Skyla Dailymed

1 Indications And Usage

Skyla^® is indicated to prevent pregnancy for up to 3 years.

Replace the system after 3 years if continued use is desired.


Skyla is a progestin-containing intrauterine system (IUS) indicated for prevention of pregnancy for up to 3 years. (1)

2 Dosage And Administration

• •Release rate of levonorgestrel (LNG) is 14 mcg/day after 24 days and declines to 5 mcg/day after 3 years; Skyla must be removed or replaced after 3 years. (2.1)
• •To be inserted by a trained healthcare provider using strict aseptic technique. Follow insertion instructions exactly as described. (2.2)
• •Patient should be re-examined and evaluated 4 to 6 weeks after insertion; then, yearly or more often if clinically indicated. (2.3)

2.1 Dosing Over Time

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 (12.3).]

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 ( 11.2)]. 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 (5.3)].

2.2. Insertion Instructions

• •Obtain a complete medical and social history to determine conditions that might influence the selection of a levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If indicated, perform a physical examination, and appropriate tests for any forms of genital or other sexually transmitted infections. [See Contraindications (4) and Warnings and Precautions (5.10).] Because irregular bleeding/spotting is common during the first months of Skyla use, exclude endometrial pathology (polyps or cancer) prior to the insertion of Skyla in women with persistent or uncharacteristic bleeding [see Warnings and Precautions (5.8)].
• •Follow the insertion instructions exactly as described to ensure proper placement and avoid premature release of Skyla from the inserter. Once released, Skyla cannot be re-loaded.
• •Skyla should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Skyla.
• •Insertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or with seizure, especially in patients with a predisposition to these conditions. Consider administering analgesics prior to insertion.

Insert Skyla any time there is reasonable certainty that the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications (4)].

If Skyla is inserted during the first seven days of the menstrual cycle or immediately after a first trimester abortion, back-up contraception is not needed.

If Skyla is not inserted during the first seven days of the menstrual cycle, a barrier method of contraception should be used, or the patient should abstain from vaginal intercourse for seven days to prevent pregnancy. Insert Skyla at any time, including during the hormone-free interval of the previous method.

If inserted during active use of the previous method, continue that method for 7 days after Skyla insertion or until the end of the current treatment cycle.

If the woman was using continuous hormonal contraception, discontinue that method seven days after Skyla insertion. Insert Skyla at any time; a non-hormonal back-up birth control (such as condoms or spermicide) should also be used for 7 days if Skyla is inserted more than 3 months (13 weeks) after the last injection. Insert Skyla on the same day the implant or IUS is removed.

Insert Skyla at any time during the menstrual cycle. Insert Skyla immediately after a first-trimester abortion or miscarriage, unless it is a septic abortion [see Contraindications (4)]. Immediate insertion after childbirth or second-trimester abortion or miscarriage Insert Skyla after removal of the placenta. Back-up contraception is not needed. [See Contraindications (4), Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)].

Wait a minimum of 6 weeks or until the uterus is fully involuted before inserting Skyla [see Warnings and Precautions (5.5, 5.6), Adverse Reactions (6.2)].

Insert Skyla any time there is reasonable certainty the woman is not pregnant.

If Skyla is not inserted during the first 7 days of the menstrual cycle, a back-up method of contraception should be used, or the woman should abstain from vaginal intercourse for 7 days to prevent pregnancy [see Contraindications (4), Warnings and Precautions (5.2)].

Table 1: When to Insert Skyla

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

Starting Skyla in women not currently using hormonal or intrauterine contraception
Switching to Skyla from an oral, transdermal or vaginal hormonal contraceptive
Switching to Skyla from an injectable progestin contraceptive
Switching to Skyla from a contraceptive implant or another IUS
Inserting Skyla after first trimester abortion or miscarriage
Inserting Skyla after childbirth or second-trimester abortion or miscarriage
Interval insertion following complete involution of the uterus

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.

• •Gloves
• •Speculum
• •Sterile uterine sound
• •Sterile tenaculum
• •Antiseptic solution, applicator

• •Sterile gloves
• •Skyla with inserter in sealed package
• •Instruments and anesthesia for paracervical block, if anticipated
• •Consider having an unopened back-up Skyla available
• •Sterile, sharp curved scissors

• •Exclude pregnancy and confirm that there are no other contraindications to the use of Skyla.
• •Check expiration date of Skyla prior to initiating insertion.
• •With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape and position of the uterus.
• •Gently insert a speculum to visualize the cervix.
• •Thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.
• •Prepare to sound the uterine cavity. Grasp the upper lip of the cervix with a tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform a paracervical block if needed. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. The tenaculum should remain in position and gentle traction on the cervix should be maintained throughout the insertion procedure.
• •Gently insert a uterine sound to check the patency of the cervix, measure the depth of the uterine cavity in centimeters, confirm cavity direction, and detect the presence of any uterine anomaly. If you encounter difficulty or cervical stenosis, use dilatation, and not force, to overcome resistance. If cervical dilatation is required, consider using a paracervical block.

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.

• •Open the package (Figure 1). The contents of the package are sterile.

Figure 1. Opening the Skyla Package

• •Using sterile gloves, lift the handle of the sterile inserter and remove from the sterile package.

• •Push the slider forward as far as possible in the direction of the arrow thereby moving the insertion tube over the Skyla T-body to load Skyla into the insertion tube (Figure 2). The tips of the arms will meet to form a rounded end that extends slightly beyond the insertion tube.

Figure 2. Move slider all the way to the forward position to load Skyla

• •Maintain forward pressure with your thumb or forefinger on the slider. DO NOT move the slider downward at this time as this may prematurely release the threads of Skyla. Once the slider is moved below the mark, Skyla cannot be re-loaded .

• •Holding the slider in this forward position, set the upper edge of the flange to correspond to the uterine depth (in centimeters) measured during sounding (Figure 3).

Figure 3. Setting the flange

• •Continue holding the slider in this forward position. Advance the inserter through the cervix until the flange is approximately 1.5–2 cm from the cervix and then pause (Figure 4).

Figure 4. Advancing insertion tube until flange is 1.5 to 2 cm from the cervix
Do not force the inserter. If necessary, dilate the cervical canal.

• •While holding the inserter steady, move the slider down to the mark to release the arms of Skyla (Figure 5). Wait 10 seconds for the horizontal arms to open completely.

Figure 5. Move the slider back to the mark to release and open the arms

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

• •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

• •Continue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus.
• • Using a sharp, curved scissor, cut the threads perpendicular, leaving about 3 cm visible outside of the cervix [cutting threads at an angle may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads when cutting to prevent displacing Skyla.

.
Figure 8. Cutting the threads

•  Skyla insertion is now complete. Prescribe analgesics, if indicated. Record the Skyla lot number in the patient records.

• •If you suspect that Skyla is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Skyla if it is not positioned completely within the uterus. Do not reinsert a removed Skyla.

If there is clinical concern, exceptional pain or bleeding during or after insertion, take appropriate steps (such as physical examination and ultrasound) immediately to exclude perforation.

2.3 Patient Follow-up

Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

2.4 Removal of Skyla

• •Skyla should not remain in the uterus after 3 years.
• •If pregnancy is not desired, remove Skyla during the first 7 days of the menstrual cycle, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle or the woman does not experience regular menses, she is at risk of pregnancy, start a new contraceptive method a week prior to removal for these women. [See Dosage and Administration (2.5).]

• •Gloves
• •Speculum

• •Sterile forceps

• •Remove Skyla by applying gentle traction on the threads with forceps (Figure 9).

Figure 9. Removal of Skyla

• •If the threads are not visible, determine location of Skyla by ultrasound [see Warnings and Precautions (5.10)].
• •If Skyla is found to be in the uterine cavity on ultrasound exam, it may be removed using a narrow forceps, such as an alligator forceps. This may require dilation of the cervical canal. After removal of Skyla, examine the system to ensure that it is intact.

Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia) or seizure, especially in patients with a predisposition to these conditions.

2.5 Continuation of Contraception after Removal

• •If pregnancy is not desired and if a woman wishes to continue using Skyla, a new system can be inserted immediately after removal any time during the cycle.
• •If a patient with regular cycles wants to start a different contraceptive method, time removal and initiation of the new method to ensure continuous contraception. Either remove Skyla during the first 7 days of the menstrual cycle and start the new method immediately thereafter or start the new method at least 7 days prior to removing Skyla if removal is to occur at other times during the cycle.

If a patient with irregular cycles or amenorrhea wants to start a different contraceptive method, start the new method at least 7 days before removal.

• •Remove Skyla if pregnancy occurs with Skyla in place. If a pregnancy occurs, there is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death), and premature labor and delivery. (5.1, 5.2)
• •Group A streptococcal infection has been reported following insertion of LNG IUS; strict aseptic technique is essential during insertion. (5.3)
• •Before using Skyla, consider the risks of PID. (5.4)
• •Uterine perforation may occur and may reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri and postpartum. (5.5)
• •Partial or complete expulsion may occur, which can be unnoticed, leading to loss of contraceptive efficacy. (5.6)
• •Evaluate persistent enlarged ovarian follicles or ovarian cysts. (5.7)
• •Bleeding patterns become altered, may remain irregular and amenorrhea may ensue. (5.8)
• •Skyla can be safely scanned with MRI only under certain conditions (5.11)

5.1 Risk of Ectopic Pregnancy

•  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.

5.2 Risks withIntrauterine Pregnancy

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 (8.1)]. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy.

5.3 Sepsis

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.

5.4 Pelvic Infection

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 (4)]. 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.

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.

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).

PID may be asymptomatic but still result in tubal damage and its sequelae.

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.

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.

5.5 Perforation

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 (6.2)].

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.

5.6 Expulsion

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 (5.10)]. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 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 (6.2)].

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.

5.7 Ovarian Cysts

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.

5.8 Bleeding Pattern Alterations

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.

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.

5.9 Breast Cancer

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 (4)].

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.

5.10 Clinical Considerations for Use and Removal

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:

• •Coagulopathy or use of anticoagulants
• •Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia
• •Exceptionally severe headache
• •Marked increase of blood pressure
• •Severe arterial disease such as stroke or myocardial infarction

In addition, consider removing Skyla if any of the following conditions arise during use:

• •Uterine or cervical malignancy
• •Jaundice
• •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 (5.5, 5.6)]. 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.

5.11 Magnetic Resonance Imaging (MRI) Safety Information

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:

• •Static magnetic field of 3.0 T or less
• •Maximum spatial field gradient of 36,000 gauss/cm (360 T/m)
• •Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode)

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.