The US Food and Drug Administration (FDA) recently approved paroxetine mesylate 7.5 mg (Brisdelle) for the treatment of moderate to severe menopausal vasomotor symptoms (VMS). Paroxetine, formerly known as low-dose mesylate salt of paroxetine (LDMP), is a nonhormonal agent, which makes it an alternative hot flash therapy for menopausal women who cannot or do not want to use hormones. Paroxetine mesylate (Pexeva, Brisdelle) and paroxetine hydrochloride (Paxil, and generics) are two salts of the same active compound (paroxetine). They may have somewhat different metabolism.

The efficacy and safety of paroxetine mesylate, a selective serotonin-reuptake inhibitor (SSRI), were evaluated individually in three Phase 2 or 3 multicenter, double-blind, randomized, placebo-controlled trials, published by James Simon, MD, from George Washington University School of Medicine, and colleagues,¹ and Joffe and colleagues.² Most treatment-emergent adverse events (TEAEs) in the individual studies were mild or moderate in severity, with minimal acute discontinuation symptoms reported on treatment cessation.

In a study³ presented April 29, at the 2014 Annual Clinical Meeting of The American College of Obstetricians and Gynecologists (ACOG) in Chicago, Illinois, Simon and colleagues further reported on the overall tolerability and safety profile of paroxetine mesylate 7.5 mg using pooled data from the three randomized trials. In their post-hoc analyses, they specifically examined the emergence of adverse events linked to the use of SSRIs when prescribed for psychiatric disorders at therapeutically higher doses than 7.5 mg. The adverse events focused on included weight gain, decreased libido, and sleep disturbance, as well as suicidality, abnormal bleeding, and bone fracture.

Study details. A total of 1,276 postmenopausal women (approximately 70% white) aged 40 years or older (median age, 54 years) with moderate to severe VMS (7−8 hot flashes/day; 50−60 hot flashes/wk) received either paroxetine mesylate or placebo at bedtime for 8 (Phase 2), 12 (Phase 3), or 24 (Phase 3) weeks. The study was sponsored by Noven Therapeutics, LLC.

Treatment-emergent adverse events and discontinuation
About half (50.4%) of the 635 women in the paroxetine group and 47.0% of the 641 women in the placebo group reported at least one TEAE. Most commonly reported TEAEs in the paroxetine group (reported in ≥2% of patients and with a twofold or higher frequency than in the placebo group) were nausea, fatigue, and dizziness.

TEAEs that were determined to be related to the study drug were reported in 19.5% in the paroxetine group and in 17.6% in the placebo group. These most frequent TEAEs were fatigue, nausea, dizziness, and diarrhea.

Severe AEs were reported in 3.9% and 3.6% of women in the paroxetine and placebo groups, respectively, although the investigator determined that less than 1% were related to paroxetine treatment.

TEAEs that led to discontinuation occurred in 4.7% of paroxetine-treated women and in 3.7% of placebo-treated women, although the incidence of study drug interruptions from TEAEs was similar (0.9%) between treatments. The most frequent adverse reactions leading to discontinuation in the paroxetine arm were abdominal pain (0.3%), attention disturbances (0.3%), headache (0.3%), and suicidal ideation (0.3%).

Of the most common AEs, nausea occurred mainly within the first 4 weeks of treatment; fatigue occurred primarily within the first week of treatment and decreased in frequency with continued therapy. Incidences and types of AEs that began after 12 weeks were similar to those that began during the first 12 weeks of treatment.

AEs related to SSRIs not found to be problematic
No differences were found between groups with regard to TEAEs related to weight, libido, or sleep. No clinically meaningful changes in laboratory values, vital signs, or ECGs were observed with either group. No clinically important findings on abnormal bleeding, bone fracture, or suicidality were evident in the paroxetine arm.

In the Phase 3 studies:

One suicide attempt was reported in the paroxetine group in the 24-week study, but was determined by investigators to be unrelated to treatment

Incidence rates of gastrointestinal and other bleeding events were similar between groups

Five bone fractures were reported: One in the paroxetine group and four among three participants in the placebo group.

One death occurred in the 12-week Phase 3 study due to acute respiratory failure with evidence of hypertension-mediated pulmonary edema and hypertensive cardiovascular disease. The investigator did not consider the death to be related to the study drug.

Study conclusion
The authors concluded that paroxetine 7.5 mg had favorable tolerability in menopausal women with moderate to severe VMS.

“Paroxetine 7.5 mg offers a nonhormonal treatment option for women who seek treatment for moderate to severe hot flashes associated with menopause,” said Dr. Simon.³

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Paroxetine mesylate 7.5 mg found to be a safe alternative to hormone therapy for menopausal women with hot flashes