AKIZZA Film coated tablet Ref.[10481] Active ingredients: 17 alpha-Ethinylestradiol Gestodene

Gestodene

Orally administered gestodene is rapidly and completely absorbed. Following single ingestion of Akizza, maximum drug serum levels of about 3.5ng/ml are reached at about 1.0 hour. Thereafter, gestodene serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of about 12hours. 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 SHBG (sex hormone binding globulin). Only about 1.3% of the total serum drug levels are present as free steroid, 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 ca. 80 % while the unbound and the albumin-bound fractions decrease.

Following daily repeated administration of Akizza, an accumulation of gestodene concentrations in the serum is observed. Mean serum levels are about fivefold higher at steady-state, which is generally reached during the second half of a treatment cycle. The pharmacokinetics of gestodene are influenced by SHBG serum levels. Under treatment with Akizza, a twofold increase in the serum SHBG levels has been observed for the first 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 three treatment cycles, the extent of SHBG induction per cycle does not seem to change further. The absolute bioavailability of gestodene was determined to be 99% of the dose administered.

Ethinylestradiol

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Akizza, maximum drug serum levels of 65pg/ml are reached at 1.7 hours.

Thereafter, ethinylestradiol serum levels decrease in two phases characterized by half-lives of about2 hours and about 21 hours, respectively. The terminal half-life of ethinylestradiol is subject to a large interindividual variation and a range of 5 to 30h has been reported in the literature. Due to 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 serum of about 5ml/min/kg were determined. Ethinylestradiol is highly but non-specifically bound to albumin. About 2% of drug levels are present unbound. During absorption and first liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. 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 5 – 6 days and are higher by 40-60% 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 CBG (corticoid binding globulin) 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 Akizza, SHBG concentrations in the serum increased from 107nmol/l to 216nmol/l in the first and to 223nmol/l in the third cycle. Serum concentrations of CBG were increased from 42μg/ml to 77μg/ml in the first cycle and remained constant thereafter.

The combination of ethinylestradiol and gestodene, like other contraceptive steroids, is associated with an increased incidence of neoplastic nodules in the rat liver, the relevance of which to man is unknown. Malignant liver tumours have been reported on rare occasions in long-term users of oral contraceptives.

There are no other preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.