Gracial ProdMonograph_cover - epgonline.org

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7. Safety aspects • The effects of Gracial on hemostatic parameters are comparable to those of classic triphasic regimens •Gracial has mainly beneficial effects on lipid metabolism and no clinically adverse effects on carbohydrate metabolism •Gracial has not been found to have any consistent adverse effects on blood pressure • The association between OCs and venous thromboembolism is likely to be influenced by the amount of estrogen in the Pill and not by the type of progestogen • The risk of AMI is significantly lower in users of third generation OCs than that seen with older-generation Pills • The risk of stroke in users of third-generation OCs is not increased • OC use substantially reduces the incidence of ovarian and endometrial cancer As oral contraceptives are used for long periods of time by healthy young women for the main purpose of preventing pregnancy, manufacturers have constantly striven to identify and minimize potential health risks. From the time of its first introduction, the Pill has provided virtually 100% contraceptive efficacy. As a result, most of the developments in oral contraception over the last 35 years have been driven by the search for ever better safety and tolerability. Consequently, any health risk attributable to modern OCs is small in comparison to the risk to health posed by an unwanted pregnancy. Epidemiological data New epidemiological data have recently become available which cast new light upon the association between cardiovascular disease and OC use. In addition, new data concerning gynecological cancer risk have also been published. 27
Safety aspects Gracial not included in epidemiology Since Gracial has been on the market for a relatively short period of time in relatively few countries, it has not been included in the epidemiological studies on OCs and cardiovascular disorders. Therefore, an overview of the effects of Gracial on intermediate endpoints associated with lipid metabolism, carbohydrate metabolism and hemostasis is also presented in this chapter. 7.1 Venous thromboembolism The association between OC use and the occurrence of venous thromboembolism (VTE) is one of the most important safety aspects that shaped the development of the Pill. It became apparent within a few years after the introduction of the Pill that this association was related to its estrogen component. Studies clearly demonstrated that as the estrogen dose was progressively reduced, from 100 µg to 50 µg EE by the 1970s and then down to 30–35 µg, the incidence of thrombotic events in oral contraceptive users decreased accordingly (Vessey 1988; Gerstmann et al 1991; RCGP 1978; Farmer 1995). Hemostasis In the early years following the introduction of low-dose (30 µg) Pills such as Marvelon, which utilizes the third-generation progestogen desogestrel, epidemiological data for their effects on VTE was not available. Therefore, measurable indicators on the function of the vascular system, such as hemostatic parameters, were investigated to determine the impact of OCs. Effect on hemostatic parameters Changes in hemostatic parameters with Gracial (both 22- and 21-day regimens) were comparable to a classic triphasic regimen. The effects of Gracial on hemostatic parametes have been compared with those of Triodeen (triphasic EE + gestodene) over a period of six treatment cycles (van Enk et al, manuscript in preparation). In general, there were significant changes in all hemostatic parameters with both Gracial and triphasic gestodene. The following specific differences were noted. Gracial produced a significantly larger increase in factor VII (in cycles 3 and 6), a significantly smaller increase in fibrinogen (in cycle 3) and plasminogen (in cycle 6), and significantly larger decreases in antithrombin III (in cycle 6), protein S (total) (in cycle 3), protein S (free) (in cycles 3 and 6) and plasminogen activator inhibitor I (PAI-I-Act) (in cycles 3 and 6). After six cycles of Gracial use, there was no significant change from baseline in fibrinopeptide A. 28
Page 1 and 2: ® indicates trademark(s) registere
Page 3 and 4: © 2000 N.V. Organon All rights res
Page 5 and 6: Contents Page 8. SUMMARY 42 9. REFE
Page 7 and 8: Introduction Since all the current
Page 9 and 10: Introduction 1.1 Rationale for Grac
Page 11 and 12: 2. Pharmacokinetics • After oral
Page 13 and 14: Pharmacokinetics ENG mainly bound t
Page 15 and 16: 3. Pharmacodynamics •Etonogestrel
Page 17 and 18: Pharmacodynamics 40 30 20 10 0 nore
Page 19 and 20: Pharmacodynamics mIU/ml 7 6 5 4 3 2
Page 21 and 22: 4. Contraceptive efficacy • The P
Page 23 and 24: Acceptability Effect of Gracial on
Page 25 and 26: Acceptability % of women 35 30 25 2
Page 27 and 28: 6. Gracial and mild to moderate acn
Page 29 and 30: Gracial and mild to moderate acne G
Page 31: Gracial and mild to moderate acne R
Page 35 and 36: Safety aspects The incidence of VTE
Page 37 and 38: Safety aspects Table 5: Relative ri
Page 39 and 40: Safety aspects Oral contraceptives
Page 41 and 42: Safety aspects Stroke With regard t
Page 43 and 44: Safety aspects Influence of adjustm
Page 45 and 46: Safety aspects On balance, this stu
Page 47 and 48: 8. Summary The most recent area of
Page 49 and 50: References Falsetti L. Acne treatme
Page 51 and 52: References Lunsen HW van. Recent or
Page 53 and 54: 10. Summary of product characterist
Page 55 and 56: Summary of product characteristics

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