Focus on Ethinylestradiol/DienogestSiegfried Golbs(1) DVM, PhD,
Herbert Kuhl(2) MD, PhD,
Claudia Moore(3) MD
(1) Department of Medical Affairs, Jenapharm GmbH & Co. KG, Jena, Germany
(2) Department of Obstetrics and Gynecology, J.W. Goethe-University of Frankfurt, Frankfurt, Germany
(3) Department of Clinical Research, Jenapharm GmbH & Co. KG, Jena, Germany
Ethinylestradiol/dienogest (EE/DNG, Valette (tm), Jenapharm GmbH & Co. KG) is a new low dose monophasic combination containing 30 µg of ethinylestradiol (EE) and 2.0 mg of dienogest (DNG). The dose of 2 mg DNG is found to be sufficient to inhibit ovulation and the dose of 30 µg EE to ensure satisfactory cycle control while at the same time keeping estrogen related adverse events to a minimum (Kovacs and Hoffmann, 1997; Kuhl, 1997; Zahradnik and Moore, 1997).
Pharmacology of the progestogenic component dienogest
The characteristic of EE/DNG is largely based on the properties of the progestogenic component DNG. The main pharmacological properties of DNG are:
· DNG is the only nortestosterone derivative, which has a cyanomethyl instead of an ethinyl group at C17a (Stanczyk, 1996; Oettel et al., 2000; Golbs et al., 2001).
· DNG is characterized by a strong progestogenic effect on the endometrium, but a less pronounced antigonadotropic action, and by an absence of estrogenic and androgenic activities (Oettel et al., 1995; 1998; 1999).
· Although DNG has a weak binding affinity to the androgen receptor, it shows no androgenic but antiandrogenic action (Oettel et al., 1997; 1998; 1999; Moore et al., 1999b). The antiandrogenic activities of DNG underline its specific pharmacodynamic profile.
· The daily dose of DNG, which is necessary to inhibit ovulation without the presence of EE is 1 mg, which is comparable to that of progesterone derivatives (Moore et al., 1999).
· DNG has no binding affinity to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), but is bound with low affinity only to albumin (Oettel et al., 1998).
The suppressive effect of EE/DNG on ovarian function and follicular development is shown in an open study on 27 women (Spona et al., 1997). The post-ovulatory increase of the serum levels of progesterone observed in the pre-treatment cycle is reliably suppressed during 6 cycles of EE/DNG use (Moore et al., 1999a). The fertility after discontinuation of the use of EE/DNG is restored rapidly (Zimmermann et al., 1999a).
The contraceptive efficacy of EE/DNG is investigated in:
1. Three European clinical studies (Moore et al., 1999a; Golbs et al., 2002, Golbs et al., 2002a). In altogether 3,278 subjects and 38,242 treatment cycles 17 on-treatment pregnancies are reported yielding an unadjusted Pearl Index of 0.55. Six of them are considered to result from the method failure giving an adjusted Pearl index of 0.19 pregnancies per 100 woman-years.
2. A surveillance study (Zimmermann et al., 1999). In 16,087 women studied and 92,146 cycles, 11 on-treatment pregnancies are reported, yielding an unadjusted Pearl Index of 0.14. The adjusted Pearl Index is 0.09 pregnancies per 100 woman-years.
Thus EE/DNG is a reliable ovulation inhibitor, the contraceptive efficacy of which is comparable to other low dose OCs (Brill et al., 1991; Corson, 1993).
The occurrence of intermenstrual bleeding, or absence of withdrawal bleeding during the use of low-dose OCs are among the most common reasons for discontinuation of OC use. Multicenter clinical studies (Moore et al., 1999a; Golbs et al., 2002, Golbs et al., 2002a), as well as a surveillance study (Zimmermann et al., 1999) reveal a good cycle control during the use of EE/DNG:
· Intermenstrual bleeding is characterised by an initial increase in both breakthrough bleeding and spotting in cycles 1-3 (shown in 3-5% of the women). Thereafter they decrease rapidly to <1% of the women.
· Cycle length remains generally unchanged at around 28 days.
· The duration of menstrual bleeding is shortened from about 5 days at baseline to about 4 days after 6 treatment cycles.
· On average the intensity of bleeding is reduced.
· The frequency of dysmenorrhea is decreased markedly.
· Absence of withdrawal bleeding is recorded in about 3% of the treatment cycles.
Thus the cycle control during use of EE/DNG is comparable with that of other low-dose OCs (Archer, 1994; Corson, 1993; Runnebaum et al., 1992).
Effects on androgen-dependent skin disorders
· In a double-blind study on acne patients EE/DNG (n=20) causes an improvement of acne in 87% of the cases after 6 cycles of use. With regards to the stage of acne, EE/DNG caused a 50% improvement. The area of the sebaceous glands significantly diminishes from 14.4% to 7.4% in the 6th cycle. EE/DNG is equipotent to the combination of 35 µg EE and 2 mg cyproterone acetate (CPA) with respect to its therapeutic efficacy in acne patients (Moore et al., 1999b).
· The improvement of the clinical symptoms correspond well with the profound reduction in the serum concentrations of total testosterone and free testosterone and a considerable increase of SHBG (Moore et al., 1999b).
· In a prospective, open-label, multicenter, uncontrolled clinical phase III study, from 108 women with acne 57% improve, and 15% are healed after the 6th cycle (Golbs et al., 2002).
· In a prospective, open-label, multicenter, uncontrolled clinical phase III study, from 50 women with acne, 80% improve and one is healed after the 6th cycle (Golbs et al., 2002a).
· In a surveillance study with 11,104 women enrolled, the preexisting mild to moderate stages of acne are improved or healed after 6 cycles (Zimmermann et al., 1999b)
Other androgen-related conditions
· EE/DNG improves considerably the skin blemishes and hair greasiness in two multicenter clinical studies (Golbs et al., 2002; 2002a)
· In a surveillance study on 11,104 women, 70% of the participants report an improvement of the hair greasiness, and 81% - an improvement of the greasy skin disorders after 6 cycles of EE/DNG use (Zimmermann et al., 1999b).
Thus the antiandrogenic action of DNG makes EE/DNG particularly suitable for treatment of women with androgen-dependent skin disorders.
EE/DNG evokes the following changes in the lipid metabolism (Moore et al., 1999a; Wiegratz et al., 2002):
· A significant increase of triglycerides level.
· A nonsignificant increase of HDL-cholesterol and HDL2- cholesterol, without changes in the HDL3-cholesterol.
· A significant rise of apolipoprotein A1, and a slight increase in apolipoprotein B.
· A significant reduction of lipoprotein (a).
· No significant changes in total cholesterol, while LDL-cholesterol tends to decrease.
The effect on lipid metabolism of EE/DNG indicates the predominance of the effect of the estrogen component. The increased HDL-cholesterol, the slight reduction in the levels of LDL-cholesterol, and the significant reduction of lipoprotein (a) which correspond to the changes described for other low-dose OCs (Godsland et al., 1990; Kuhl et al., 1990), is considered to be a favorable rather than an unfavorable effect of EE/DNG.
EE/DNG evokes the following changes in carbohydrate metabolism at the end of the treatment period of 3 cycles in the conditions of an open, uncontrolled, phase III multicenter trial in a subgroup of 29 women (Moore et al., 1999a):
· A slight but significant increase of the fasting serum concentrations of insulin and C-peptide.
· Serum concentrations of glucose and HbA1c, as well as the insulin/glucose ratio do not increase significantly.
No difference in the effect on carbohydrate metabolism is observed between EE/DNG and a levonorgestrel-containing OC (Boehme and Moore, 2001). The slight hyperinsulinemia and insulin resistance caused by EE/DNG is similar to that evoked by other low dose OCs (Godsland et al., 1990; Jandrain et al., 1990). These changes are within the normal range, but in predisposed women may cause a pathological glucose tolerance.
EE/DNG induces the following changes in the hemostasis parameters (double-blind placebo-controlled study, n=20 vs. 20 women who took placebo for a period of 3 weeks)(Spona et al., 1997a):
· Procoagulatory parameters: only factor VII increases significantly (by 20%).
· Anticoagulatory parameters - a slight (10%), but significant increase in protein C is observed, while antithrombin III and protein S are not significantly changed.
· Fibrinolytic parameters - only plasminogen increases significantly (by 30%), while TPA decreases significantly (by 25%).
· Although such changes were observed, all individual values stayed in the normal range and were therefore without clinical relevance.
Treatment with EE/DNG (n=20) and the reference preparation EE/desogestrel (n=20) evoke similar changes in the coagulation and fibrinolysis parameters (Moore et al., 1999a):
· A rise in fibrin turnover as demonstrated by elevated prothrombin fragments 1+2 and D-dimers.
· An increase in fibrinogen, factor VII activity, plasminogen, protein C activity, and plasmin/antiplasmin complex.
· A decrease of protein S, tissue-plasminogen activator (t-PA), and plasminogen activator-inhibitor (PAI).
· No significant changes in the thrombin/antithrombin complex (TAT).
· A transient and slight decrease of antithrombin III.
Similar changes have been observed during the use of other low-dose OCs (Winkler et al., 1996). They reflect an increase in intravascular coagulatory and fibrinolytic activity due mainly to the effects of EE on the hepatic synthesis of coagulation and fibrinolysis factors. In healthy users the effect of EE/DNG should not be thrombogenic, but in predisposed women the risk of thromboembolic disease might be increased, as reported with other low dose OCs.
EE/DNG has a minimal impact on body weight. A small increase of weight by 0.5 kg on average is reported during treatment with EE/DNG in some of the clinical studies (Moore et al., 1999a; Golbs et al., 2002). Similar changes are found in other clinical studies with low dose OCs (Rekers, 1988).
No significant changes in diastolic or systolic blood pressure are observed during treatment with EE/DNG (Moore et al., 1999a; Golbs et al., 2002; Golbs et al, 2002a). Other studies report a development of hypertension in a small proportion of women (2.5%) during OC use (Rekers, 1988; Fuchs et al., 1995).
· In an open, uncontrolled phase III multicenter clinical trial (n=2,290), the most frequently observed adverse events at the end of the 3rd cycle are headache (12.3%), breast tension (8.8%), nausea/vomiting (3.9%), depression (1.5%), edema 0.5%). At the end of the 18th cycle the frequency of the adverse events decreases merkedly, e.g. headache (3.5%), breast tension (1.8%). Only 7 serious adverse drug reactions are reported (Moore et al., 1999a).
· In a prospective, open-label, multicenter, uncontrolled, clinical phase III study on 557 healthy women, the adverse events documented on the checklist by 1% or more subjects after one or more cycles are breast tenderness, headache, gastric complaints, depressive mood, increased and reduced libido. Reduced tolerance to contact lenses is reported by 1 contact lens users. In addition to the checklist, adverse events are also spontaneously reported by 17 % of subjects after the 1st cycle and by 12% after the 2nd and 3rd cycle. After that the frequency of subjects spontaneously reporting events drops to less than 10% after cycle 4 and to less than 5% after cycle 8. Only 7.7% of the women discontinue the use due to adverse reactions (Golbs et al., 2002).
· In a prospective, open-label, multicenter, uncontrolled, clinical phase III study on 431 healthy women, the adverse events documented on the checklist by 1% or more women after one or more cycles are breast tenderness, gastric complaints, headache, increased and reduced libido, edema and depressive mood. In addition to the checklist, adverse events are also spontaneously reported by 8% of subjects after the 1st cycle, 7% after the 2nd and by 6% after the 3rd - 5th cycles. After that the frequency of subjects spontaneously reporting events drops to less than 5%. Only 5.6% of the women discontinue the use due to adverse reactions (Golbs et al., 2002a).
· In the surveillance study (n=16,267) 5.7% of the women report adverse drug reactions. The most frequently observed adverse reactions are breast pain (1.5%), weight gain (1.1%), headache (1.1%), nausea/vomiting (1.0%), dysmenorrhea (0.35%), decreased libido (0.32%), depression (0.29%), and nonspecific abdominal pain (0.14%). Only 6 serious adverse drug reactions are reported (Zimmermann et al., 1999).
The progestogenic component dienogest of the oral contraceptive EE/DNG is a unique progestogen as it is the only nortestosterone derivative without a 17a-ethinyl group. DNG combines some of the typical effects of the progesterone derivatives (low hepatic impact, antiandrogenic action, low antigonadotropic activity, high ovulation inhibition dose) with those of the modern 19-nortestosterone derivatives (low transformation dose, short half-life, high oral bioavailability).
EE/DNG is a reliable ovulation inhibitor. The Pearl Index values indicate that the contraceptive efficacy of EE/DNG is comparable to that of other low dose OCs. EE/DNG provides a good cycle control, reduces the incidence of intermenstrual bleeding, the intensity and duration of menstrual bleeding, and the frequency of dysmenorrhea. As DNG exerts antiandrogenic instead of androgenic effects, EE/DNG is particularly suitable for the treatment of acne and other androgenic disorders. Furthermore, the effects of EE/DNG on carbohydrate metabolism and hemostasis are similar to that of other low dose OCs. The changes in the lipid metabolism appeared to be more favorable. EE/DNG is safe and well tolerated by most of the women.
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Siegfried Golbs DVM, PhD
Department of Medical Affairs, Jenapharm GmbH & Co. KG, Otto-Schott St. 15, 07745 Jena, Germany. Tel.: +49-3641-646 527; Fax: +49-3641-646104