Kyleena

Mechanism Of Action

The local mechanism by which continuously released LNG contributes to the contraceptive effectiveness of Kyleena has not been conclusively demonstrated. Studies of Kyleena and similar LNG IUS prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.

Pharmacodynamics

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

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

Pharmacokinetics

Low doses of LNG are administered into the uterine cavity with the Kyleena intrauterine delivery system. The in vivo release rate is approximately 17.5 mcg/day after 24 days and is reduced to approximately 15.3 mcg/day after 60 days and to 9.8 mcg/day after 1 year. It then declines progressively to approximately 7.9 mcg/day after 3 years and 7.4 mcg/day after 5 years. The average LNG in vivo release rate is approximately 9 mcg/day over the period of 5 years.

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

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 6 subjects, the concentration of SHBG declined on average by about 30% during the first 3 months after insertion of Kyleena and remained relatively stable over the 5 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.

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, 5αtetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG.

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.

Specific Populations

Pediatric: Safety and efficacy of Kyleena have been established in women of reproductive age. Use of this product before menarche is not indicated.

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

Race: No studies have evaluated the effect of race on the pharmacokinetics of Kyleena.

Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Kyleena.

Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Kyleena.

Drug-Drug Interactions

No drug-drug interaction studies were conducted with Kyleena [see DRUG INTERACTIONS].

Clinical Studies

The contraceptive efficacy of Kyleena was evaluated in a clinical trial that enrolled generally healthy women aged 18-35, of whom 1,452 received Kyleena. Of these, 40% (574) were nulliparous women, 870 (60%) women completed 3 years of the study, 707 (49%) elected to enroll in an extension phase up to a total of 5 years, and 550 (38%) completed 5 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 563 (39%) were treated at US sites and 889 (61%) were at non-US sites. The racial demographics of enrolled women who received Kyleena was: Caucasian (80%), Black/African American (5.1%), Other (2.6%) and Asian (1.2%); 11% indicated Hispanic ethnicity. The clinical trial had no upper or lower weight or BMI limit. The weight range was 38 to 173 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m²(range 15.2-57.6 kg/m²). Of Kyleena-treated women, 22% discontinued the study treatment due to an adverse reaction, 5.0% were lost to follow-up, 2.3% withdrew for unspecified reasons, 1.2% discontinued due to a protocol deviation, 0.9% discontinued due to pregnancy, and 20% 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. The Year 1 PI was based on 2 pregnancies and the cumulative 5-year pregnancy rate was based on 13 pregnancies that occurred after the onset of treatment and within 7 days after Kyleena removal or expulsion. Table 4 shows the calculated annual and cumulative pregnancy rates.

Table 4: Pearl Indices by Year and 5-Year Cumulative Pregnancy Rate

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

Kyleena is a prescription medication that is a hormone-releasing system placed in the uterus to prevent pregnancy for up to 5 years.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• barbiturates
• bosentan
• carbamazepine
• felbamate
• griseofulvin
• oxcarbazepine
• phenytoin
• rifampin
• St. John’s wort
• topiramate
• HIV protease inhibitors
• non-nucleoside reverse transcriptase inhibitors

This is not a complete list of Kyleena drug interactions. Ask your doctor or pharmacist for more information.

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 thin plastic tube containing the intrauterine device (IUD) into your uterus. Your healthcare provider will then remove the plastic tube, and leave the IUD in your uterus. Your healthcare provider will cut the threads to the right length. Placement takes only a few minutes during an office visit.

You may experience pain, bleeding or dizziness during and after placement. If these symptoms do not pass 30 minutes after placement, the IUD may not have been placed correctly. Your healthcare provider will examine you to see if the IUD needs to be removed or replaced.

You should check that the IUD is in proper position by feeling the removal threads. You should do this after each menstrual period. First, wash your hands with soap and water. Feel for the threads at the top of your vagina with your clean fingers. The threads are the only part of the IUD you should feel when it is in your uterus. Be careful not to pull on the threads. If you feel more than just the threads, the IUD is not in the right position and may not prevent pregnancy. Call your healthcare provider to have it removed. If you cannot feel the threads at all, ask your healthcare provider to check the IUD is still in the right place. In either case, use a non-hormonal birth control method (such as condoms or spermicide) until otherwise advised by your healthcare provider.

Call your healthcare provider if you have any questions or concerns. Otherwise, you should return to your healthcare provider for a follow-up visit 4 to 12 weeks after the IUD is placed to make sure that it is in the right position.

Tampons may be used with the IUD.

Call your healthcare provider if you have any concerns about this medication. Be sure to call if you:

• think you are pregnant
• have pelvic pain or pain during sex
• have unusual vaginal discharge or genital sores
• have unexplained fever
• might be exposed to sexually transmitted diseases (STDs)
• cannot feel the IUD threads
• develop very severe or migraine headaches
• have yellowing of the skin or whites of the eyes. These may be signs of liver problems.
• have a stroke or heart attack
• or your partner becomes HIV positive
• have severe vaginal bleeding or bleeding that lasts a long time

The intrauterine device (IUD) contains 19.5 mg of Kyleena. Initially, Kyleena is released at a rate of approximately 17.5 mcg/day. This rate decreases over time to 7.4 mcg/day after 5 years. Kyleena must be removed or replaced after 5 years. 

Get emergency medical help if you have severe pain in your lower stomach or side. This could be a sign of a tubal pregnancy (a pregnancy that implants in the fallopian tube instead of the uterus). A tubal pregnancy is a medical emergency.

The levonorgestrel IUD may become embedded into the wall of the uterus, or may perforate (form a hole) in the uterus. If this occurs, the device may no longer prevent pregnancy, or it may move outside the uterus and cause scarring, infection, or damage to other organs. Your doctor may need to surgically remove the device.

Call your doctor at once if you have:

• severe cramps or pelvic pain, pain during sexual intercourse;

• extreme dizziness or light-headed feeling;

• severe migraine headache;

• heavy or ongoing vaginal bleeding, vaginal sores, vaginal discharge that is watery, foul-smelling discharge, or otherwise unusual;

• pale skin, weakness, easy bruising or bleeding, fever, chills, or other signs of infection;

• sudden numbness or weakness (especially on one side of the body), confusion, problems with vision, sensitivity to light;

• jaundice (yellowing of the skin or eyes); or

• signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Common side effects may include:

• pelvic pain, vaginal itching or infection, irregular menstrual periods, changes in bleeding patterns or flow;

• stomach pain, nausea, vomiting, bloating;

• headache, depression, mood changes;

• back pain, breast tenderness or pain;

• weight gain, acne, changes in hair growth, loss of interest in sex; or

• puffiness in your face, hands, ankles, or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may interact with levonorgestrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

In the U.S.

• Kyleena
• Liletta
• Mirena
• Skyla

Available Dosage Forms:

• Insert, Extended Release

Therapeutic Class: Contraceptive, Local

Pharmacologic Class: Progestin

This section provides information on the proper use of a number of products that contain levonorgestrel. It may not be specific to Kyleena. Please read with care.

Your doctor will give you this medicine in a hospital or clinic. The intrauterine device (IUD) is inserted into your uterus.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Your doctor may want to do tests to make sure you do not have an infection before putting in an IUD. The IUD is usually inserted during your monthly period, immediately after a miscarriage or an abortion in the first trimester of your pregnancy, at least 6 weeks after a miscarriage or an abortion in the second trimester of your pregnancy, or at least 6 weeks after giving birth. Putting an IUD in during a monthly period also helps to make sure that you are not pregnant. You will also need to see your doctor within 4 to 6 weeks of having your IUD placed and then once a year. Use another form of birth control or refrain from having sex if the IUD is not inserted during the first 7 days of your menstrual cycle.

Levonorgestrel IUD has a string or "tail" which is made of plastic thread. About one or two inches of this string hangs into your vagina. You cannot see this string, and it will not cause problems when you have sex. Check your IUD string every few days during the first few months that you have your IUD. After that, check the string after each monthly period. You may not be protected against pregnancy if you cannot feel the string or if you feel the plastic. Do the following to check the placement of your IUD:

• Wash your hands with soap and warm water. Dry them with a clean towel.
• Bend your knees and squat low to the ground.
• Gently put your index (pointing) finger high inside your vagina. The cervix is at the top of the vagina and feels like the tip of your nose. Find the IUD string coming from your cervix. Never pull on the string. You should not be able to feel the firm plastic of the IUD itself.
• Wash your hands after you are finished checking your IUD.

You will need to have your levonorgestrel-releasing IUD replaced every 3 years for Liletta™ or Skyla™, or 5 years for Kyleena™ or Mirena®, or sooner if it comes out of your uterus unexpectedly.

If you are using Mirena® IUD and want to stop, your doctor can remove it at any time. However, you may become pregnant as soon as it is removed. Use another form of birth control (eg, condoms, spermicides) or have a new IUD inserted at the same day of removal to keep from getting pregnant.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Absent, missed, or irregular menstrual periods
• longer or heavier menstrual periods
• mild bloating
• stomach or pelvic pain
• stopping of menstrual bleeding
• unusually heavy or unexpected menstrual bleeding
• uterine bleeding between menstrual periods
• vaginal bleeding or spotting

• Blurred vision
• cramps
• dizziness
• headache
• heavy bleeding
• itching of the vagina or genital area
• nervousness
• pain
• pain during sexual intercourse
• pale skin
• pounding in the ears
• slow or fast heartbeat
• swelling
• thick, white vaginal discharge with mild or no odor
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• white or brownish vaginal discharge

• Chills
• confusion
• dizziness, lightheadedness, fainting
• fast heartbeat
• fast, weak pulse
• fever
• pale, cold, clammy skin
• rapid, shallow breathing
• sudden increase in stomach or shoulder pain
• sweating
• unusual or large amount of vaginal bleeding

• Clear or bloody discharge from the nipple
• dimpling of the breast skin
• dull or aching stomach pain
• foul-smelling vaginal discharge
• increased urge to urinate
• inverted nipple
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lump in the breast or under the arm
• pain during urination
• persistent crusting or scaling of the nipple
• redness or swelling of the breast
• severe stomach pain or cramping
• sharp pain on insertion
• shivering fever
• sores on the skin of the breast that does not heal

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blemishes on the skin
• depression
• pimples

• Back pain
• breast tenderness or pain
• decreased interest in sexual intercourse
• full or bloated feeling
• hair loss
• hives or welts, itching, or rash
• increased hair growth, especially on the face
• increased weight
• loss in sexual ability, desire, drive, or performance
• nausea
• pressure in the stomach
• redness of the skin
• skin rash, encrusted, scaly, and oozing
• swelling of the stomach area
• thinning of the hair

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Kyleena is indicated to prevent pregnancy for up to 5 years. Replace the system after 5 years if continued use is desired.

Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.9).]