Gracial ProdMonograph_cover - epgonline.org

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Safety aspects Adjusting for bias In more recent epidemiological studies (Farmer et al 1997, 1998; Lewis et al 1999; Lidegaard et al 1998; Suissa et al 1997), it was possible to adjust more appropriately for these newly recognized biases than in previous studies. This was due to a better understanding of the ways in which these biases influence results. In this context, the user age and duration of OC use appear to be closely related to prescribing bias and the ‘healthy user’ effect. When adjusting for these factors, the newer analyses consistently observed no difference in the risk of VTE between second- and third-generation OC users, thus confirming the likelihood that the initial differences in the 1995 studies were caused by bias and confounding. The view that the initial studies were biased was substantiated by a recent analysis by Farmer et al (1999), which reduced the confounding effects of age and, indirectly, duration of use to a minimum. This study observed no differences between odds ratios for VTE in second- and third-generation OC users. This finding was confirmed in the final analysis of the Transnational study (Lewis et al 1999), which integrated the full OC exposure history in their original case-control analysis. The results of the final analysis are shown in the table below and suggest that the odds ratio of VTE compared to non-users is related to the dose of estrogen in the OC and is independent of the type of progestogen used. The lowest odds ratios (1.6–2.5) were associated with the low-dose, thirdgeneration OCs and the highest (8.5) with the first-generation OCs containing 50 µg estrogen or more. The odds ratios for VTE with OCs containing 30 µg of EE but different progestogens (DSG, GSD or LNG) were similar. 31
Safety aspects Table 5: Relative risk estimates for VTE for different exposures compared with non-use or second-generation OC use Current exposure Reference group Odds ratio 95% CI All OCs No current use 2.9 2.1-4.1 1st generation OCs No current use 8.5 3.0-23.9 2nd generation OCs No current use 2.9 1.9-4.2 Levon<strong>org</strong>estrel OCs No current use 2.6 1.8-4.0 N<strong>org</strong>estimate OCs No current use 3.7 2.2-6.1 3rd generation OCs No current use 2.3 1.5-3.5 Desogestrel/30 EE OCs No current use 2.5 1.6-4.1 Gestodene OCs No current use 2.3 1.4-3.6 Desogestrel/20 EE OCs No current use 1.6 0.9-2.9 3rd generation OCs 2nd generation OCs 0.8 0.5-1.3 (Lewis et al 1999) Conclusion It can be concluded that after appropriate adjustments for relevant confounders and distorting factors, the risk of VTE is similar for OCs containing the same estrogen doses, irrespective of the progestogen component. 32
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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
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Page 15 and 16: 3. Pharmacodynamics •Etonogestrel
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Page 19 and 20: Pharmacodynamics mIU/ml 7 6 5 4 3 2
Page 21 and 22: 4. Contraceptive efficacy • The P
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Page 33 and 34: Safety aspects Gracial not included
Page 35: Safety aspects The incidence of VTE
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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