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KYLEENA
(levonorgestrel-releasing) intrauterine system
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 C21H28O2, and the following structural formula:
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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.
Figure 10:Kyleena
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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.
Figure 11:Diagram of Inserter
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Kyleena is indicated to prevent pregnancy for up to 5 years. Replace the system after 5 years if continued use is desired.
Kyleena contains 19.5 mg of levonorgestrel (LNG) released in vivo at a rate of approximately 17.5 mcg/day after 24 days. This rate decreases progressively to 9.8 mcg/day after 1 year and to 7.4 mcg/day after 5 years. The average in vivo release rate of LNG is approximately 9 mcg/day over a period of 5 years. [See CLINICAL PHARMACOLOGY]
Kyleena must be removed by the end of the fifth year and can be replaced at the time of removal with a new Kyleena if continued contraceptive protection is desired.
Kyleena can be distinguished from other intrauterine systems (IUSs) by the combination of the visibility of the silver ring on ultrasound and the blue color of the removal threads.
Kyleena 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].
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Preparation
Procedure
Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Kyleena. Ensure use of aseptic technique throughout the entire procedure.
Step 1-Opening of the package
Figure 1: Opening the
Kyleena Package
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Step 2-Load Kyleena into the insertion tube
Figure 2: Move slider all
the way to the forward position to load Kyleena
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Step 3-Setting the Flange
Figure 3: Setting the flange
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Step 4 - Kyleena is now ready to be inserted
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.
Step 5 - Open the arms
Figure 5: Move the slider
back to the mark to release and open the arms
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Step 6 - Advance to fundal position
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. Kyleena is now in the fundal position (Figure 6). Fundal positioning of Kyleena is important to prevent expulsion.
Figure 6: Move Kyleena into
the fundal position
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Step 7-Release Kyleena and withdraw the inserter
Figure 7: Move the slider
all the way down to release Kyleena from the insertion tube
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Figure 8: Cutting the
threads
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Kyleena insertion is now complete. Prescribe analgesics, if indicated. Keep a copy of the Consent Form with lot number for your records.
Preparation
Procedure
Removal Procedure
Figure 9: Removal of Kyleena
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Kyleena 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 19.5 mg LNG.
Kyleena (levonorgestrel-releasing intrauterine system), containing a total of 19.5 mg LNG, is available in a carton of one sterile unit.
NDC# 50419-424-01
Kyleena is supplied sterile. Kyleena 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 Manufactured in Finland © 2016, Bayer HealthCare Pharmaceuticals Inc. Revised: Sep 2016
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 of 1,697 healthy 18 to 41-year-old women (mean age 27.8 ± 5.2 years) to Kyleena. These data come from two multi-center contraceptive trials: A phase 2 study with a 3-year duration was conducted in Europe, enrolling generally healthy, 21 to 41-year old women; 217 subjects were exposed to Kyleena for one year and 174 completed three years. The data in this trial cover approximately 8,000 cycles of exposure. A phase 3 study with a 3-year duration and an optional extension of Kyleena use up to 5 years was conducted in the United States (US), Canada, Europe, and Latin America. The population was generally healthy, 18 to 35-year old women. A total of 1,208 subjects were exposed to Kyleena for at least one year; 707 women entered the optional extension phase after 3 years and 550 completed five years. The data in this trial cover approximately 60,000 cycles.
In total for both studies, 1,425 subjects were exposed for at least 1 year, and 550 subjects completed 5 years of use. Of the total of 1,697 subjects exposed to Kyleena, 563 were from the US and 1,134 were from Europe, Canada and Latin America; 623 (37%) were nulliparous (mean age 24.6 ± 4.5 years) and 1,074 (63%) were parous (mean age 29.7 ± 4.7 years). Most women who received Kyleena were Caucasian (83%) or Black/African American (4.4%); 9.4% of women were of Hispanic ethnicity. The clinical trials had no upper or lower weight or body mass index (BMI) limit. Mean BMI of Kyleena subjects was 25.2 kg/m²(range 15.2 - 57.6 kg/m²); 16% had a BMI ≥ 30 kg/m², and 2.0% had a BMI ≥ 40 kg/m². The frequencies of reported adverse drug reactions represent crude incidences.
The most common adverse reactions (occurring in ≥ 5% users) were vulvovaginitis (24%), ovarian cyst (22%), abdominal pain/pelvic pain (21%), headache/migraine (15%), acne/seborrhea (15%), dysmenorrhea/uterine spasm (10%), breast pain/breast discomfort (10%), and increased bleeding (8%).
In the combined studies, 22% discontinued prematurely due to an adverse reaction. The most common adverse reactions ( > 1%) leading to discontinuation were increased bleeding (4.5%), abdominal pain/pelvic pain (4.2%), device expulsion (3.1%), acne/seborrhea (2.3%), and dysmenorrhea/uterine spasm (1.3%).
Common adverse reactions (occurring in ≥ 1% users) are summarized in Table 3 (presented as crude incidences).
Table 3: Adverse reactions
that occurred in at least 1% of Kyleena users in clinical trials by System
Organ Class (SOC)
| System Organ Class | Adverse Reaction | Incidence (%) (N=1,697) |
| Reproductive System and Breast Disorders | Vulvovaginitis | 24.3 |
| Ovarian cysta | 22.2 | |
| Dysmenorrhea/uterine spasm | 8.0/2.4 | |
| Increased bleedingb | 7.9 | |
| Breast pain/discomfort | 7.1/3.5 | |
| Genital discharge | 4.5 | |
| Device expulsion (complete and partial) | 3.5 | |
| Upper genital tract infection | 1.5 | |
| Gastrointestinal Disorders | Abdominal pain/pelvic pain | 13.3/8.2 |
| Nausea | 4.7 | |
| Skin and Subcutaneous Tissue Disorders | Acne/Seborrhea | 14.1/1.8 |
| Alopecia | 1.0 | |
| Nervous System Disorders | Headache/Migraine | 12.9/3.3 |
| Psychiatric Disorders | Depression/ Depressed mood | 4.4/0.2 |
| 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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In the clinical trials, serious adverse reactions occurring in more than a single subject included: ectopic pregnancy/ruptured ectopic pregnancy (10 subjects); pelvic inflammatory disease (6 subjects); missed abortion/incomplete spontaneous abortion/spontaneous abortion (4 subjects); ovarian cyst (3 subjects); abdominal pain (4 subjects); depression/affective disorder (4 subjects); and uterine perforation/embedded device (myometrial perforation) (3 subjects).
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.
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.
Included as part of the PRECAUTIONS section.
Evaluate women for ectopic pregnancy if they become pregnant with Kyleena in place because the likelihood of a pregnancy being ectopic is increased with Kyleena. Approximately one-half of pregnancies that occur with Kyleena 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 Kyleena, which excluded women with a history of ectopic pregnancy, was approximately 0.2% per year. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Kyleena 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 Kyleena, remove Kyleena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Kyleena, 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 Kyleena in place and if Kyleena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Kyleena increases the risk of miscarriage, sepsis, premature labor and premature delivery. 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 Kyleena 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 Kyleena in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment.
Kyleena 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 0.5% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Kyleena.
Women at increased risk for PID
PID is often associated with a sexually transmitted infection (STI), and Kyleena 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 Kyleena after initiation of antibiotic therapy is usually appropriate.1
Actinomycosis has been associated with IUDs. Remove Kyleena 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 Kyleena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures.
Perforation (total or partial, including penetration/embedment of Kyleena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. Perforation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during clinical trials was < 0.1%.
If perforation occurs, locate and remove Kyleena. Surgery may be required. Delayed detection or removal of Kyleena in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera.
Clinical trials with Kyleena excluded breast-feeding women. An analysis from a large postmarketing safety study with another LNG-releasing IUS and copper IUDs shows an increased risk of perforation in lactating women. The risk of perforation may be increased if Kyleena is inserted when the uterus is fixed retroverted or not completely involuted during the postpartum period. Delay Kyleena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion.
Partial or complete expulsion of Kyleena may occur resulting in the loss of contraceptive protection. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Kyleena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported.
Delay Kyleena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Kyleena. If expulsion has occurred, Kyleena may be replaced within 7 days after the onset of a menstrual period after pregnancy has been ruled out.
Because the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Kyleena. 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 22% of women using Kyleena, and 0.6% 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.
Kyleena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3-6 months of Kyleena 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 Kyleena clinical trials, amenorrhea developed by the end of the first year of use in approximately 12% of Kyleena users. A total of 81 subjects out of 1,697 (4.8%) discontinued due to uterine bleeding complaints. Table 1 shows the bleeding patterns as documented in the Kyleena clinical trials based on 90-day reference periods. Table 2 shows the number of bleeding and spotting days based on 28-day cycle equivalents.
Table 1: Bleeding Patterns Reported with Kyleena in
Contraception Studies (by 90-day reference periods)
| Kyleena | First 90 days N=1,566 |
Second 90 days N=1,511 |
End of year 1 N=1,371 |
End of year 3 N=975 |
End of year 5 N=530 |
| Amenorrhea1 | < 1% | 5% | 12% | 20% | 23% |
| Infrequent bleeding2 | 10% | 20% | 26% | 26% | 26% |
| Frequent bleeding3 | 25% | 10% | 4% | 2% | 2% |
| Prolonged bleeding4 | 57% | 14% | 6% | 2% | 1% |
| Irregular bleeding5 | 43% | 25% | 17% | 10% | 9% |
| 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 2: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent
