Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2020 Publisher: Bayer New Zealand Limited, P O Box 2825, Shortland Street, Auckland 1140, New Zealand Free phone 0800 233 988 www.bayer.co.nz
The active ingredient in JADELLE implants, levonorgestrel, is a synthetic progestogen. Levonorgestrel released from JADELLE has been shown to affect ovarian function in various ways, ranging from absence of follicular and luteal activity through normal follicular activity but deficient luteal activity to normal ovulatory patterns. Levonorgestrel causes thickening of the cervical mucus, thus preventing passage of spermatozoa into the uterus. It also suppresses the endometrium and may prevent implantation of the blastocyst.
The contraceptive efficacy of JADELLE was studied in multicentre trials involving 1393 women observed for 4657 woman-years. The Pearl Index during five years was 0.17 per 100 woman-years. The annual pregnancy rate per 100 users was 0.1 at one, two and three years, 0.00 at four years, and 0.8 at five years. In all women with body weight 60 kg or more the annual pregnancy rates per 100 users were 0.2 during year 1, 0.2 during year 2, 0.3 during year 3, 0.0 during year 4 and 1.1 during year 5.
After removal of the implants, women return quickly to their normal fertility. When women had JADELLE implants removed for planned pregnancy, 45% became pregnant within 3 months and 86% within a year.
The efficacy of JADELLE does not depend on patient compliance.
The only active ingredient in JADELLE is levonorgestrel, a progestogen. The implants are inserted subdermally, and they have been shown to provide effective contraception over the intended five years lifetime of the product.
Levonorgestrel is released from the implants directly into tissue fluid. Maximum serum levonorgestrel concentrations of approximately 772 pg/mL are reached 48 hours after insertion. After the initial phase, levonorgestrel concentrations decline to 435 pg/mL within one month, 355 pg/mL within six months, 341 pg/mL within one year, and 277 pg/mL within five years.
Serum levonorgestrel concentrations are inversely related to body weight. The difference is approximately 2-fold between women weighing 50 and 70 kg. However, due to the great variation in serum levonorgestrel concentrations and in individual response, serum concentrations alone are not predictive of the risk of pregnancy in an individual woman. In JADELLE implant users, serum levonorgestrel concentrations are substantially below those observed in women taking oral contraceptives containing levonorgestrel.
In serum, levonorgestrel is mainly bound to sex hormone binding globulin (SHBG). Levonorgestrel lowers SHBG concentrations within a few days, reducing the total serum levonorgestrel concentrations.
Levonorgestrel is extensively metabolised. The most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for levonorgestrel compared to reduction and conjugation.
There is wide interindividual variation in the metabolic clearance rate. This is believed to be the reason for the wide variation in serum levonorgestrel levels in various users. The elimination half-life of levonorgestrel is 13 to 18 hours. Levonorgestrel and its metabolites are primarily excreted in the urine (40 to 68%) and partly in faeces (16 to 48%). After removal of the implants, serum levonorgestrel concentrations decrease below the detection limit within 5 to 14 days.
The toxicity profile of levonorgestrel is well-established and reveals no particular human health risks beyond those discussed in the Data Sheet.
Mutagenicity and biocompatibility testing gave no indication of genotoxicity or unacceptable local tolerance of levonorgestrel or the non-active polymeric components of JADELLE.
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