NORISTERAT Solution for injection Ref.[50750] Active ingredients: Norethisterone

Absorption

Norethisterone enantate was completely absorbed after intramuscular injection. The ester was quickly and eventually completely hydrolyzed to its pharmacologically active compound norethisterone once it was released from the depot.

Distribution

Maximum levels of norethisterone were measured about 3-20 days after i.m. administration. They amounted on average to 13.4 ± 5.4 ng/ml and 12.2 ± 2.7 ng/ml about 7 days (median) after i.m. administration of 200 mg norethisterone enantate in 2 ml and 1 ml oily solution, respectively.

Plasma levels of norethisterone declined in two disposition phases with half-lives of 4-5 days and 15-20 days, respectively, which were due to a biphasical release of norethisterone enantate from the depot.

Biotransformation

Norethisterone enantate is metabolised completely. Norethisterone enantate is split mainly in the liver by enzymatic hydrolysis into norethisterone and heptanoic acid.

While the fatty acid is metabolised by means of (β-oxidation, norethisterone is transformed mainly through the reduction of the C4 -C5 double bond and the C3 keto group. The majority of metabolites found in urine were present as conjugates, mainly as sulfates, which are expected to be inactive.

Norethisterone is partly metabolised to ethinylestradiol (EE) after intramuscular administration in humans. This conversion results in a systemic EE exposure corresponding to an oral equivalent dose of about 4 µg EE per day, on average, over 8 weeks. Mean oral equivalent doses per day are about 10 µg EE during the first 2 weeks after Noristerat administration and decline to about 5 µg EE in the 3rd week and about 2 µg EE from the 5th week onwards. Therefore systemic estrogen effects cannot be excluded. The C_max of EE after i.m. administration of 200 mg NETE was significantly lower than after oral administration of 0.03 mg EE/0.15 mg LNG once daily for 21 days (approximately 68% lower). Post-marketing experience with Noristerat indicates that the safety profile of Noristerat does not resemble that of combined hormonal contraceptives.

Elimination

Up to 85% of the norethisterone enantate dose were excreted within 30 days in urine (40%) and faeces (60%). No unchanged norethisterone enantate was recovered in urine or faeces. In urine and faeces, similar excretion half-lives of 6-9 days were estimated for radioactive labelled substances during the observation period of 30 days and – in a further study – an excretion half-life of 20-30 days was measured in urine between day 30 and 80 after i.m. administration of 200 mg 3H-norethisteteroneenantate. Based on animal studies, retention of the drug in the body is not to be expected.

In plasma of women, 96% of norethisterone are bound to proteins. The respective percentages bound to SHBG and albumin are approximately 35% and 61% as long as SHBG levels are within the normal range.

Due to the half-life of the terminal disposition phase from plasma (about 2.5 weeks) and the initial dose regimen (one injection every 2 months), a slight accumulation of the drug will be expected after multiple administrations. A steady state will already be reached after the second administration.

Transfer of norethisterone into mother’s milk was negligible. During the first week after i.m. injection of 200 mg norethisterone enantate, a daily intake of norethisterone with mother’s milk in the range of 0.5 μg to 2.4 μg was calculated from norethisterone concentrates in the milk, assuming that the infant ingests 600 ml milk daily.

Linearity/non-linearity

Although there is no direct investigation on bioavailability of norethisterone after i.m. administration of norethisterone enantate reported, complete availability can be estimated by comparison of norethisterone AUC values determined in different studies after i.v. injection of norethisterone and after i.m. injection of norethisterone enantate.

Non-clinical data reveal no special risk for humans based on studies of repeated dose toxicity, genotoxicity, carcinogenicity and toxicity to reproduction which is not already included in other relevant sections.

Besides the studies with the active ingredient norethisterone enantate, data recorded for norethisterone and norethisterone acetate were also taken into consideration for the toxicological evaluation of the risk from use of Noristerat.

In animal studies on systemic tolerance with repeated administration (including studies for evaluation of a tumorigenic activity), no systemic intolerance reactions were observed which would raise objections to the use of the preparation in dosages required for contraception.

On principle, however, it should be kept in mind that sex steroids might stimulate the growth of hormone-dependent tissues and tumours.

In reproduction toxicological studies no indication of a teratogenic potential was noted. This is in accordance with reports on clinical experience after accidental administration of Noristerat during pregnancy or on the rare cases of pregnancies occurring during use of Noristerat, where no indication of a teratogenic potential was noted.

Local tolerance was assessed in the course of systemic tolerance studies and indicated only a mild irritant potential of the drug substance. The good local tolerance has been confirmed by long-term clinical experience.

Experimental investigations into possible sensitising effects of norethisterone enantate have not been carried out.

In vitro studies for evaluation of genotoxicity did not indicate that norethisterone or its esters possess a mutagenic potential.