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Skyla (levonorgestrel-releasing intrauterine system) contains 13.5 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately14 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 Skyla, has a molecular weight of 312.4, a molecular formula of C21H28O2, and the following structural formula:
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Skyla 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 13.5 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 brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polyethylene of the removal thread contains iron oxide as a colorant (see Figure 10).
The components of Skyla, including its packaging, are not manufactured using natural rubber latex.
Figure 10: Skyla
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Skyla is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Skyla 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 Skyla 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 Skyla has been placed, the inserter is discarded.
Figure 11: Diagram of Inserter
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Skyla® is indicated to prevent pregnancy for up to 3 years. Replace the system after 3 years if continued use is desired.
Skyla contains 13.5 mg of levonorgestrel (LNG) released in vivo at a rate of approximately 14 mcg/day after 24 days. This rate decreases progressively to approximately 6 mcg/day after 1 year and to 5 mcg/day after 3 years. The average in vivo release rate of LNG is approximately 8 mcg/day over the first year of use and 6 mcg/day over a period of 3 years. [See CLINICAL PHARMACOLOGY]
Skyla must be removed by the end of the third year and can be replaced at the time of removal with a new Skyla if continued contraceptive protection is desired.
Skyla can be physically distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the brown color of the removal threads.
Skyla is supplied in a sterile package within an inserter that enables single-handed loading (see Figure 1). Do not open the package until required for insertion [see DESCRIPTION]. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see WARNINGS AND PRECAUTIONS].
Skyla and Inserter
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Table 1: When to Insert Skyla
| Starting Skyla in women not currently using hormonal or intrauterine contraception |
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| Switching to Skyla from an oral, transdermal or vaginal hormonal contraceptive |
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| Switching to Skyla from an injectable progestin contraceptive |
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| Switching to Skyla from a contraceptive implant or another IUS |
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| Inserting Skyla after first-trimester abortion or miscarriage |
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| Inserting Skyla after childbirth or second-trimester abortion or miscarriage | |
| Immediate insertion after childbirth or second-trimester abortion or miscarriage |
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| Interval insertion following complete involution of the uterus |
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Tools For Insertion
Note: The inserter provided with Skyla (see Figure 1) and the Insertion Procedure described in this section are not applicable for immediate insertion after childbirth or second-trimester abortion or miscarriage. For immediate insertion, remove Skyla from the inserter by first loading (see Figure 2) and then releasing (see Figure 7) Skyla from the inserter, and insert according to accepted practice.
Preparation For Insertion
Insertion Procedure
Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Skyla. Ensure use of aseptic technique throughout the entire procedure.
Figure 1: Opening the Skyla Package
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Using sterile gloves, lift the handle of the sterile inserter and remove from the sterile package.
Figure 2: Move slider all the way to the forward position to load Skyla
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Figure 3: Setting the flange
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Figure 4: Advancing insertion tube until flange is 1.5 to 2 cm from the cervix
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Do not force the inserter. If necessary, dilate the cervical canal.
Figure 5: Move the slider back to the mark to release and open the arms
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Advance the inserter gently towards the fundus of the uterus until the flange touches the cervix. If you encounter fundal resistance do not continue to advance. Skyla is now in the fundal position (Figure 6). Fundal positioning of Skyla is important to prevent expulsion.
Figure 6: Move Skyla into the fundal position
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Holding the entire inserter firmly in place, release Skyla by moving the slider all the way down (Figure 7).
Figure 7: Move the slider all the way down to release Skyla from the insertion tube
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Figure 8: Cutting the threads
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Skyla insertion is now complete. Prescribe analgesics, if indicated. Record the Skyla lot number in the patient records.
Important Information To Consider During Or After Insertion
Tools For Removal
Preparation
Procedure
Removal Procedure
Figure 9: Removal of Skyla
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Skyla is a LNG-releasing IUS (a type of intrauterine device, or IUD) consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 13.5 mg LNG.
Skyla (levonorgestrel-releasing intrauterine system), containing a total of 13.5 mg LNG, is available in a carton of one sterile unit. NDC# 50419-422-01
Skyla is supplied sterile. Skyla is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the inner package is damaged or open. Insert before the end of the month shown on the label.
Store at 25°C (77°F); with excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room Temperature].
Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: Mar 2023
The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data described below reflect exposure to Skyla in 1,672 patients in two contraception studies, including 1,383 exposed for one year and 993 who completed the three year studies. The population was generally healthy, 18 to 40-year old females requesting contraception and predominately Caucasian (82.6%). The data cover more than 40,000 cycles of exposure. The frequencies of reported adverse drug reactions represent crude incidences.
Most common adverse reactions (occurring in ≥ 5% users) were increased bleeding (7.8%), vulvovaginitis (20.2%), abdominal/pelvic pain (18.9%), acne/seborrhea (15.0%), ovarian cyst (13.2%), headache (12.4%), dysmenorrhea (8.6%), breast pain/discomfort (8.6%) and nausea (5.5%).
In the contraception studies, 18% discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation (in >1% of users) were uterine bleeding complaints (4.6%), device expulsion (3.2%), acne/seborrhea (2.9%), abdominal pain (2.5%) dysmenorrhea/uterine spasms (2.0%) and pelvic pain (1.8%).
Other common adverse reactions (occurring in ≥1% users) by System Organ Class (SOC): The frequencies of adverse reactions observed in clinical trials are summarized in Table 4 by SOC (presented as crude incidences).
Table 4: Adverse reactions that occurred in at least 1% of Skyla users in clinical trials by SOC
| System Organ Class | Adverse Reaction | Incidence (%) (N=1,672) |
| Reproductive System and Breast Disorders | Vulvovaginitis | 20.2 |
| Ovarian cysta | 13.2 | |
| Dysmenorrhea | 8.6 | |
| Increased bleeding b | 7.8 | |
| Breast pain/discomfort | 5.3/3.3 | |
| Genital discharge | 4.2 | |
| Device expulsion (complete and partial) | 3.2 | |
| Upper genital tract infection | 1.4 | |
| Gastrointestinal Disorders | Abdominal pain/pelvic pain | 12.7/6.2 |
| Nausea | 5.5 | |
| Skin and Subcutaneous Tissue Disorders | Acne/Seborrhea | 13.6/1.4 |
| Alopecia | 1.2 | |
| Nervous System Disorders | Headache | 12.4 |
| Migraine | 2.3 | |
| Psychiatric Disorders | Depression/Depressed mood | 3.8/0.5 |
| a Ovarian cysts were reported as adverse events if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination b Not all bleeding alterations were captured as adverse reactions [see WARNINGS AND PRECAUTIONS]. |
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The following adverse reactions have been identified during post approval use of LNG-releasing IUSs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Assessment Of Perforation And Expulsion of Intrauterine Devices (APEX IUD) Study
APEX IUD was a large US retrospective cohort study to assess the impact of breastfeeding and timing of postpartum IUD insertion on uterine perforation and IUD expulsion. The analyses included a total of 326,658 insertions, 30% (97,824 insertions) of which were performed in women with a delivery in the previous 12 months. For insertions performed in women who had delivered ≤ 52 weeks before IUD insertion, the majority of postpartum insertions, 57.3% (56,047 insertions) occurred between 6 and 14 weeks postpartum. Breastfeeding data were available in 94,817 insertions performed in women 52 weeks or less after delivery.
The study results indicated that the risk of uterine perforation was highest in women with IUD insertion ≤ 6 weeks postpartum. Immediate postpartum insertion (0-3 days) findings are limited due to the relatively small number of insertions occurring within this time interval. Women who were breastfeeding at the time of insertion were at 33% higher risk of perforation (adjusted hazard ratio [HR]=1.33, 95% confidence interval [CI]: 1.07-1.64) compared to women who were not breastfeeding at the time of insertion. Progressively lower risk of uterine perforation was observed in postpartum time windows beyond 6 weeks, in both breastfeeding and not breastfeeding women. Table 5 presents the uterine perforation rates for LNG IUS stratified by breastfeeding status and postpartum interval.
Table 5: Uterine Perforation1 rates for LNG IUS, by Breastfeeding Status and Postpartum Interval
| Postpartum interval at time of insertion | Breastfeeding at time of insertion | Not breastfeeding at time of insertion | ||
| Number of events/ insertions | Uterine perforation rate per 1,000 insertions | Number of events/ insertions | Uterine perforation rate per 1,000 insertions | |
| 0 to 3 days | 8/1,896 | 4.22 | 0/277 | 0.00 |
| 4 days to ≤ 6 weeks | 120/10,735 | 11.18 | 28/2,377 | 11.78 |
| > 6 to ≤ 14 weeks | 268/29,677 | 9.03 | 80/12,011 | 6.66 |
| > 14 to ≤ 52 weeks | 43/6,139 | 7.00 | 22/9,089 | 2.42 |
| > 52 weeks or no delivery | no data available | 243/184,733 | 1.32 | |
| 1Uterine perforation includes both complete and partial perforation | ||||
Risk of expulsion was variable over the postpartum intervals through 52 weeks. Women who were breastfeeding were at 28% lower risk of IUD expulsion (adjusted HR=0.72, 95% CI: 0.64-0.80) compared to women who were not breastfeeding at time of insertion. Table 6 presents the IUD expulsion rates for LNG IUS stratified by breastfeeding status and postpartum interval.
Table 6: Expulsion1 Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval
| Postpartum interval at time of insertion | Breastfeeding at time of insertion | Not breastfeeding at time of insertion | ||
| Number of events/ insertions | Expulsion rate per 1,000 insertions | Number of events/ insertions | Expulsion rate per 1,000 insertions | |
| 0 to 3 days | 187/1,896 | 98.63 | 12/277 | 43.32 |
| 4 days to ≤ 6 weeks | 185/10,735 | 17.23 | 52/2,377 | 21.88 |
| > 6 to ≤ 14 weeks | 421/29,677 | 14.19 | 306/12,011 | 25.48 |
| > 14 to ≤ 52 weeks | 120/6,139 | 19.55 | 273/9,089 | 30.04 |
| > 52 weeks or no delivery | no data available | 5,481/184,733 | 29.67 | |
| 1Expulsion includes both complete and partial expulsion | ||||
No drug-drug interaction studies have been conducted with Skyla.
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 Skyla. However, the contraceptive effect of Skyla 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.
Included as part of the PRECAUTIONS section.
Evaluate women for ectopic pregnancy if they become pregnant with Skyla in place because the likelihood of a pregnancy being ectopic is increased with Skyla. Approximately one-half of pregnancies that occur with Skyla in place are likely to be ectopic. Also consider the possibility of ectopic pregnancy in the case of lower abdominal pain, especially in association with missed menses or if an amenorrheic woman starts bleeding.
The incidence of ectopic pregnancy in clinical trials with Skyla, which excluded women with a history of ectopic pregnancy, was approximately 0.1% per year. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Skyla is unknown. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility.
If pregnancy occurs while using Skyla, remove Skyla because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Skyla or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Skyla, consider the following:
In patients becoming pregnant with an IUS in place, septic abortion—with septicemia, septic shock, and death—may occur.
If a woman becomes pregnant with Skyla in place and if Skyla cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Skyla increases the risk of miscarriage, sepsis, premature labor and premature delivery. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place [see Use In Specific Populations]. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy.
Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of a LNG-releasing IUS. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Skyla is essential in order to minimize serious infections such as GAS.
Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Skyla in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment.
Skyla is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy [see CONTRAINDICATIONS]. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, PID was observed in 0.4% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Skyla.
Women At Increased Risk For PID
PID is often associated with a sexually transmitted infection (STI), and Skyla does not protect against STI. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for a recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], intravenous drug abuse).
Subclinical PID
PID may be asymptomatic but still result in tubal damage and its sequelae.
Treatment Of PID
Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained, and antibiotic therapy should be initiated promptly. Removal of Skyla after initiation of antibiotic therapy is usually appropriate.1
Actinomycosis has been associated with IUDs. Remove Skyla from symptomatic women and treat with antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Skyla removal and treatment. When possible, confirm a Pap smear diagnosis with cultures.
Perforation (total or partial, including penetration/embedment of Skyla in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was < 0.1%.
The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In a large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within ≤ 6 weeks postpartum, and also higher with breastfeeding at the time of insertion [see ADVERSE REACTIONS].
The risk of perforation may be increased if Skyla is inserted when the uterus is fixed, retroverted or not completely involuted.
If perforation occurs, locate and remove Skyla. Surgery may be required. Delayed detection or removal of Skyla in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera. In addition, perforation may reduce contraceptive efficacy and result in pregnancy.
Partial or complete expulsion of Skyla may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Skyla typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see WARNINGS AND PRECAUTIONS]. In clinical trials, a 3-year expulsion rate of 3.2% (54 out of 1,665 subjects) was reported.
The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In a large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see ADVERSE REACTIONS].
Remove a partially expelled Skyla. If expulsion has occurred, a new Skyla can be inserted any time the provider can be reasonably certain the woman is not pregnant.
Because the contraceptive effect of Skyla is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Skyla. Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 13.2% of women using Skyla, and 0.3% of subjects discontinued because of an ovarian cyst. Most ovarian cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required.
Skyla can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3–6 months of Skyla use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular.
In Skyla clinical trials, amenorrhea developed by the end of the first year of use in approximately 6% of Skyla users. A total of 77 subjects out of 1,672 (4.6%) discontinued due to uterine bleeding complaints. Table 2 shows the bleeding patterns as documented in the Skyla clinical trials based on 90-day reference periods. Table 3 shows the number of bleeding and spotting days based on 28-day cycle equivalents.
Table 2: Bleeding Patterns Reported with Skyla in Contraception Studies (by 90-day reference periods)
| Skyla | First 90 days N=1,531 |
Second 90 days N=1,475 |
End of year 1 N=1,329 |
End of year 3 N=903 |
| Amenorrhea1 | <1% | 3% | 6% | 12% |
| Infrequent bleeding2 | 8% | 19% | 20% | 22% |
| Frequent bleeding3 | 31% | 12% | 8% | 4% |
| Prolonged bleeding4 | 55% | 14% | 6% | 2% |
| Irregular bleeding5 | 39% | 25% | 18% | 15% |
| 1Defined as subjects with no bleeding/spotting throughout the 90-day reference period 2Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period. Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea) 5Defined as subjects with 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days. |
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Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent
| 28-day Cycle Equivalent | Cycle 1 N=1,588 |
Cycle 4 N=1,535 |
Cycle 7 N=1,468 |
Cycle 13 N=1,345 |
Cycle 39 N=781 |
| Days on treatment | 1-28 | 85-112 | 169-196 | 337-364 | 1065-1092 |
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | |
| Number of bleeding days | 7.3 (5.6) | 3.5 (3.4) | 2.8 (3.1) | 2.1 (2.7) | 1.4 (2.1) |
| Number of spotting days | 9.2 (6.1) | 4.8 (4.4) | 3.8 (3.6) | 3.3 (3.1) | 2.7 (2.7) |
If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology. Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain.
Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception, including Skyla, because some breast cancers are hormone-sensitive [see CONTRAINDICATIONS].
Spontaneous reports of breast cancer have been received during postmarketing experience with a LNG-releasing IUS. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk.
Use Skyla with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use:
In addition, consider removing Skyla if any of the following conditions arise during use:
If the threads are not visible or are significantly shortened, they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced (for example, expelled or perforated the uterus) [see WARNINGS AND PRECAUTIONS]. Exclude pregnancy and verify the location of Skyla, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Skyla is displaced, remove it. A new Skyla may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Skyla is in place with no evidence of perforation, no intervention is indicated.
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Non-clinical testing has demonstrated that Skyla is MR Conditional. A patient with Skyla can be safely scanned in an MR system meeting the following conditions:
Under the scan conditions defined above, the Skyla IUS is expected to produce a maximum temperature rise of less than 2°C after 15 minutes of continuous scanning.
In non-clinical testing, the image artifact caused by the IUS extended up to 5 mm from the IUS when imaged with a gradient echo pulse sequence and a 3.0 T MRI system.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)
[See WARNINGS AND PRECAUTIONS]
The use of Skyla is contraindicated in pregnancy or with a suspected pregnancy and Skyla may cause adverse pregnancy outcomes [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. If a woman becomes pregnant with Skyla in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Skyla, if possible, if pregnancy occurs in a woman using Skyla. If Skyla cannot be removed, follow the pregnancy closely [see WARNINGS AND PRECAUTIONS].
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 Skyla.
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 Skyla and any potential adverse effects on the breastfed child from Skyla or from the underlying maternal condition.
About 77% of women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Skyla.
Safety and efficacy of Skyla 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.
Skyla has not been studied in women over age 65 and is not approved for use in this population.
No Information provided
The use of Skyla is contraindicated when one or more of the following conditions exist:
The local mechanism by which continuously released LNG contributes to the 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 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 Skyla, 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 34 out of 35 women in the first year, in 26 out of 27 women in the second year, and in all 26 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 declines progressively to approximately 6 mcg/day after 1 year and 5 mcg/day after 3 years. The average LNG in vivo release rate is approximately 8 mcg/day over the first year of use and 6 mcg/day over the period of 3 years.
In a subset of 7 subjects, the maximum observed serum LNG concentration (mean ±SD) was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, the LNG serum concentrations (mean ±SD) at year 1, 2, and 3 were 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader database (>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. LNG 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 remained relatively stable over the 3 year period of use. Less than 2% of the circulating LNG is present as free steroid.
Following intravenous administration of 0.09 mg LNG to healthy volunteers, the total clearance of LNG is approximately 1 mL/min/kg and the elimination half-life is approximately 20 hours. 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.
Metabolism
Following absorption, LNG is extensively metabolized. The most important metabolic pathways are the reduction of the Δ4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. Significant amounts of conjugated and unconjugated 3α, 5β-are also present in serum, along with much smaller amounts of 3α, 5α tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative  metabolism of LNG.
Excretion
LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
Safety and efficacy of Skyla have been established in women of reproductive age. Use of this product before menarche is not indicated.
In a one-year phase 3 study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) using Skyla, the population pharmacokinetic analysis of 278 adolescents showed mean estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to prior data in adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie within the ranges estimated for adults.
Skyla has not been studied in women over age 65 and is not approved for use in this population.
A three-year phase 3 study in the Asian-Pacific region (93% Asian women, the majority of whom were Chinese, 7% other ethnicities) using Skyla was performed. The population pharmacokinetic analysis of the Asian (Chinese) population in this study showed that estimated LNG serum concentrations in Asian women were slightly higher (approximately 4 to 16%) than those in another phase 3 study which was performed in mainly Caucasian women (79.7%). This slightly higher exposure might be explained by the lower body weight of Asian women.
No studies were conducted to evaluate the effect of hepatic disease on the disposition of Skyla.
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].
The contraceptive efficacy of Skyla was evaluated in a clinical trial that enrolled generally healthy women aged 18–35, 1,432 of whom received Skyla. Of these, 38.8 % (556) were nulliparous women, and 819 women completed 3 years of use. 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. A total of 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographics of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black/African Americans (5.2%), Other (2.7%) and Asian (0.8%). The weight range was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m² (range 16– 55 kg/m²). The clinical trial had no upper or lower weight or BMI limit. 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 for unspecified reasons, 1.1% discontinued due to protocol deviation, 0.6% discontinued due to pregnancy, and 13.0% discontinued due to other reasons.
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%.
Skyla
(sky-lah)
(levonorgestrel-releasing intrauterine system)
Read this Patient Information carefully before you decide if Skyla is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in women’s health. If you have any questions about Skyla, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.
Skyla does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).
What is Skyla?
Skyla is a small, flexible plastic T-shaped system that slowly releases a progestin hormone called levonorgestrel (LNG) that is often used in birth control pills. Because Skyla releases LNG into your uterus, only small amounts of the hormone enter your blood. Skyla does not contain estrogen. Two thin threads are attached to the stem (lower end) of Skyla. The threads are the only part of Skyla you can feel when Skyla is in your uterus; however, unlike a tampon string, the threads do not extend outside your body.
Skyla Is Small And Flexible
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What if I need birth control for more than 3 years?
Skyla must be removed after 3 years. Your healthcare provider can place a new Skyla during the same office visit if you choose to continue using Skyla.
What if I want to stop using Skyla?
Skyla is intended for use up to 3 years, but you can stop using Skyla at any time by asking your healthcare provider to remove it. You could become pregnant as soon as Skyla is removed, so you should use another method of birth control if you do not want to become pregnant. Talk to your healthcare provider about the best birth control methods for you, because your new method may need to be started 7 days before Skyla is removed to prevent pregnancy.
What if I change my mind about birth control and want to become pregnant in less than 3 years?
Your healthcare provider can remove Skyla at any time. You may become pregnant as soon as Skyla is removed. About 3 out of 4 women who want to become pregnant will become pregnant sometime in the first year after Skyla is removed.
How does Skyla work?
Skyla may work in several ways including thickening cervical mucus, inhibiting sperm movement, reducing sperm survival, and thinning the lining of your uterus. It is not known exactly how these actions work together to prevent pregnancy.
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How well does Skyla work for contraception?
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
Skyla, an intrauterine device (IUD), also known as an intrauterine system (IUS), is in the box at the top of the chart.
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Who might use Skyla?
You might choose Skyla if you:
Do not use Skyla if you:
Before having Skyla placed, tell your healthcare provider about all of your medical conditions including if you:
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How is Skyla placed?
Skyla is placed by your healthcare provider during an in-office visit or immediately after giving birth.
First, your healthcare provider will examine your pelvis to find the exact position of your uterus. Your healthcare provider will then clean your vagina and cervix with an antiseptic solution and slide a slim plastic tube containing Skyla through the cervix into your uterus. Your healthcare provider will then remove the plastic tube and leave Skyla in your uterus. Your healthcare provider will cut the threads to the right length.
You may experience pain, bleeding or dizziness during and after placement. If your symptoms do not pass within 30 minutes after placement, Skyla may not have been placed correctly. Your healthcare provider will examine you to see if Skyla needs to be removed or replaced.
Should I check that Skyla is in place?
Yes, you should check that Skyla is in proper position by feeling the removal threads. It is a good habit to do this 1 time a month. Your healthcare provider should teach you how to check that Skyla is in place. First, wash your hands with soap and water. You can check by reaching up to the top of your vagina with clean fingers to feel the removal threads. Do not pull on the threads. If you feel more than just the threads or if you cannot feel the threads, Skyla may not be in the right position and may not prevent pregnancy. Avoid intercourse or use non-hormonal back-up birth control (such as condoms or spermicide) and ask your healthcare provider to check that Skyla is still in the right place.
How soon after placement of Skyla should I return to my healthcare provider?
Call your healthcare provider if you have any questions or concerns (see “When should I call my healthcare provider?”). Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 6 weeks after Skyla is placed to make sure that Skyla is in the right position.
Can I use tampons or menstrual cups with Skyla?
Yes, tampons or menstrual cups may be used with Skyla. Change tampons or menstrual cups with care to avoid pulling the threads of Skyla. If you think you may have pulled Skyla out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider.
What if I become pregnant while using Skyla?
Call your healthcare provider right away if you think you may be pregnant. If possible, also do a urine pregnancy test. If you get pregnant while using Skyla, you may have an ectopic pregnancy. This means that the pregnancy is not in the uterus. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy.
Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.
There are also risks if you get pregnant while using Skyla and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device (IUD). Because of this, your healthcare provider may try to remove Skyla, even though removing it may cause a miscarriage.
If Skyla cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancy and possible effects of the hormone on your unborn baby. If you continue your pregnancy, see your healthcare provider regularly. Call your healthcare provider right away if you get flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge, or fluid leaking from your vagina. These may be signs of infection.
How will Skyla change my periods?
For the first 3 to 6 months, your period may become irregular and the number of bleeding days may increase. You may also have frequent spotting or light bleeding. Some women have heavy bleeding during this time. You may also have cramping during the first few weeks. After you have used Skyla for a while, the number of bleeding and spotting days is likely to lessen. For some women, periods will stop altogether. When Skyla is removed, your menstrual periods should return.
Is it safe to breastfeed while using Skyla?
You may use Skyla when you are breastfeeding. Skyla is not likely to affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. The risk of Skyla going into the wall of the uterus (becoming embedded) or going through the wall of the uterus is increased if Skyla is inserted while you are breastfeeding.
Will Skyla interfere with sexual intercourse?
You and your partner should not feel Skyla during intercourse. Skyla is placed in the uterus, not in the vagina. Sometimes your partner may feel the threads. If this occurs, or if you or your partner experience pain during sex, talk with your healthcare provider.
Can I have an MRI with Skyla in place?
Skyla can be safely scanned with MRI only under specific conditions. Before you have an MRI, tell your healthcare provider that you have Skyla, an intrauterine device (IUD), in place.
What are the possible side effects of Skyla?
Skyla can cause serious side effects, including:
Common side effects of Skyla include:
Other common side effects include:
These are not all of the possible side effects with Skyla. For more information, ask your healthcare provider.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937.
After Skyla has been placed, when should I call my healthcare provider?
If Skyla is accidentally removed and you had vaginal intercourse within the preceding week, you may be at risk of pregnancy, and you should talk to a healthcare provider.
Call your healthcare provider if you have any concerns about Skyla. Be sure to call if you:
General advice about the safe and effective use of Skyla
Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Skyla that is written for healthcare professionals.
What are the ingredients in Skyla?
Active ingredient: levonorgestrel
Inactive ingredients: silicone, polyethylene, silver, silica, barium sulfate, iron oxide
This Patient Information has been approved by the U.S. Food and Drug Administration.
