"Today, the U.S. Food and Drug Administration announced it has approved the use of Plan B One-Step (levonorgestrel) as a nonprescription product for all women of child-bearing potential. This action complies with the April 5, 2013 order of the Uni"...
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Mechanism of Action
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.
Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of levonorgestrel1 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.
Low doses of levonorgestrel are administered into the uterine cavity with the Mirena intrauterine delivery system. Initially, levonorgestrel is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years. A stable serum concentration, without peaks and troughs, of levonorgestrel of 150–200 pg/mL occurs after the first few weeks following insertion of Mirena. Levonorgestrel concentrations 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 apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β- tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. 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.
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of levonorgestrel after daily oral doses is approximately 17 hours.
Pediatric: Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated.
Geriatric: Mirena has not been studied in women over age 65 and is not currently approved for use in this population.
Race: No studies have evaluated the effect of race on pharmacokinetics of Mirena.
Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Mirena.
Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mirena.
No drug-drug interaction studies were conducted with Mirena [see DRUG INTERACTIONS].
Clinical Trials on Intrauterine Contraception
Mirena has been studied for safety and efficacy in two large clinical trials in Finland and Sweden. In study sites having verifiable data and informed consent, 1,169 women 18 to 35 years of age at enrollment used Mirena for up to 5 years, for a total of 45,000 women-months of exposure. Subjects had previously been pregnant, had no history of ectopic pregnancy, had no history of pelvic inflammatory disease over the preceding 12 months, were predominantly Caucasian, and over 70% of the participants had previously used IUDs (intrauterine devices). The reported 12-month pregnancy rates were less than or equal to 0.2 per 100 women (0.2%) and the cumulative 5-year pregnancy rate was approximately 0.7 per 100 women (0.7%).
About 80% of women wishing to become pregnant conceived within 12 months after removal of Mirena.
Clinical Trial on Heavy Menstrual Bleeding
The efficacy of Mirena in the treatment of heavy menstrual bleeding was studied in a randomized, open-label, active-control, parallel-group trial comparing Mirena (n=79) to an approved therapy, medroxyprogesterone acetate (MPA) (n=81), over 6 cycles. The subjects included reproductive-aged women in good health, with no contraindications to the drug products and with confirmed heavy menstrual bleeding ( ≥ 80 mL menstrual blood loss [MBL]) determined using the alkaline hematin method. Excluded were women with organic or systemic conditions that may cause heavy uterine bleeding (except small fibroids, with total volume not > 5 mL). Treatment with Mirena showed a statistically significantly greater reduction in MBL (see Figure 10) and a statistically significantly greater number of subjects with successful treatment (see Figure 11). Successful treatment was defined as proportion of subjects with (1) end-of-study MBL < 80 mL and (2) a ≥ 50% decrease in MBL from baseline to end-of-study.
Figure 10: Median Menstrual Blood Loss (MBL) by Time
Figure 11: Proportion of Subjects with Successful
1Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue Concentrations of Levonorgestrel in Women Using a Levonorgestrel-releasing IUD. Clinical Endocrinol 1982;17:529-536. NDA 21225 Mirena LNG IUS 11 Feb 13 21
Last reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.
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