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Acceptability Acceptability Terminology The current WHO criteria (Belsey et al. 1986) for describing vaginal bleeding patterns are: – bleeding (B): any vaginal blood loss requiring the use of 2 or more sanitary pads or tampons per day – spotting (S): any vaginal blood loss requiring no or at most 1 sanitary pad or tampon per day – bleeding/spotting (B/S) episode: 1 or more consecutive day(s) during which vaginal blood loss (bleeding or spotting) occurs, each episode being bounded by B/S-free days – amenorrhea: no bleeding throughout a 90-day reference period – infrequent bleeding: 1 or 2 B/S episodes in a 90-day reference period – frequent bleeding: 6 or more B/S episodes in a 90-day reference period – prolonged bleeding: any B/S episode lasting more than 14 day FIGURE 3 Vaginal bleeding patterns during the early treatment phase (shifted reference period) among starters and switchers (B/S= bleeding/spotting). Women (%) 80 60 40 20 0 Amenorrhea Cerazette ® (n=484) Levonorgestrel 30 µg/day (n=167) 1–2 B/S episodes 3–5 B/S episodes ≥6 B/S episodes Prolonged bleeding (Korver et al. 1998) Shifted reference period During the 1-year, phase III, comparative study with Cerazette® and levonorgestrel 30 µg/day, bleeding patterns were analyzed using these WHO recommendations (Korver et al. 1998). However, to avoid artifacts introduced by the different procedures for initiating treatment among starters, switchers and breast-feeding women, the first reference period was taken as commencing 28 days after the first day of treatment, i.e. days 29 – 118 of treatment, and this is referred to as the “shifted reference period”. Time-related trends were assessed by comparing bleeding patterns in the shifted reference period with those in “reference period 4”, the final 3 months of the study (days 271 – 360). Separate analyses were performed for starters and switchers combined and for breastfeeding women, as lactation may affect the bleeding pattern. Bleeding patterns in starters and switchers Shifted reference period The bleeding pattern in starters and switchers receiving Cerazette® or levonorgestrel 30 µg/day during the shifted reference period is shown in Figure 3 (Korver et al. 1998). The incidence of amenorrhea was 3.4 times higher with Cerazette® than with levonorgestrel (p=0.008), while the incidence of infrequent bleeding, frequent bleeding and prolonged bleeding was 1.5 – 2 times higher. Within this population, switchers experienced a higher incidence of amenorrhea and infrequent bleeding with Cerazette® than starters did, presumably on Fewer bleeding days account of continued ovarian suppression following previous oral contraceptive usage. Subgroup analysis of younger (16 – 34 years) and older (≥ 35 years) women showed no clear age-related difference in bleeding patterns. Overall, there was greater variability in the initial bleeding pattern among Cerazette® users compared to levonorgestrel users, and this is most likely related to the mode of action of Cerazette®. Regular bleeding is most likely to occur in women with ovulatory cycles. However, if ovarian function is suppressed and ovulation is inhibited, continuous progestogen administration will interfere with the normal cyclical changes in the endometrium and bleeding will become less predictable and, consequently, more variable. An inverse relationship between inhibition of ovulation and bleeding irregularity has been noted previously (Landgren et al. 1981, 1982; Moghissi et al. 1973). The total number of bleeding and spotting days during the shifted reference period was comparable between Cerazette® and levonorgestrel. However, Cerazette® users experienced fewer bleeding as opposed to spotting days (Korver et al. 1998) (see Table 5, shifted reference periods). 20 21
Acceptability Acceptability Trends over time Over time, the bleeding pattern in the levonorgestrel group remained relatively constant. In contrast, in women receiving Cerazette®, amenorrhea and infrequent bleeding episodes became more common while frequent bleeding episodes became much less common (Fig. 4). During reference period 4, about 50% of women experienced amenorrhea or infrequent bleeding with Cerazette®, compared to some 10% with levonorgestrel. In contrast, only 4% of women experienced frequent bleeding with Cerazette®, compared to approximately 10% with levonorgestrel. The incidence of prolonged bleeding declined with time in both FIGURE 4 Vaginal bleeding patterns during the late treatment phase (reference period 4) among starters and switchers (B/S= bleeding/spotting). Women (%) 80 60 40 20 Cerazette ® (n=325) Levonorgestrel 30 µg/day (n=111) TABLE 7. Mean number of bleeding/spotting days and mean number of bleeding days per reference period among starters and switchers No. of bleeding/spotting days Cerazette® Levonorgestrel 30 µg/day Shifted reference period 20.8 21.0 Reference period 2 16.4 19.4 Reference period 3 13.8 19.8 Reference period 4 13.5 18.7 No. of bleeding days Shifted reference period 8.4 11.9 Reference period 2 6.3 11.1 Reference period 3 5.4 11.4 Reference period 4 5.0 10.2 (NV Organon scientific development group 1998, data on file) treatment groups, but it remained higher with Cerazette® than with levonorgestrel (Korver et al. 1998). The total number of bleeding and spotting days also declined on continued treatment, the reduction being more pronounced with Cerazette® than with levonorgestrel (see Table 7). Moreover, the number of bleeding days also declined with continued use of Bleeding pattern and age Changes in bleeding pattern are likely to be favorable 0 Amenorrhea 1–2 B/S episodes 3–5 B/S episodes ≥6 B/S episodes Prolonged bleeding (Korver et al. 1998) Cerazette®, while the number for the LNG users did not change. As noted in the early phase of treatment, no age-related difference in bleeding pattern was evident after 1 year’s treatment with Cerazette®. The overall changes in bleeding patterns with Cerazette® from the shifted reference period to reference period 4 are shown in Table 8. These indicate that about three-quarters of women who initially experienced amenorrhea with Cerazette® can expect to have the same bleeding pattern after 1 year of treatment, while about half of those with 3 – 5 B/S episodes, infrequent or prolonged bleeding during the first few months can also expect this to continue. In the remainder, the most likely change is towards less frequent bleeding episodes (Korver et al. 1998). For the purposes of counseling, therefore, it may be concluded that the change in bleeding pattern that occurs with Cerazette® over time is most likely to be a favorable one, as infrequent or no bleeding is less disruptive with respect to lifestyle. 22 23
Page 1 and 2: Product Monograph ® indicates trad
Page 3 and 4: Contents Product Monograph 1 2 Intr
Page 5 and 6: Introduction A reliable alternative
Page 7 and 8: Pharmacodynamics Pharmacodynamics T
Page 9 and 10: Pharmacodynamics Pharmacodynamics a
Page 11 and 12: Contraceptive efficacy Contraceptiv
Page 13: 5 Acceptability ■ ■ ■ ■ The
Page 17 and 18: Acceptability Acceptability TABLE 9
Page 19 and 20: 6 Use during lactation ■ ■ ■
Page 21 and 22: 7 Safety aspects ■ ■ ■ Ceraze
Page 23 and 24: Safety aspects Safety aspects Hemos
Page 25 and 26: 8 Summary The estrogen component of
Page 27 and 28: References References Coutinho EM,
Page 29 and 30: References References Rekers H. Mul
Page 31 and 32: Summary of Product Characteristics
Page 33: Summary of Product Characteristics

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