ParoXetine: A First for Selective Serotonin Reuptake Inhibitors – a New Use: Approved for Vasomotor Symptoms in Postmenopausal Women

Abstract

In the USA, over 30 million women are In or near menopause. Menopause Is associated with a cluster of Issues. Vasomotor symptoms (VMS) are the number one complaint of most menopausal women. VMS are disruptive to women during the day and at night, which leads to poor sleep, anxiety, depression and poor concentration. Up until now, the only US FDA-approved medication for moderate-to-severe VMS was hormone therapy. Hormone therapy may not be appropriate for all women. Many drugs are used off-label to treat VMS. The most often used agents are agents that are FDA-approved medications, such as selective serotonin reuptake Inhibitors and serotonin–norepinephrine reuptake Inhibitors. The pharmaceutical company, Noven Pharmaceuticals (FL, USA), has studied paroxetine mesylate 7.5 mg, previously known as low-dose mesylate salt of paroxetine, specifically to treat moderate-to-severe VMS In postmenopausal women. Paroxetine is a selective serotonin reuptake Inhibitor, and Is thought to help decrease VMS by regulating body temperature via neurotransmitters. Paroxetine Is approved to treat various psychiatric disorders, but Is used at much higher doses (20–60 mg/day).

Keywords

menopause nonhormonal options for vasomotor symptoms selective serotonin reuptake inhibitors

Menopause statistics

Menopause is a natural occurrence in a women's life, where she is no longer capable of ovulating. It is marked by a 12-month cessation of menstruation and where the ovaries are no longer producing follicles, and thus, no longer producing estradiol. The average age for menopause in the USA is 51.3 [1]. Vasomotor symptoms (VMS) are also referred to as a hot flash/flush, or when they occur at night, night sweats. VMS are a hallmark sign of menopause and are the number one reason menopausal women see their physicians, occurring in approximately 75–80% women [2,3]. A hot flash typically begins as an abrupt onset sensation of heat beginning in the upper chest, quickly rising to the face, which can rapidly become generalized throughout the body. A hot flash is an elevation in body temperature, accompanied typically by an increase in heart rate and perspiration, usually lasting between 1–5-min long. Night sweats usually wake women up in a cold sweat, and their sheets and pajamas are usually soaked from the sweat. VMS can be quite disruptive, interfering with a woman's ability to work or sleep, and has been shown to have an impact on the economy, with regard to productivity [4,5]. Some women will have more bothersome night sweats, whereas others will have both hot flashes during the day and night sweats at night. The mechanism of VMS is not completely understood, however, it is thought to be due to a thermoregulatory zone dysfunction. The thermoregulatory zone is located within the hypothalamus and is responsible for the regulation of temperature within the body. The thermoregulatory zone will control whether someone sweats when hot or shivers when cold. It has been noted that, in some postmenopausal women this zone becomes narrower and, therefore, a small increase in body temperature can trigger a hot flash [6]. Norepinephrine and serotonin may play a role in the complex neuroendocrine pathway governing the thermoregulatory zone [7].

Some women are fortunate enough to not suffer with VMS; VMS are experienced by the majority of women during the late menopausal transition into menopause. Staging of Reproduction Workshop +10 defines the late menopausal transition as the last 1–3 years prior to the final menstrual period, where a woman may have amenorrhea ≥60 days along with VMS. According to SWAN, which enrolled 33,302 participants and followed them over a 10-year period, reports that 60–80% of women experience VMS at some point during the menopausal transition, with prevalence rates varied by race/ethnic group [8]. According to the US Census Bureau, in the year 2000, there were approximately 50 million women aged 45–60-years-old, and with our growing population this number is only going to increase. Worldwide, approximately 360 million are older than 45 years of age and are going to experience hot flashes [9].

There are three categories describing the severity of hot flashes: mild, feeling hot without perspiration; moderate, feeling hot with perspiration and without disruption of activity; and severe, feeling hot with perspiration and causing a disruption or cessation of activity [10]. Typically, women experience symptoms for 6 months to 3 years, but can last much longer; in one study, the average length of VMS lasted 10.2 years [4,11,12].

Unmet medical needs

Previously, the only medication approved for moderate-to-severe VMS was hormone therapy (HT). Although this treatment is very effective, there are many women that are unable to take HT (those that have had a venous thromboembolism due to a high estrogen state or an estrogen-related malignancy) or those women who do not want to, owing to their own perceived risks. HT should be prescribed on an individual basis, assessing the patient(s) symptoms and risks for using or not using HT. There is also the lack of physician awareness of the risk versus benefits of using HT. Recently the US FDA approved low-dose mesylate paroxetine (LDMP), which is nonhormonal option for women that are not able to, or choose not to, use HT.

Selective serotonin reuptake inhibitors (SSRIs) are approved for psychiatric disorders, such as depression, anxiety, obsessive–compulsive disorder, panic attacks and premenstrual dysphoric disorder. However, the dosages are quite different than the drug we are discussing, it is much lower.

At present, having over 30 million women in menopause, an alternative treatment to HT is prudent. In one study, it was found that only 17% of women with moderate-to-severe VMS currently receive a prescription of either HT or an off-label medication [13]. Many women with VMS resort to unproven remedies and herbal supplements, which are not regulated and have been found to be less than effective at treating VMS.

Present treatment guidelines

Body of review

Overview of the market: unmet needs of current available therapies

An unmet need for an FDA-approved nonhormonal therapy for the treatment of moderate-to-severe VMS associated with menopause, will be satisfied by the ability to use LDMP, as it has demonstrated efficacy for this group of women.

Competitor compounds and other classes of compounds that are in development for nonhormonal, nonantide-pressant drugs include extended-release gabapentin, which has been studied for VMS but is not FDA-approved.

Introduction to the compound

Noven Pharmaceuticals (FL, USA) developed paroxetine mesylate 7.5 mg, referred to as LDMP, specifically to treat moderate-to-severe VMS associated with menopause. The LDMP capsule contains 9.69 mg of paroxetine mesylate, which is equivalent to 7.5 mg of paroxetine base. LDMP is a SSRI, and its mechanism of action for the treatment of VMS are not completely understood but are thought to be related to neurotransmitters in the CNS that affect the thermoregulatory pathways. LDMP is administered as a 7.5-mg capsule taken once-daily at bedtime. The LDMP clinical development program included one Phase I trial (study N30-005, one single and multiple-dose pharmacokinetics trial), one Phase II trial and two Phase III trials [3]. Efficacy was assessed in the Phase III trials (N30-003 and N30-004), and both were randomized, double-blind, placebo-controlled [3,14]. Coprimary end points were reductions in frequency and severity of moderate-to-severe VMS from LDMP versus placebo, evaluated from baseline to week 4 and 12, and the effects were monitored until week 24. The studies enrolled 614 and 570 patients, respectively, for a total of 1184 postmenopausal women in the USA who met the hot flash eligibility criteria. Criteria included at least 50 moderate-to-severe hot flashes per week or at least seven per day on average prior to randomization. Women who met the hot flash criteria were randomized to receive 7.5 mg of LDMP or placebo once-daily at bedtime for 12 weeks (study N30-003) or 24 weeks (study N30-004) [13]. In the 24-week study, results showed that at week 4, patients in the LDMP group had a mean weekly reduction from baseline of 28.9 hot flashes compared with a mean weekly reduction of 19.0 hot flashes for patients in the placebo group (p < 0.0001). Mean weekly reductions in VMS frequency were also greater at 12; 37.2 fewer for LDMP and 27.6 fewer for placebo (p = 0.0001). Daily VMS were also significantly reduced with LDMP. At week 4, 60% of women compared with 48% of those on placebo reported relief (p = 0.0072), and also at week 12 (61 in LDMP vs 45% in placebo-treated women; p = 0.0001) in the N30-004 study [3]. During the Phase III study, it was noted that during the recording of symptoms at week 4, there were slightly fewer awakenings at night in the LDMP group versus the placebo group (8.5 vs 6.25, respectively; p = 0.0104). By week 24, there was further reduction of awakenings at night by 14.56 (LDMP) versus 10.54 (placebo) change from baseline (p = 0.0001) [14]. Phase III studies statistical analysis showed that, 155 patients per treatment group were required for 95% power-based on a type I error rate of 0.05 (α = 0.05; 2-sided), a clinically significant reduction of greater than 50% in severity (mean difference: 0.17–0.08), and the collective standard deviation of 0.22. For the coprimary end point of VMS frequency, 227 patients per treatment group were required for 85% statistical power to detect an average difference between the treatments of 1.41 hot flashes per day based on a type I error rate of 0.05 (α = 0.05; 2-sided) and the collective standard deviation of 5 [14].

A study performed by Stearns et al. in 2005 included 430 participants [15]. Women were randomly assigned to 4 weeks of paroxetine 10 or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for 1 week prior to the beginning of the study and throughout the study, and quality-of-life questionnaires at baseline, week 5 and 9. In total, 151 women were randomly assigned the medication or placebo, as described above. Paroxetine 10 mg reduced hot flash frequency and combined score by 40.6 and 45.6%, respectively, compared with 13.7 and 13.7% for placebo (p = 0.0006 and p = 0.0008, respectively). Paroxetine 20 mg reduced hot flash frequency and combined score by 51.7 and 56.1%, respectively, compared with 26.6 and 28.8% for placebo (p = 0.002 and p = 0.004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (p = 0.01) [15].

Chemistry

Pharmacodynamics

LDMP is thought to work through neurotransmitters in the CNS that affect the thermoregulatory pathways. Paroxetine acts within the hypothalamus to increase the amount of serotonin in the synapse by inhibiting its reuptake, therefore, making more serotonin available. It has been hypothesized that increased levels of serotonin activate the 5-HT2c receptors, which results in the inhibition of the 5-HT2a receptors, the latter of which, along with norepinephrine, lower the thermoregulatory set point in the hypothalamus. Inhibition of these receptors may restore the thermoregulatory set point to normal, removing the need for heat-loss mechanisms [16,17].

Pharmacokinetics & metabolism

Paroxetine undergoes a substantial first-pass effect in the liver. As with several other SSRIs, paroxetine mesylate is metabolized by CYP450 2D6; and CYP450 3A4 also metabolize paroxetine, but this is not the main pathway [18,19]. Paroxetine is a powerful inhibitor of CYP450 2D6, causing an irreversible binding of the paroxetine metabolite to the heme-complex within the P450 enzyme [19].

Of note, women on tamoxifen should not be given paroxetine as it may lower tamoxifen levels of its active metabolite due to effects on CYP450 enzymes. Aromatase inhibitors (AI) are not used in premenopausal women because the hypothalamic–pituitary–ovarian axis is activated in response to the decrease in systemic levels of estrogen after AI use. This activation increases gonadotropin secretion, which in turn can increase the ovarian production of estrogen and androgens, which is not the intended consequence when using an AI. The goal of AIs is to block the production of estrogen. Side effects of tamoxifen and AIs are VMS, SSRIs and serotonin–norepinephrine reuptake inhibitors are able to be used safely with AI therapy [20].

Clinical efficacy: Phase I, II & III trials

Phase I trial: assessing the pharmacokinetics of paroxetine mesylate 7.5 mg in postmenopausal women

The participants were screened for 3 weeks prior to initiating the study drug. The participants received LDMP 7.5-mg capsule as a single dose on day 1 and then once-daily for 14 days on days 6–19. Steady-state was achieved after approximately 12 doses (day 18). The peak exposure, measured as C_max, increased from 2.77 ng/ml after a single dose to 13.1 ng/ml at steady-state after 2 weeks of once-a-day dosing (day 19). Mean area under the plasma concentration time curve from time 0–24 h of LDMP at steady-state was 3.01-times greater than the mean area under the plasma concentration time curve extrapolated to infinity, which was observed after a single dose and demonstrated nonlinear kinetics. The results were consistent with those results obtained previously during the pharmacokinetic characterization of higher doses of paroxetine in earlier studies [14].

Phase II trial: demonstrating proof-of-concept

The 7.5-mg dose of paroxetine mesylate was chosen because it is substantially lower than the doses of paroxetine used off-label to treat VMS (20–40mg). Results of the Phase II study provided proof-of-concept, and showed that the 7.5-mg dose was well tolerated [14].

Phase III trials: demonstrating efficacy for the treatment of moderate-to-severe VMS

Patients who received LDMP had a statistically significant reduction in hot flash occurrence at weeks 4 and 12 in both studies, and in hot flash severity at week 4 in both studies and week 12 in the N30-004 study. LDMP revealed both rapid onset and persistence of benefit. Persistence of benefit, shown in Figure 1, was shown in the N30-004 study, with significantly more patients being treated with LDMP attaining at least a 50% reduction in frequency of moderate-to-severe hot flashes compared with placebo at week 24 [14].

Figure 1.

Persistence of benefit at week 24 in the N30-004 study.

In the 12-week N30-003 study, 614 patients were randomized across 70 US study sites, 306 in the LDMP group and 308 in the placebo group. A similar percentage of patients in both groups completed the study, 271 out of 306 patients treated with LDMP (88.6%) and 278 out of 308 with placebo (90.3%) [3,14].

In the 24-week N30-004 study, 570 patients were randomized across 65 US study sites, 285 patients in each treatment group. More patients treated with LDMP (235 out of 285 [82.5%]) compared with placebo (218 out of 285 [76.5%]) completed the study [3,14].

Modified intent-to-treat was very similar to the intent-to-treat number as shown in Table 1. The missing data were not regarded as a major issue in this study because in the N30-003 study, 89.9 and 87.7% of patients had assessments in week 12 in the control and experimental arms, respectively [14]. In the N30-004 study, 86.6 and 90.5% of patients had assessments in week 12 in the control and experimental arms, respectively [14].

Table 1.

Phase III trials.

Analysis populations	N30-003 placebo	N30-003 LDMP	N30-004 placebo	N30-004 LDMP
Randomized patients (n)	308	306	285	285
mITT population (n)	305	301	284	284
Completed the trial (n)	278	271	218	235
Discontinued (n)	27	30	66	50

LDMP: Low-dose mesylate paroxetine; mITT: Modified intent-to-treat.

Reproduced with permission from [14].

Missing data

Tables 2 & 3 represent the missing data for the primary end point of hot flash frequency. The amount of data missing is not a large amount. The calculations done by Noven of the effect of missing data on the results found no change in general conclusions compared with analyses using all available data during the N30-003 or N30-004 studies.

Table 2.

Missing data: weekly visit in the N30-003 study.

Week	Placebo, n (%)	Placebo missing data, n	LDMP, n (%)	LDMP missing data, n
0	305 (100)	0	301 (100)	0
1	305 (100)	0	301 (100)	0
2	301 (98.7)	4	296 (98.3)	5
3	298 (97.7)	7	292 (97.0)	9
4	294 (96.4)	12	289 (96.0)	12
5	289 (94.8)	16	288 (95.7)	13
6	287 (94.1)	19	281 (93.4)	20
7	285 (93.4)	20	280 (93.0)	24
8	283 (92.8)	22	279 (92.7)	24
9	281 (92.1)	25	276 (91.7)	26
10	279 (91.5)	27	275 (91.4)	28
11	279 (91.5)	29	270 (89.7)	33
12	274 (89.8)	31	264 (87.7)	37

LDMP: Low-dose mesylate paroxetine;

Reproduced with permission from [14].

Table 3.

Missing data: weekly visit in the N30-004 study.

Week	Placebo, n (%)	Placebo missing data, n	LDMP, n (%)	LDMP missing data, n
0	284 (100)	0	284 (100)	0
1	284 (100)	0	284 (100)	0
2	282 (99.3)	2	280 (98.6)	5
3	279 (98.2)	5	278 (97.9)	6
4	274 (96.5)	10	276 (97.2)	8
5	267 (94.0)	17	272 (95.8)	13
6	261 (91.9)	23	268 (94.4)	16
7	256 (90.1)	28	266 (93.7)	19
8	254 (89.4)	30	263 (92.6)	22
9	252 (88.7)	32	262 (92.3)	24
10	252 (88.7)	32	261 (91.9)	26
11	251 (88.4)	34	259 (91.2)	26
12	246 (86.6)	40	257 (90.5)	27
13	240 (84.5)	45	250 (88.0)	37
14	233 (82.0)	52	248 (87.3)	36
15	232 (81.7)	53	248 (87.3)	36
16	231 (81.3)	53	246 (86.6)	40
17	228 (80.3)	57	244 (85.9)	40
18	226 (79.6)	60	241 (84.9)	48
19	222 (78.2)	65	240 984.5)	48
20	222 (78.2)	64	239 (84.2)	50
21	220 (77.5)	66	239 (84.2)	49
22	220 (77.5)	65	237 (83.5)	50
23	218 (76.8)	66	236 (83.1)	51
24	215 (75.7)	69	234 (82.4)	50

LDMP: Low-dose mesylate paroxetine

Reproduced with permission from [14].

LDMP was generally well tolerated; there was no increase in average weight gain, no female sexual dysfunction or discontinuation symptoms in patients treated with LDMP compared with placebo.

The most common adverse event experienced by patients treated with LDMP was consistent with the known safety profile of paroxetine. A total of 50.4% of patients treated with LDMP and 47.0% with placebo reported at least one adverse event; 19.5 and 17.6%, respectively, had adverse events considered related to LDMP (Table 4). Most of the adverse events were mild or moderate in intensity. The most commonly reported adverse events were headache, fatigue, nausea and diarrhea, which occurred mainly within the first 4 weeks of treatment; however, there was evidence of adjustment with continued therapy. Insomnia, nasopharyngitis, sinusitis and upper respiratory tract infections occurred throughout the study. In the controlled studies pool, 14 (2.2%) patients treated with LDMP and nine (1.4%) patients in the placebo group reported a serious adverse event. Suicidal ideation was the most common serious adverse event, three (0.5%) in patients treated with LDMP and 0 in placebo. In addition, one patient had a serious adverse event of a suicide attempt in the LDMP group, but this attempt was deemed to be unrelated to LDMP by the principle investigator.

Table 4.

All controlled studies pool, safety population.

Parameter	Placebo, n (%)	LDMP 7.5 mg, n (%)
Total (n)	641	635
Completed the study	547 (85.3)	551 (86.8)
Discontinued	94 (14.7)	84 (13.2)
Reason for discontinuation
AE/SAE	20 (3.1)	24 (3.8)
At their own request	46 (7.2)	25 (3.9)
C-SSRS/STS	2 (0.3)	4 (0.6)
In the investigator's or sponsor's opinion, continuation in the study would be detrimental to the patient's wellbeing	3 (0.5)	2 (0.3)
The patient is not able to comply with the study requirements	6 (0.9)	2 (0.3)
Other: not specified	1 (0.2)	0
Other: elective surgery	0	1 (0.2)
Other: eligibility criteria not met	4 (0.6)	3 (0.5)
Other: lack of efficacy	2 (0.3)	2 (0.3)
Other: lost to follow-up	7 (1.1)	14 (2.2)
Other: noncompliance	1 (0.2)	2 (0.3)
Other: relocation	1 (0.2)	2 (0.3)
Other: withdrew consent	1 (0.2	3 (0.5)

AE: Adverse event; C-SSRS: Columbia Suicide Severity Rating Scale; LDMP: Low-dose mesylate paroxetine; SAE: Serious adverse event; STS: Suicidality Tracking Scale.

Reproduced with permission from [14].

Another serious adverse event reported was appendicitis, which was found in two patients (0.3%) treated with LDMP and none with the placebo. Of the 14 patients that were treated with LDMP that had serious adverse events, 13 had participated in the 24-week N30-004 study and one in the 12-week N30-003 study (the latter being the single death within the studies, however, the death was considered by the investigator to be irrelevant to the study drug). Among the nine placebo-treated patients with serious adverse events, one had participated in the N30-002 study, one in the N30-003 study and seven in the N30-004 study. Fractures were reported as a serious adverse event in three (0.5%) patients treated with placebo and 0 with LDMP [14].

Postmarketing surveillance

Noven will have a risk-management strategy in place postmarketing for potential risk factors, such as suicidality, abnormal bleeding and bone fracture.

Safety & tolerability

Regulatory affairs: status of the drug & where it is approved

The drug, low-dose paroxetine called ‘Brisdelle™’ (Noven Therapeutics, LLC, FL, USA) is FDA-approved in the USA and has been out in US retail pharmacies since November 2013.

Conclusion

LDMP is a nonhormonal drug that has demonstrated safety, well tolerated to 24 weeks and tolerably safe for 20 years at higher doses. LDMP is efficacious in reducing both the frequency and severity of VMS associated with menopause at week 4 and 12, as well as demonstrated persistence of treatment benefit at week 24. Reductions in frequency of VMS associated with menopause at week 4 and 12 were clinically meaningful. LDMP represents a new treatment option (that has been used off-label at higher doses for years) that may improve the lives of women with moderate-to-severe VMS, which does not cause weight gain or female sexual dysfunction.

Financial & competing interests disclosure

HL Thacker was a consultant for Noven in 2013. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Development of an old drug for a new purpose

New low-dose mesylate paroxetine (LDMP) is a selective serotonin reuptake inhibitor that helps decease moderate-to-severe symptomatic hot flashes or vasomotor symptoms in postmenopausal women.

Pharmacodynamic profile

LDMP mechanism of action for the treatment of vasomotor symptoms is thought to be related to neurotransmitters in the CNS that affect the thermoregulatory pathways.

Pharmacokinetic profile

Maximum serum LDMP concentrations were reached after 12 daily doses.

Therapeutic efficacy

In the Phase III study, the persistence of benefit of LDMP treatment extended to 24 weeks.

Tolerability

Paroxetine has been an approved drug since 1992 and has more than 20 years of use on the market.

The most common adverse events reported were nasopharyngitis, headache, fatigue and nausea.

References

Papers of special note have been highlighted as:

of considerable interest

Kato

Toniolo

Akhmedkhanov

Koenig

Shore

Zeleniuch-Jacquotte

. Prospective study of factors influencing the onset of natural menopause. J. Clin. Epidemiol. 51, 1271–1276 (1998).

Gold

Sternfeld

Kelsey

Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40–55 years of age. Am. J. Epidemiol. 152(5), 463–473 (2000).

Simon

Sanacora

Bhaskar

Lippman

. Safety and efficacy of low-dose mesylate salt of paroxetine (LDMP) for the treatment of vasomotor symptoms (VMS) associated with menopause: a 24-week, randomized, placebo-controlled Phase 3 study. Menopause 19(12), 137 (2013).

Very good review of the study carried out to evaluate low-dose mesylate paroxetine.

Utian

. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual. Life Outcomes 3, 47 (2005).

Very interesting review article on the burden of vasomotor symptoms on a woman's life, mentally and monetarily.

Woods

Mitchell

. Symptom interference with work and relationships during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health study. Menopause 18(6), 654–661 (2011).

10.

Freedman

Krell

. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am. J. Obstet. Gynecol. 181(1), 66–70 (1999).

11.

Pachman

Jones

Loprinzi

. Management of menopause-associated vasomotor symptoms: current treatment options, challenges and future directions. Int. J. Womens Health 2, 123–135 (2010).

12.

Great article illustrating nonhormonal treatment options for vasomotor symptoms.

13.

Gold

Colvin

Avis

Longitudinal analysis of vasomotor symptoms and race/ethnicity across the menopausal transition: Study of Women's Health Across the Nation (SWAN). Am. J. Public Health 96(7), 1226–1235 (2006).

14.

United States Census 2000. Census 2000 profile. US Department of Commerce. Economics and Statistics Administration. US Census Bureau (2000). www.census.gov

15.

US FDA. 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

16.

Warren

. Hormone therapy for menopausal symptoms: putting benefits and risks into perspective. J. Fam. Pract. 59(12), E1–E7 (2010).

17.

Freeman

Sammel

Lin

Liu

Gracia

. Duration of menopausal hot flushes and associated risk factors. Obstet. Gynecol. 117, 1095–1104 (2011).

18.

Williams

Kalilani

DiBenedetti

Healthcare seeking and treatment for menopausal symptoms in the United States. Maturitas 58, 348–358 (2007).

19.

Noven Pharmaceuticals Inc. Paroxetine mesylate 7.5 mg advisory committee briefing document (2013). www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/eproductiveHealthDrugsAdvisoryCommittee/UCM341592.pdf

20.

Stearns

Slack

Greep

Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J. Clin. Oncol. 23, 6919–6930 (2005).

21.

Very good article displaying effectiveness of paroxetine on vasomotor symptoms.

22.

Berendsen

. The role of serotonin in hot flushes. Maturitas 36(3), 155–164 (2000).

23.

Shanafelt

Barton

Adjei

Pathophysiology and treatment of hot flashes. Mayo Clin. Proc. 77(11), 1207–1218 (2002).

24.

Hiemke

Hartter

. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol. Ther. 85, 11–28 (2000).

25.

Jornil

Jensen

Larsen

Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. Drug Metab. Dispos. 38, 376–385 (2010).

26.

Files

Pruthi

. Managing aromatase inhibitors in breast cancer survivors: not just for oncologists. Mayo Clin. Proc. 85(6) 560–566 (2010).