Meliane/Meliane ED contains a small amount of 2 different female hormones - gestodene (a progestogen) and ethinylestradiol (an estrogen). Because of the small amounts of hormones, Meliane/Meliane ED is considered a low-dose oral contraceptive. As all active tablets in the pack combine the same hormones in the same dose, it is considered a monophasic combined oral contraceptive.
Pharmacology: The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings and Side Effects), can be useful in deciding the method of birth control. The cycle is more regular and the menstruation is often less painful, and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. Apart from this, with the higher-dosed COCs (ethinylestradiol 50 mcg), there is evidence of a reduced risk of fibrocystic tumors of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy, and endometrial and ovarian cancer. Whether this also applies to lower-dosed COCs remains to be confirmed.
Pharmacokinetics: Gestodene: Orally administered gestodene is rapidly and completely absorbed. Following single ingestion of Meliane, maximum drug serum levels of about 3.5 ng/mL are reached at about 1 hr. Thereafter, gestodene serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life of about 12 hrs. For gestodene, an apparent volume of distribution of 0.7 L/kg and a metabolic clearance rate from serum of about 0.8 mL/min/kg were determined.
Gestodene is not excreted in unchanged form but as metabolites which are eliminated with a half-life of about 1 day. Gestodene metabolites are excreted at a urinary to biliary ratio of about 6:4. The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.
Gestodene is bound to serum albumin and to sex hormone-binding globulin (SHBG). Only about 1.3% of the total serum drug levels are present as free steroid, but about 69% are specifically bound to SHBG. The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentrations in the serum. Following induction of the binding protein, the SHBG-bound fraction increases to approximately 80% while the unbound and the albumin-bound fraction decrease.
Following daily repeated administration of Meliane, gestodene concentrations in the serum increase by a factor of 2.3. Mean serum levels are 4-fold higher at steady-state conditions which are generally reached during the 2nd half of a treatment cycle. The pharmacokinetics of gestodene is influenced by SHBG serum levels. Under treatment with Meliane, a 2-fold increase in the serum SHBG levels has been observed for the 1st treatment cycle. Due to the specific binding of gestodene to SHBG, the increase in SHBG levels is accompanied by an almost parallel increase in gestodene serum levels. After 3 treatment cycles, the extent of SHBG induction per cycle does not change anymore. The absolute bioavailability of gestodene was determined to be 99% of the dose administered.
Ethinylestradiol (EE): Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Meliane, maximum drug serum levels of about 65 pg/mL are reached at 1.7 hrs. Thereafter, ethinylestradiol serum levels decrease in 2 phases characterized by half-lives of 1-2 hrs and about 20 hrs. Because of analytical reasons, these parameters can only be calculated following the administration of higher doses. For ethinylestradiol, an apparent volume of distribution of about 5 L/kg and a metabolic clearance rate from plasma of about 5 mL/min/kg were determined. Ethinylestradiol is highly but nonspecifically bound to serum albumin. About 2% of drug levels are present unbound. During absorption and first liver passage, ethinylestradiol is metabolized, resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.
According to the half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels are reached after 3-4 days and are higher by 30-40% as compared to a single dose.
During established lactation, 0.02% of the daily maternal dose could be transferred to the newborn via milk.
The systemic availability of ethinylestradiol might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C. Ethinylestradiol induces the hepatic synthesis of SHBG and corticoid-binding globulin (CBG) during continuous use. The extent of SHBG induction, however, depends on the chemical structure and the dose of the co-administered progestogen. During treatment with Meliane, SHBG concentrations in the serum increased from 107-216 nmol/L in the 1st cycle and to 223 nmol/L in the 3rd cycle. Serum concentrations of CBG were increased from 42-77 mcg/mL in the 1st cycle and remained constant thereafter.
Toxicology: Preclinical Safety Data: Animal toxicity studies for human risk estimation were performed for both components of Meliane, ethinylestradiol and gestodene, and the combination.
No effects which might indicate an unexpected risk to humans were observed during systemic tolerance studies after repeated administration.
Long-term repeated-dose toxicity studies did not indicate a tumorigenic potential. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Studies on embryotoxicity and teratogenicity of ethinylestradiol and the evaluation of effects of the combination on the fertility of parent animals, fetal development, lactation and reproductive performance of the offspring gave no indication of a risk of adverse effects in humans after recommended use of Meliane.
In vitro and in vivo studies gave no indication of a mutagenic potential.