LUBION Solution for injection Ref.[28021] Active ingredients: Progesterone

Absorption

Progesterone serum concentrations increased following the subcutaneous (s.c.) administration of 25 mg of Lubionto 12 healthy post-menopausal females. By one hour post-administration of a single s.c. dose the mean C_max was 50.7 ± 16.3 ng/ml. The progesterone serum concentration decreased following a mono-exponential decay, and by twelve hours post-administration the average concentration was 6.6 ± 1.6 ng/ml. The minimum serum concentration, 1.4 ± 0.5 ng/ml, was reached at the 96-hour time-point. Pharmacokinetic analysis demonstrated linearity of the three s.c. doses tested (25 mg, 50 mg and 100 mg).

Following multiple dosing of 25 mg/daily via subcutaneous administration, steady state concentrations were attained within approximately 2 days of treatment with Lubion. Trough values of 4.8 ± 1.1 ng/mL were observed with AUCs of 346.9 ± 41.9 ng*hr/mL on Day 11.

Distribution

In humans, 96-99% of progesterone is bound to serum proteins like albumin (50-54%) or transcortin (43-48%), and the remainder is free in the plasma. Owing to its lipid solubility, progesterone travels from the bloodstream to its target cells through passive diffusion.

Biotransformation

Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

Excretion

Progesterone undergoes renal and biliary elimination.

Rabbits were treated with 6.7 mg/kg/dayof Lubionfor up to 7 consecutive days by s.c. and i.m. injection. No relevant effect attributed to the treatment with Lubionby the s.c. route was seen at local, macroscopic and histopathological examination.

At local examinations, animals dosed with the vehicle and progesteroneby the i.m. route for 7 days had slight local reaction such as haematoma or red induration of the muscle. A higher incidence of oedema was observed in animals dosed with Lubion. These signs were correlated with a local tissue necrosis and macrophage response at histopathological examination. Moderate fibrosis was associated with intramuscular administration of Lubionafter the seven day post-treatment observation period. However, none of the histological changes observed were marked or extensive.

A longer term study was performed with administration of Lubionat 1 mg/kg/day s.c. or at 4 mg/kg/day i.m. No toxicologically important clinical signs were recorded and the minor signs observed were generally similar to those receiving vehicle. Histopathological examination of the injection sites after 28 days of treatment identified minor changes these were generally similar to those animals receiving vehicle. After the post-treatment observation period (14 days) there were no changes associated with injection of Lubion.

Other preclinical studies have not revealed other effects than those which can be explained based on the known hormone profile of progesterone. However, it should be borne in mind that sex steroids such as progesterone can promote the growth of certain hormone-dependent tissues and tumours.

The active substance progesterone shows an environmental risk for the aquatic environment especially to fish.