Skyla

Mechanism Of Action

The local mechanism by which continuously released LNG enhances 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.

Pharmacodynamics

Skyla has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 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 observed in the majority of a subset of subjects studied. Evidence of ovulation 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 27 women in the third year.

Pharmacokinetics

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 decreases progressively to approximately 5 mcg/day after three years. The average LNG in vivo release rate is approximately 6 mcg/day over the period of three years.

In a subset of 7 subjects, maximum observed serum LNG concentration was 192 ± 105 pg/mL, reached after 2 days (median) of Skyla insertion. Thereafter, LNG serum concentration decreased after long-term use of 12, 24, and 36 months to concentrations of 77 ± 21 pg/mL, 62 ± 38 pg/mL, and 72 ± 29 pg/mL, respectively. A population pharmacokinetic evaluation based on a broader data base (>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. Levonorgestrel 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 remains relatively stable over the 3 year period of use. Thereafter, plateau-like SHBG concentrations were observed. Less than 2 % of the circulating LNG is present as free steroid.

Following absorption, LNG is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. LNG and its phase I metabolites are excreted primarily as glucuronide conjugates. 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. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4.

About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of LNG after parenteral administration is approximately 20 hours.

Specific Populations

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

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

No studies have evaluated the effect of race on pharmacokinetics of Skyla.

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.

Drug-Drug Interactions

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

Clinical Studies

The contraceptive efficacy of Skyla was demonstrated in a clinical trial that enrolled generally healthy women aged 18– 35, 1,432 of whom received Skyla. The Skyla arm included 38.8 % (556) nulliparous women. 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. For Skyla-treated women, 540 (37.7%) were treated at US sites and 892 (62.3%) were at non-US sites. The racial demographic of enrolled women who received Skyla was: Caucasian (79.7%), Hispanic (11.5%), Black (5.2%), Asian (0.8%), and Other (2.7%). The weight range for treated women was 38 to 155 kg (mean weight: 68.7 kg) and mean BMI was 25.3 kg/m2 (range 16–55 kg/m2). 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 their consent, 13.0% discontinued due to other reason, 1.1% discontinued due to protocol deviation, and 0.6% discontinued due to pregnancy.

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%.

About 77% of women wishing to become pregnant conceived within 12 months after removal of Skyla.

• Birth Control Options (Types and Side Effects)

Skyla is a prescription implantable intrauterine system (IUS) containing a hormone and is used to prevent pregnancy for up to 3 years at a time. Skyla belongs to a group of drugs called progestins which work to prevent pregnancy by altering the lining of the uterus and cervical mucus, which prevents sperm from entering the uterus.

This medication comes in a plastic device that is manually inserted into the uterus by a healthcare provider.

Common side effects of Skyla include vaginal irritation and/or inflammation, acne, and ovarian cysts.

Skyla is a prescription implantable intrauterine system (IUS) containing a hormone and is used to prevent pregnancy for up to 3 years at a time.

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

• Bayer Healthcare Pharmaceuticals Inc.

Avoid having more than one sexual partner. The IUD can increase your risk of developing a serious pelvic infection, which is often caused by sexually transmitted disease. Levonorgestrel intrauterine system will not protect you from sexually transmitted diseases, including HIV and AIDS. Using a condom is the only way to help protect yourself from these diseases.

Call your doctor if your sexual partner develops HIV or a sexually transmitted disease, or if you have any change in sexual relationships.

In the U.S.

• Kyleena
• Liletta
• Mirena
• Skyla

Available Dosage Forms:

• Insert, Extended Release

Therapeutic Class: Contraceptive, Local

Pharmacologic Class: Progestin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of levonorgestrel in teenage females. This medicine may be used for birth control in teenage females but is not recommended before the start of menstruation.

Geriatric

Appropriate studies on the relationship of age to the effects of levonorgestrel have not been performed in the geriatric population. This medicine is not recommended for use in elderly women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Tranexamic Acid

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aprepitant
• Bosentan
• Carbamazepine
• Ceritinib
• Dabrafenib
• Darunavir
• Dexamethasone
• Efavirenz
• Eliglustat
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Oxcarbazepine
• Phenytoin
• Pitolisant
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Ulipristal

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acitretin
• Alprazolam
• Amprenavir
• Atazanavir
• Bacampicillin
• Betamethasone
• Bexarotene
• Colesevelam
• Cyclosporine
• Delavirdine
• Eslicarbazepine Acetate
• Fosamprenavir
• Fosaprepitant
• Lamotrigine
• Licorice
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nelfinavir
• Perampanel
• Prednisolone
• Rifapentine
• Ritonavir
• Rosuvastatin
• Rufinamide
• Selegiline
• Tacrine
• Telaprevir
• Troglitazone
• Troleandomycin
• Voriconazole
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Abnormally-shaped uterus or uterine fibroids or
• Breast cancer, known or suspected, or a history of or
• Cancer of the uterus or cervix, known or suspected or
• Genital tract infections (eg, bacterial vaginosis, cervicitis, endometritis, vaginitis), acute and untreated or
• Infection (eg, leukemia, pneumonia, HIV/AIDS) or
• Liver disease, including tumors or cancer or
• Pelvic infection (active or untreated), history of or
• Pelvic inflammatory disease (a serious pelvic infection), or history of—Should not be used in patients with these conditions.

• Bleeding problems or
• Blood clots or
• Diabetes or
• Heart attack, history of or
• Heart disease or other heart problems (eg, congenital heart disease, heart valve problems) or
• Hypertension (high blood pressure), severe or
• Migraine headaches, severe or
• Ovarian cysts or
• Stroke, history of—Use with caution. May make these conditions worse.

• If you have an allergy to Skyla (levonorgestrel (IUD)) or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are pregnant or may be pregnant. Do not use Skyla if you are pregnant.
• If you have an IUD (intrauterine device) in place.
• If you have any of these health problems: Active liver disease, chlamydia or gonorrhea, endometritis after a birth, genital tract infection, infected abortion in the last 3 months, liver tumor, pelvic infection, uterine or cervical tumor or growth, uterine problems like uterine fibroids, or untreated cervicitis or vaginitis.
• If you have unexplained vaginal bleeding.
• If you have ever had any of these health problems: Breast cancer, cancer where hormones make it grow, or pelvic inflammatory disease.
• If you have not started your period.
• If you or your partner have sex with more than one person.
• If your body is weak at fighting infections.
• If you have ever abused drugs.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Skyla with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Other drugs may interact with levonorgestrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.