Kyleena (Page 7 of 10)

7 DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with Kyleena.

Drugs or herbal products that induce or inhibit LNG metabolizing enzymes, including CYP3A4, may decrease or increase, respectively, the serum concentrations of LNG during the use of Kyleena. However, the contraceptive effect of Kyleena is mediated via the direct release of LNG into the uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The use of Kyleena is contraindicated in pregnancy or with a suspected and Kyleena may cause adverse pregnancy outcomes [see Contraindications (4), Warnings and Precautions (5.1, 5.2)]. If a woman becomes pregnant with Kyleena in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Kyleena, if possible, if pregnancy occurs in a woman using Kyleena. If Kyleena cannot be removed, follow the pregnancy closely [see Warnings and Precautions (5.1, 5.2)].

There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. Animal reproduction studies have not been conducted with Kyleena.

8.2 Lactation

Risk Summary

Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs, resulting in exposure of LNG to the breastfed infants. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Isolated cases of decreased milk production have been reported with a LNG-releasing IUS. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kyleena and any potential adverse effects on the breastfed child from Kyleena or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Return to Fertility After Discontinuing Kyleena

About 71% of 163 women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Kyleena.

8.4 Pediatric Use

Safety and efficacy of Kyleena have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use

Kyleena has not been studied in women over age 65 and is not approved for use in this population.

11 DESCRIPTION

Kyleena (levonorgestrel-releasing intrauterine system) contains 19.5 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately17.5 mcg/day of LNG after 24 days.

Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Kyleena, has a molecular weight of 312.4, a molecular formula of C21 H28 O2 , and the following structural formula:

Chem Diagram
(click image for full-size original)

11.1 Kyleena

Kyleena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The white T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. The reservoir consists of a whitish or pale yellow cylinder, made of a mixture of LNG and silicone (polydimethylsiloxane), containing a total of 19.5 mg LNG. The reservoir is covered by a semi-opaque silicone membrane, composed of polydimethylsiloxane and colloidal silica. A ring composed of 99.95% pure silver is located at the top of the vertical stem close to the horizontal arms and is visible by ultrasound. The polyethylene of the T-body is compounded with barium sulfate, which makes it radiopaque. A monofilament blue polypropylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polypropylene of the removal thread contains <0.5% phthalocyaninato(2-) copper as a colorant (see Figure 10).

The components of Kyleena, including its packaging, are not manufactured using natural rubber latex.

Kyleena
(click image for full-size original)

Figure 10. Kyleena

11.2 Inserter

Kyleena is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Kyleena into the uterine cavity, consists of a symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The outer diameter of the insertion tube is 3.8 mm. The vertical stem of Kyleena is loaded in the insertion tube at the tip of the inserter. The arms are pre-aligned in the horizontal position. The removal threads are contained within the insertion tube and handle. Once Kyleena has been placed, the inserter is discarded.

Inserter
(click image for full-size original)

Figure 11. Diagram of Inserter

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Kyleena has not been conclusively demonstrated. Studies of Kyleena 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.

12.2 Pharmacodynamics

Kyleena has mainly local progestogenic effects in the uterine cavity. The local concentrations of LNG lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.

In clinical trials with Kyleena, ovulation was assessed based on serum progesterone values >2.5 ng/mL in one study and serum progesterone values >2.5 ng/mL together with serum estradiol levels <27.24 pg/mL in another study. Evidence of ovulation by these criteria was seen in 23 out of 26 women in the first year, in 19 out of 20 women in the second year, and in all 16 women in the third year. In the fourth year, evidence of ovulation was observed in the one woman remaining in the subset and in the fifth year, no women remained in this subset.

12.3 Pharmacokinetics

Absorption

Low doses of LNG are administered into the uterine cavity with the Kyleena intrauterine delivery system. The in vivo release rate is approximately 17.5 mcg/day after 24 days and is reduced to approximately 15.3 mcg/day after 60 days and to 9.8 mcg/day after 1 year. It then declines progressively to approximately 7.9 mcg/day after 3 years and 7.4 mcg/day after 5 years. The average LNG in vivo release rate is approximately 12.6 mcg/day over the first year and 9.0 mcg/day over the period of 5 years.

In a subset of 6 subjects, the maximum observed serum LNG concentration (mean ±SD) was 302 ± 170 pg/mL, reached after 7.5 days (median) of Kyleena insertion. Thereafter, the LNG serum concentrations (mean ±SD) at Year 1, 2, 3, 4 and 5 were 199 ± 171 pg/mL (N=6), 120 ± 57 pg/mL (N=6), 122 ± 65 pg/mL (N=6), 79 ± 12 pg/mL (N=3) and 65 ± 15 pg/mL (N=3), respectively. A population pharmacokinetic evaluation based on a broader database (>1000 patients) showed a similar declining concentration profile, with 175 ± 74 pg/mL at 7 days after placement, 125 ± 50 pg/mL at 1 year, 99 ± 41 pg/mL after 3 years, and 90 ± 35 pg/mL after 5 years.

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