"The U.S. Food and Drug Administration on Wednesday approved a request by Danco Laboratories to expand authorized use of its abortion pill Mifeprex (mifepristone), formerly known as RU-486, to 70 days of gestation from 49 days.
Mechanism of Action
The local mechanism by which continuously released LNG enhances contraceptive effectiveness of Skyla has not been conclusively demonstrated. Studies of Skyla and similar LNG IUS 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.
Skyla has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.
In clinical trials with Skyla, ovulation was observed in the majority of a subset of subjects studied. Evidence of ovulation was seen in 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 27 women in the third year.
Low doses of LNG are administered into the uterine cavity with the Skyla intrauterine delivery system. The in vivo release rate is approximately 14 mcg/day after 24 days and is reduced to approximately 10 mcg/day after 60 days and then decreases progressively to approximately 5 mcg/day after three years. The average LNG in vivo release rate is approximately 6 mcg/day over the period of three years.
In a subset of 7 subjects, maximum observed serum LNG concentration was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, LNG serum concentration decreased after long-term use of 12, 24, and 36 months to concentrations of 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader data base ( > 1000 patients) showed similar concentration data of 168 ± 46 pg/mL at 7 days after placement. Thereafter, LNG serum concentrations decline slowly to a value 61 ± 19 pg/mL after 3 years.
The apparent volume of distribution of LNG is reported to be approximately 1.8 L/kg. Levonorgestrel is bound non-specifically to serum albumin and specifically to sex hormone binding globulin (SHBG). Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentration) or a decrease (at lower SHBG concentration) of the total LNG concentration in serum. In a subset of 7 subjects, the concentration of SHBG declined by a mean value of 18% within 2 weeks after insertion of Skyla and remains relatively stable over the 3 year period of use. Thereafter, plateau-like SHBG concentrations were observed. Less than 2 % of the circulating LNG is present as free steroid.
Following absorption, LNG 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-tetrahydroLNG are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. LNG 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 LNG concentrations seen in individuals using LNG–containing contraceptive products. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4.
About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of LNG after parenteral administration is approximately 20 hours.
Pediatric: Safety and efficacy of Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated.
Geriatric: Skyla 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 Skyla.
Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla.
Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Skyla.
No drug-drug interaction studies were conducted with Skyla [see DRUG INTERACTIONS].
Clinical Trials on Contraception
The contraceptive efficacy of Skyla was demonstrated in a clinical trial that enrolled generally healthy women aged 18– 35, 1,432 of whom received Skyla. The Skyla arm included 38.8 % (556) nulliparous women. The trial was a multicenter, multi-national, randomized open label study conducted in 11 countries in Europe, Latin America, the US and Canada. Women less than six weeks postpartum, with a history of ectopic pregnancy, with clinically significant ovarian cysts or with HIV or otherwise at high risk for sexually transmitted infections were excluded. For Skyla-treated women, 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographic of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black (5.2%), Asian (0.8%), and Other (2.7%). The weight range for treated women was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m² (range 16–55 kg/m² ). Of Skyla-treated women, 21.9% discontinued the study treatment due to an adverse event, 4.4% were lost to follow up, 1.8% withdrew their consent, 13.0% discontinued due to other reason, 1.1% discontinued due to protocol deviation, and 0.6% discontinued due to pregnancy.
The pregnancy rate calculated as the Pearl Index (PI) in women aged 18–35 years was the primary efficacy endpoint used to assess contraceptive reliability. The PI was calculated based on 28-day equivalent exposure cycles; evaluable cycles excluded those in which back-up contraception was used unless a pregnancy occurred in that cycle. Skyla-treated women provided 15,763 evaluable 28-day cycle equivalents in the first year and 39,368 evaluable cycles over the three year treatment period. The PI estimate for the first year of use based on the 5 pregnancies that occurred after the onset of treatment and within 7 days after Skyla removal or expulsion was 0.41 with a 95% upper confidence limit of 0.96. The cumulative 3-year pregnancy rate, based on 10 pregnancies, estimated by the Kaplan-Meier method was 0.9 per 100 women or 0.9%, with a 95% upper confidence limit of 1.7%.
About 77% of women wishing to become pregnant conceived within 12 months after removal of Skyla.
2 Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of LNG in women using a LNG-releasing IUD. Clinical Endocrinol 1982; 17:529-536.
Last reviewed on RxList: 10/10/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Skyla Information
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