CLINICAL PHARMACOLOGY
Levonorgestrel is a progestogen used in a variety of contraceptive products. Low doses of levonorgestrel can be administered into the uterine cavity with the Mirena intrauterine delivery system. Initially, levonorgestrel is released at a rate of approximately 20 μg/day. This rate decreases progressively to half that value after 5 years.
Mirena has mainly local progestogenic effects in the uterine cavity. Morphological changes of the endometrium are observed, including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.
Ovulation is inhibited in some women using Mirena. In a 1-year study approximately 45% of menstrual cycles were ovulatory and in another study after 4 years 75% of cycles were ovulatory.
The local mechanism by which continuously released levonorgestrel enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.
Clinical Pharmacokinetics
Following insertion of Mirena, the initial release of levonorgestrel into the uterine cavity is 20 μg/day. A stable plasma level of levonorgestrel of 150-200 pg/mL occurs after the first few weeks following insertion of Mirena. Levonorgestrel levels after long-term use of 12, 24, and 60 months were 180±66 pg/mL, 192±140 pg/mL, and 159±59 pg/mL, respectively. The plasma concentrations achieved by Mirena are lower than those seen with levonorgestrel contraceptive implants and with oral contraceptives. Unlike oral contraceptives, plasma levels with Mirena do not display peaks and troughs.
The mean ± SD levonorgestrel endometrial tissue concentration in four women using levonorgestrel intrauterine systems releasing 30 μg/day of levonorgestrel for 36-49 days was 808 ± 511 ng/g wet tissue weight. The endometrial tissue concentration in 2 women who had been taking a 250 μg levonorgestrel–containing oral contraceptive for 7 days was 3.5 ng/g wet tissue weight. In contrast, fallopian tube and myometrial levonorgestrel tissue concentrations were of the same order of magnitude in the Mirena group and the oral contraceptive group (between 1 and 5 ng/g of wet weight of tissue).
The pharmacokinetics of levonorgestrel itself have been extensively studied and reported in the literature. Levonorgestrel in serum is primarily bound to proteins (mainly sex hormone binding globulin) and is extensively metabolized to a large number of inactive metabolites. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in levonorgestrel concentrations seen in individuals using levonorgestrel–containing contraceptive products. The elimination half-life of levonorgestrel after daily oral doses is approximately 17 hours; both the parent drug and its metabolites are primarily excreted in the urine.
Pharmacokinetic studies of this product have not been conducted in special populations (pediatric, renal insufficiency, hepatic insufficiency, and different ethnic groups).
Drug-Drug Interactions
The effect of other drugs on the efficacy of Mirena has not been studied.
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