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Pharmacology: Pharmacodynamics: Mechanism of action: The continuous intake of Belara for 21 days inhibits pituitary FSH and LH secretion, and thus ovulation. The endometrium proliferates and undergoes secretory transformation. The consistency of the cervical mucus is changed. This prevents sperm migration through the cervical canal and alters sperm motility.
The lowest daily dose of chlormadinone acetate for complete inhibition of ovulation is 1.7 mg. The required dose for full endometrial transformation is 25 mg per cycle.
Chlormadinone acetate is an antiandrogenic progestogen. Its effect is based on its ability to displace androgens from their receptors.
Clinical efficacy: In clinical studies in which the administration of Belara was tested for up to 2 years in 1,655 women and throughout more than 22,000 menstruation cycles, 12 pregnancies occurred. In 7 women the following factors were present during the period of conception: administration errors, concurrent diseases causing nausea or vomiting, or concurrent administration of medicines that were known to reduce the contraceptive effect of hormonal contraceptives. (See Table 1.)
Click on icon to see table/diagram/imagePharmacokinetics: Chlormadinone acetate (CMA): Absorption: After oral administration CMA is rapidly and almost completely absorbed. The systemic bioavailability of CMA is high as it is not subject to first-pass metabolism. Peak plasma concentrations are reached after 1-2 hours.
Distribution: The binding of CMA to human plasma proteins, mainly albumin, is more than 95%. CMA has no binding affinity for SHBG or CBG. CMA is stored primarily in the adipose tissue.
Biotransformation: Various reduction and oxidation processes and conjugation to glucuronides and sulphates result in various of metabolites. The principal metabolites in human plasma are the 3α- and 3β-hydroxy-CMA with biological half-lives not differing substantially from that of non-metabolised CMA. The 3-hydroxy metabolites show similar antiandrogenic activity as CMA itself. In the urine the metabolites appear mainly as conjugates. After enzymatic cleavage the main metabolite is 2α-hydroxy-CMA besides the 3-hydroxy-metabolites and dihydroxy metabolites.
Elimination: CMA is eliminated from the plasma with a mean half-life of about 34 hours (after a single dose) and about 36-39 hours (after multiple doses). After oral administration CMA and its metabolites are excreted both via the kidneys and in the faeces in about equal amounts.
Ethinylestradiol (EE): Absorption: EE is rapidly and almost completely absorbed after oral administration and mean peak plasma concentrations are reached after 1.5 hours. Because of presystemic conjugation and first-pass metabolism in the liver the absolute bioavailability is only about 40% showing considerable interindividual variation (20-65%).
Distribution: The EE plasma concentrations reported in the literature vary considerably. Approximately 98% of the EE is bound to plasma proteins, almost exclusively to albumin.
Biotransformation: Like natural estrogens, EE is biotransformed via (cytochrome P-450 mediated) hydroxylation at the aromatic ring. The main metabolite is 2-hydroxy-EE, which is metabolised to other metabolites and conjugates. EE undergoes presystemic conjugation both in the mucosa of the small intestine and in the liver. In the urine mainly glucuronides, and in the bile and plasma mainly sulphates are detected.
Elimination: The mean plasma half-life of EE is approximately 12-14 hours. EE is excreted via the kidneys and faeces at a ratio of 2 to 3. The EE sulphate excreted into the bile after hydrolysis by intestinal bacteria, enters the enterohepatic circulation.
