are supported by the finding that patients with breast cancer who receive concurrent paroxetine and tamoxifen therapy are at increased risk of breast cancer-related death. Also, the relationship between mortality and paroxetine use in these patients appears to be time dependent.25 For these reasons, paroxetine should not be used in women who are currently receiving tamoxifen for the treatment or prevention of breast cancer.9 Like the other SSRIs, paroxetine salts increase the risk of serotonin syndrome and other adverse effects (eg, dyskinesias) when used in combination with other agents that have serotonergic activity (eg, linezolid, serotonin 1 agonists, buspirone, tricyclic antidepressants [TCAs], and monoamine oxidase inhibitors [MAOIs]).9,26 Specifically, MAOI use is contraindicated within 14 days of starting Brisdelle.9,26 Finally, due to the severity of serotonin syndrome, patients should be educated about avoiding over-the-counter products such as St John’s Wort while taking a paroxetine salt.9,26 In general, SSRIs may result in increased bleeding risk when used in combination with certain anticoagulants, antiplatelets, and nonsteroidal anti-inflammatory agents (NSAIDs). The source of this interaction is related to the ability of SSRI’s to inhibit the reuptake of serotonin into platelets, which results in decreased platelet aggregation.26 Due to the underlying mechanism, patients who are receiving these agents in combination with a paroxetine salt may be at increased risk of bleeding without significant changes in prothrombin time.9 Although paroxetine has been shown to cause mild bleeding, hematuria, and increased

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Journal of Pharmacy Practice

international normalized ratio (INR) in patients receiving warfarin, reports of severe bleeding are limited.26 Also, studies that examine bleeding risk in patients receiving SSRIs and aspirin have produced inconsistent results.25 However, the manufacturers of paroxetine salts recommend that caution be used when warfarin and aspirin are used in combination. NSAIDs have also been shown to increase the risk of bleeding (ie, gastrointestinal) when used in combination with SSRIs.27 Consequently, patients should be closely monitored when combinations of the aforementioned drugs are used.9 Caution should also be taken when initiating a patient on Brisdelle that is taking tamoxifen, an antiestrogenic drug. The manufacturers advise to avoid the concomitant use of Brisdelle for VMS treatment. When initiating a nonsteroidal anti-inflammatory therapy, the risk may increase for bleeding events. Patients should be aware of this precaution and know the signs and symptoms of abnormal bleeding. Brisdelle may also increase the risk of hyponatremia, especially in elderly patients. This can be due to the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion, concomitant use of diuretics, or patients who are volume depleted.9 Caution should be strongly advised when considering the use of Brisdelle in patients with a history of bipolar disorder, seizure risk, bone fracture, or closed angle glaucoma. In clinical studies, rare but serious adverse events have occurred with the concomitant use of Brisdelle in these concurrent disease states. Although it has not been studied in clinical trials with Brisdelle, it is strongly believed that concurrent use of SSRIs in patients with bipolar disorder can potentiate mania/hypomania.9 In patients with seizure disorders, caution is advised although it has not been proven in clinical trials as a common effect. The only instances of seizure published were in extreme overdose situations.14 Patients with osteoporosis or at increased risk of bone fractures should use extreme caution when taking paroxetine. In a case–control study conducted in 2010, SSRIs posed a statistically significantly increased risk of bone fracture compared to no use of SSRIs (OR ¼ 1.86, 95% CI 1.63-2.13).28 In patients with closed angle glaucoma, there is already an increase in intraocular pressure present. Paroxetine can potentially cause mydriasis, which may increase the intraocular pressure further; therefore, caution is advised in predisposed patients.14 Caution is generally advised upon initiation of paroxetine HCl or mesylate in patients with hepatic and/or renal dysfunction; however, the 7.5-mg dose of Brisdelle is the only formulation in which a dosage adjustment for these conditions is not advised.9

Discussion The current standard of care for most patients consists HRT; however, many patients cannot or will not utilize this treatment. This has led to the rampant emergence of off-label medication prescribing for clonidine, gabapentin, SSRIs, and SNRIs. Over-the-counter medications and homeopathic remedies are also gaining popularity. Despite the marginal evidence of efficacy and recommendations by the FDA Advisory Panel

to deny approval of Brisdelle, the FDA still approved it for the treatment of VMS associated with menopause.2-4 Although the details of this approval are not published, it is likely that the approval was based on the need for other treatment options for VMS, its mild adverse effect profile as well as the patient satisfaction with the treatment. Overall, most (>80%) patients in the studies were willing to continue treatment with Brisdelle after conclusion of the studies. Although Brisdelle was marginally more effective than placebo, more well-designed studies with active controls are needed to determine the best treatments for VMS. In general, the studies evaluated were limited by inconsistency in design, small sample sizes, and short durations of treatment. However, all of the studies met the minimal duration requirement of 4 weeks recommended by the FDA guidance on studying estrogen or estrogen/progestin medications for the treatment of VMS.29 Although the end points were measured with validated outcome measures, some of the tools were clinician administered while others were patient-administered assessments making evaluation between study end points difficult. However, the studies were strengthened by consistency in medication doses used, reporting of adverse event information, low attrition rates, and good external validity.

Conclusion The paroxetine salts (mesylate and HCl) have proven to be safe and reasonably effective treatments for VMS associated with menopause. In comparison with placebo, paroxetine slightly reduced the frequency and severity of hot flashes and improved patient’s quality of life. Head-to-head comparison trials of paroxetine with active medications still need to be completed to determine the best treatments for VMS; however, treatment with a paroxetine salt provides an alternative in patients who desire a nonhormonal therapy. Specifically, Brisdelle is advantageous in that it is available in a lower dose that may cause less unwarranted adverse effects and provide some benefit over other unconventional VMS treatments. However, it does not provide any unique pharmacological advantage over lowdose paroxetine HCl which may also be administered at bedtime to reduce adverse effects. Although paroxetine HCl is not indicated for treatment of VMS, it has been used off-label for treatment of this condition for many years. As with any pharmacological treatment, the adverse effects of the medication should be evaluated on an individualized patient level to determine whether it is the best therapy. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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References 1. Kalantaridou SN, Dang DK, Davis SR, et al. Hormone therapy in women. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011:1417-1436. 2. National Institutes of Health State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med. 2005;142(12):1003-1013. 3. Fugate SE, Church CO. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. Ann Pharmacother. 2004;38(9):1482-1499. 4. Hall E, Frey VN, Soares CN. Non-hormonal treatment strategies for vasomotor symptoms: a critical review. Drugs. 2011;71(3):287-304. 5. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. 6. Rossouw JE, Manson JE, Kaunitz AM, et al. Lessons learned from the women’s health initiative trials of menopausal hormone therapy. Obstet Gynecol. 2013;121(1):172-176. 7. Goodman NF, Cobin RH, Ginzburg SB, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract. 2011;17(suppl 6):1-25. 8. Schmidt P. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause. 2012;9(3):257-271. 9. Brisdelle™ [prescribing information]. Noven Therapuetics, LLC., Miami, FL; June 2013. http://www.brisdelle.com/pdf/PI_MedGuide.pdf. Accessed July 18, 2013. 10. Brisdelle™. Food and Drug Administration (FDA) website. In: Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Rockville, MD: FDA. http://www.accessdata. fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No¼204516&TAB LE1¼OB_Rx. Updated July 24, 2013. Accessed July 23, 2013. 11. DeBattista C. Antidepressant agents. In: Katzung B, Masters S, Trevor A, eds. Basic and Clinical Pharmacology. 11th ed. New York, NY: The McGraw-Hill Companies, Inc; 2009:509. 12. Schatzberg A, Cole J, DeBattista C. Manual of clinical psychopharmacology. 4th ed.Washington, DC: American Psychiatric Publishing, Inc; 2003:47-67. 13. Catelli M, Bhaskar S, Lippman J. Pharmacokinetic properties of once-daily oral low-dose mesylate salt of paroxetine (LDMP 7.5 mg) following single and multiple doses in healthy postmenopausal women. Clin Ther. 2013;35(6):862-869. 14. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013 Oct;20(10):1027-1035. 15. Soares CN, Joffe H, Viguera AC, et al. Paroxetine versus placebo for women in midlife after hormone therapy discontinuation. Am J Med. 2008;121(2):159-162.

16. Stearns V, Beebe KL, Iyengar M, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289(21):2827-2834. 17. Stearns V, Isaacs C, Rowland J, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil1) in controlling hot flashes in breast cancer survivors. Ann Oncol. 2000; 11(1):17-22. 18. Weitzner M, Moncello J, Jacobsen P, et al. A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. J Pain Sympton Manage. 2002;23(4): 337-345. 19. Stearns V, Slack R, Greep N, et al. Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol. 2005;23(28):6919-6930. 20. Paroxetine. In: Clinical Pharmacology [internet database]. Tampa, FL: Elsevier & Gold Standard. Available at http://clinicalpharmacology-ip.com.ezproxy.samford.edu. Updated July 01, 2013. Accessed July 15, 2013. 21. Red Book Online [internet database]. Greenwood Village, Colo: Truven Health Analytics, Inc. Available at http://www.micromedex solutions.com.ezproxy.samford.edu/micromedex2. Accessed July 23, 2013. 22. Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmacetics Review. http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2001/21-299.pdf_Paroxetine%20Mesylate_ BioPharmr.pdf. Accessed January 14, 2014. 23. Generali J, Cada DJ. Paroxetine: hot flashes. Hosp Pharm. 2004; 39(2):130-132, 190. 24. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95(23):1758-1764. 25. Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010;340: c693. http://www.bmj.com/content/340/bmj.c693?view¼long& pmid¼20142325. Accessed July 18, 2013. 26. Baxter K. Stockley’s Drug Interactions. 9th ed. Chicago, IL: Pharmaceutical Press; 2010. 27. Abajo FJ, Montero D, Rodriquez LA, Madurga M. Antidepressants an d risk of upper gastrointestinal bleeding. Basic Clin Pharmacol Toxicol.2006;98(3):304-310. 28. Verdel B, Souverein P, Egberts T, et al. Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures. Bone. 2010;47(3):604-609. 29. Guidance for Industry—Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Recommendations for Clinical Evaluation. www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM135338.pdf. Accessed November 18, 2013.

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