Gracial ProdMonograph_cover - epgonline.org

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Safety aspects Since falling levels of LDL-cholesterol and rising levels of HDLcholesterol are both considered positive changes, Gracial's influence on lipid metabolism can be regarded as favorable. Carbohydrate metabolism Insulin resistance and accompanying hyperinsulinemia may induce adverse changes in MI risk via metabolic mechanisms and effects on blood pressure. Insulin can also have deleterious effects on the vascular wall by inducing smooth muscle proliferation and lipid deposition. All oral contraceptives cause some degree of insulin resistance, but the effects of currently used low-estrogen-dose OCs vary considerably. The greatest degree of insulin resistance is seen with Pills containing levonorgestrel and the least with those containing desogestrel (Godsland and Crook 1996). Effect of Gracial on carbohydrate metabolism Gracial has been shown (Kuhl 1993) to have only minor effects on plasma insulin and glucose levels following glucose loading, and no clinically significant effect on fasting insulin levels or plasma glucose levels. These results are similar to those reported for other low-dose oral contraceptives and show that Gracial has no clinically significant effects on carbohydrate metabolism. No adverse effect on blood pressure Blood pressure Older studies have shown small increases in blood pressure with prolonged use of high-estrogen dose OCs. However, Gracial has not been found to have any consistent adverse effects on blood pressure. In the multicenter study of Dieben et al (1991), blood pressure was measured both before use and after every three cycles of Gracial. Particular attention was paid to the 499 women who had not used oral contraception before ('starters'), as any change in blood pressure as a result of Gracial use ought to be most evident in this group. In fact, blood pressure changes were inconsistent and their magnitude was close to the limits of error in measurement. Epidemiological data In the last few years, several studies have provided new epidemiological data on arterial disease, acute myocardial infarction (AMI) and stroke (Jick et al 1996; Heinemann et al 1997; Lewis et al 1997; Lidegaard 1998; Dunn 1999; WHO 1996). 35
Safety aspects Stroke With regard to ischemic stroke, new data have been generated in the WHO study (WHO 1996), the Transnational study (Heinemann et al 1997) and a Danish case-control study (Lidegaard and Kreiner 1998). The studies are not entirely consistent in their findings. The stroke publication of the WHO Collaborative Group provides separate information for the participating centers in Europe and for those in developing countries. Although the European data show no difference in the risk of stroke between Pill generations, the risk of stroke in second-generation OC users is statistically significantly increased in the centers from the developing countries, while no increase was found for users of the third-generation OCs. The odds ratios in the Transnational study (Heinemann et al 1997) are higher than those observed in the WHO study and also depend on the type of control group. No differences between OCs of the second- and third-generation were observed. The study by Lidegaard and Kreiner (1998) concluded that OCs with 50 µg EE and OCs with second-generation progestogens significantly increased the risk of cerebral thromboembolic attacks (CTA), which include thrombotic strokes. However, OCs with third-generation progestogens did not have any significant influence on the risk of CTA. Acute MI The risk of myocardial infarction was assessed in five studies. In the Transnational AMI study (Lewis et al 1997), the risk of AMI was observed to be significantly increased in secondgeneration OC users versus no use, and was not increased in third-generation OC users compared to no use. When comparing second- and third-generation OC users, a statistically significant, three times lower risk was observed for users of the third-generation OCs (OR 0.3, 95% CI 0.1–0.9). The authors of the publication concluded that third-generation OCs are the first class of OCs not to be associated with MI. 36
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 and 32: Gracial and mild to moderate acne R
Page 33 and 34: Safety aspects Gracial not included
Page 35 and 36: Safety aspects The incidence of VTE
Page 37 and 38: Safety aspects Table 5: Relative ri
Page 39: Safety aspects Oral contraceptives
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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