Low-dose paroxetine (7.5 mg) improves sleep in women with vasomotor symptoms associated with menopause.

OBJECTIVE: Sleep disturbances are common among women in midlife; prevalence increases among perimenopausal/postmenopausal women with vasomotor symptoms. Paroxetine 7.5 mg is the only nonhormonal treatment that has been approved in the United States for moderate to severe vasomotor symptoms associated with menopause. In two pivotal phase 3 studies evaluating its efficacy and safety, improvements in sleep disturbances were also prospectively evaluated. METHODS: Postmenopausal women with moderate to severe vasomotor symptoms were randomly assigned to paroxetine 7.5 mg (n = 591) or placebo (n = 593) once daily for 12 weeks (both studies) or 24 weeks (24-wk study). Predefined assessments on weeks 4, 12, and 24 included number of nighttime awakenings attributed to vasomotor symptoms, sleep-onset latency, sleep duration, and sleep-related adverse events. The two studies' data for weeks 1 to 12 were pooled. RESULTS: At baseline, participants reported a mean of 3.6 awakenings/night attributed to vasomotor symptoms. Nighttime awakenings attributed to vasomotor symptoms were significantly reduced within 4 weeks of initiating paroxetine 7.5 mg treatment (39% reduction vs 28% for placebo; P = 0.0049), and reductions were sustained through 12 or 24 weeks of treatment. Paroxetine 7.5 mg treatment also significantly increased nighttime sleep duration (week 4, +31 vs +16 min for placebo; P = 0.0075), but no significant between-group differences in sleep-onset latency or sleep-related adverse events such as sedation were observed. CONCLUSIONS: In postmenopausal women treated for menopausal vasomotor symptoms, paroxetine 7.5 mg significantly reduces the number of nighttime awakenings attributed to vasomotor symptoms and increases sleep duration without differentially affecting sleep-onset latency or sedation.

Effects of low-dose paroxetine 7.5 mg on weight and sexual function during treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Two phase 3, randomized, placebo-controlled trials demonstrated that low-dose paroxetine 7.5 mg reduced the frequency and severity of vasomotor symptoms (VMS) associated with menopause and had a favorable tolerability profile. The impact of paroxetine 7.5 mg on body weight and sexual function was evaluated in a pooled analysis. METHODS: Postmenopausal women aged 40 years or older who had moderate to severe VMS were randomly assigned to receive paroxetine 7.5 mg or placebo once daily for 12 or 24 weeks. Assessments included changes in body mass index (BMI) and weight, Arizona Sexual Experiences Scale score, Hot Flash-Related Daily Interference Scale sexuality subscore, and adverse events related to weight or sexual dysfunction. RESULTS: Pooled efficacy and safety populations comprised 1,174 and 1,175 participants, respectively. Baseline values were similar for median weight (∼75 kg), median BMI (∼28 kg/m), and the proportion of women with sexual dysfunction (∼58%). No clinically meaningful or statistically significant changes from baseline in weight or sexual function assessments occurred in the paroxetine 7.5 mg group. Small but statistically significant increases in weight and BMI were observed in the placebo group only on week 4. No significant difference between treatment groups was observed in the proportion of participants who had 7% or higher gain in body weight on week 4, 12, or 24. Rates of adverse events suggestive of sexual dysfunction were low and similar in both treatment groups. CONCLUSIONS: Paroxetine 7.5 mg does not cause weight gain or negative changes in libido when used to treat menopause-associated VMS in postmenopausal women.

Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials.

OBJECTIVE: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks' duration. METHODS: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24. RESULTS: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and 593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P < 0.0001 for both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no short-term discontinuation of symptoms followed treatment cessation. CONCLUSIONS: Paroxetine 7.5 mg is well-tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment.

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.

BACKGROUND: Low-dose mesylate salt of paroxetine (LDMP 7.5 mg) is being investigated for the treatment of vasomotor symptoms associated with menopause. OBJECTIVE: This Phase I, open-label, single- and multiple-dose study evaluated the pharmacokinetic properties, safety and tolerability of LDMP in postmenopausal, nonsmoking women aged ≥40 years. METHODS: After a 3-week screening period, subjects received LDMP 7.5-mg capsules as a single dose on day 1 and then as multiple doses (once daily for 14 days) on Days 6-19. Blood samples were collected predose and up to 120 hours postdose on day 1 (single-dose pharmacokinetic profile), at predose (after 12 doses) on day 18, and at predose and up to 24 hours postdose on day 19 (multiple-dose pharmacokinetic profile). Capsules were taken with 240 mL of water while subjects were fasted. Safety was evaluated throughout the study. RESULTS: Twenty-four women (mean age, 56 years) completed the study. On day 1, median Tmax was ~6 hours, and mean t1/2 was 17.30 hours. Mean plasma concentrations attained predose on days 18 and 19 (days 13 and 14 of multiple dosing) and at 24 hours postdose (day 20) were similar, suggesting that steady state was achieved by day 13 of multiple dosing after 12 daily doses. Mean AUC0-24 h at steady state (day 14 of multiple dosing) was ~3-fold greater than AUC0-∞ on day 1, indicating nonlinear pharmacokinetics. Mean Cmax on day 14 of multiple dosing was ~5-fold greater than that attained on day 1, and the accumulation index (AUCday 19/AUCday 1) at steady state was 9.71. Fluctuation index (calculated as [(Cmax - Cmin)/Cavg ss] × 100) was 75.8%. Most subjects (23/24 [95.8%]) experienced at least 1 treatment-emergent adverse event (AE); however, most AEs (67 events in 22/24 subjects [91.7%]) were mild, and the remainder were moderate. Seventeen subjects experienced 33 AEs that were deemed possibly or probably related to LDMP. No serious AEs were reported, and no clinically meaningful changes in laboratory values, vital signs, or ECGs were observed. CONCLUSIONS: On multiple dosing, LDMP exhibited nonlinear pharmacokinetics and was well tolerated in these healthy postmenopausal women; the extent of accumulation was consistent with data from the published literature.

The effect of extending the pill-free interval on follicular activity: triphasic norgestimate/35 micro g ethinyl estradiol versus monophasic levonorgestrel/20 micro g ethinyl estradiol.

This study was designed to evaluate follicular activity in women taking oral contraceptives with imposed imperfect compliance. After completing a 28-day cycle of either triphasic norgestimate/EE (NGM/EE) (Ortho Tri-Cyclen, Ortho-McNeil Pharmaceutical, Raritan, NJ) or monophasic levonorgestrel/EE (LNG/EE) (Alesse, Wyeth-Ayerst Laboratories, Philadelphia, PA), women were instructed to intentionally "miss" the first two active pills of the next pack. The first two tablets in the second treatment cycle were deliberately omitted, thereby extending the pill-free interval from 7 days to 9 days. Subjects were randomized to take NGM/EE (n = 40) or LNG/EE (n = 39) for two consecutive cycles. The mean maximum follicular diameter was significantly greater in women taking LNG/EE than in those taking NGM/EE (16.4 +/- 7.1 mm vs. 12.6 +/- 8.3 mm, p = 0.047). The LNG/EE group had significantly higher median serum estradiol concentrations compared to women taking NGM/EE on pill Days 10 [29.5 pg/mL (range: 10.0-540.0 pg/mL) vs. 2.5 pg/mL (range: 2.0-6.0 pg/mL), p < 0.001] and 14 [11.0 pg/mL (range: 2.0-416.0 pg/mL) vs. 2.0 pg/mL (range: 2.0-3.0 pg/mL), p = 0.001]. Two women in the NGM/EE group and three women in the LNG/EE group had at least one progesterone level > or =3 ng/mL; none of these women demonstrated a maximum follicular diameter >13 mm. Significantly greater follicular activity was observed after an extended pill-free interval in women taking LNG/EE compared to those taking triphasic NGM/EE. The clinical implications of these findings require further study.