CLINICAL PHARMACOLOGY
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.
Pharmacodynamics
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.
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.
Pharmacokinetics
Absorption
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.
Distribution
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.
Metabolism
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.
Excretion
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.
Specific Populations
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.
Drug-Drug Interactions
No drug-drug interaction studies were conducted with Mirena [see Drug Interactions (7)].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
Long-term studies in animals to assess the carcinogenic potential of levonorgestrel releasing intrauterine system have not been performed. There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorigenicity following parenteral administration of levonorgestrel to rats for 2 years at approximately 5 mcg/day, or following oral administration to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 mcg/kg/day. In another 7 year dog study, oral administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies. The nonclinical doses above are respectively 16, 200, 240 and 810 times the release rate of levonorgestrel by Mirena (20 mcg/day), based on body surface area [see Warnings and Precautions ].
Mutagenicity
Levonorgestrel was not found to be genotoxic in the Ames assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.
Impairment of Fertility
There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.
Animal Toxicology and/or Pharmacology
Carcinogenicity
Long-term studies in animals to assess the carcinogenic potential of levonorgestrel releasing intrauterine system have not been performed. There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorigenicity following parenteral administration of levonorgestrel to rats for 2 years at approximately 5 mcg/day, or following oral administration to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 mcg/kg/day. In another 7 year dog study, oral administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies. The nonclinical doses above are respectively 16, 200, 240 and 810 times the release rate of levonorgestrel by Mirena (20 mcg/day), based on body surface area [see Warnings and Precautions].
Mutagenicity
Levonorgestrel was not found to be genotoxic in the Ames assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.
Impairment of Fertility
There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.
|