Kyleena (Page 8 of 10)

Distribution

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.

Elimination

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.

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 (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.9).]

14 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 5 shows the calculated annual and cumulative pregnancy rates.

Table 7: Pearl Indices by Year and 5-Year Cumulative Pregnancy Rate

Kyleena Clinical Trial

Pearl Index

Cumulative 5-Year Kaplan Meier Rate

Year 1

Year 2

Year 3

Year 4

Year 5

Number of Evaluable 28-day Cycles of Exposure

16,207

13,853

11,610

8,556

7,087

57,313

Pregnancy Rate (95% Confidence Interval)

0.16

(0.02, 0.58)

0.38

(0.10, 0.96)

0.45

(0.12, 1.15)

0.15

(0.00, 0.85)

0.37

(0.04, 1.33)

1.45

(0.82, 2.53)

15 REFERENCES

1 http://www.cdc.gov/std/tg2015/pid.htm. Accessed August 22, 2016.

16 HOW SUPPLIED/STORAGE AND HANDLING

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].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Sexually Transmitted Infections: Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).
Risk of Ectopic Pregnancy: Advise the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See Warnings and Precautions (5.1).]
Risks of Intrauterine Pregnancy: Advise the patient to contact her healthcare provider if she thinks she might be pregnant. Inform the patient about the risks of intrauterine pregnancy while using Kyleena, including the risks of leaving Kyleena in place and the risks of removing Kyleena or probing of the uterus. If Kyleena cannot be removed in a pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy. 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 Warnings and Precautions (5.2) and Use in Special Populations (8.1).]
Sepsis: Advise the patient that severe infection or sepsis, including Group A streptococcal sepsis (GAS), can occur within the first few days after Kyleena is inserted. Instruct her to contact a healthcare provider immediately if she develops severe pain or fever shortly after Kyleena is inserted. [See Warnings and Precautions (5.3).]
Pelvic Infection: Advise the patient about the possibility of pelvic infections, including PID, and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach patients to recognize and report to their healthcare provider promptly any symptoms of pelvic infection. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See Warnings and Precautions (5.4).]
Perforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Kyleena placement, worsening pain or bleeding after placement, or the inability to feel Kyleena strings may occur with Kyleena perforation and expulsion. Caution her not to pull on the threads and displace Kyleena. Inform her that there is no contraceptive protection if Kyleena is displaced or expelled. Instruct the patient to contact her healthcare provider if she cannot feel the threads and to avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) until the location of Kyleena has been confirmed. Advise her that if perforation occurs, Kyleena will have to be located and removed; surgery may be required. [See Warnings and Precautions (5.5, 5.6, 5.10).]
Ovarian Cysts: Advise the patient regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia. Advise the patient to contact her healthcare provider if she experiences these symptoms. [See Warnings and Precautions (5.7).]
Bleeding Pattern Alterations: Advise the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. Inform the patient that, during the first 6 months of Kyleena use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. If her symptoms continue or are severe she should report them to her healthcare provider. [See Warnings and Precautions (5.8).]
Clinical Considerations for Use and Removal: Advise the patient to contact her healthcare provider if she experiences any of the following:
A stroke or heart attack
Very severe or migraine headaches
Unexplained fever
Yellowing of the skin or whites of the eyes, as these may be signs of serious liver problems
Pregnancy or suspected pregnancy
Pelvic pain, abdominal pain, or pain during sex
HIV positive seroconversion in herself or her partner
Possible exposure to STIs
Unusual vaginal discharge or genital sores
Severe vaginal bleeding or bleeding that lasts a long time, or if she misses a menstrual period
Inability to feel Kyleena’s threads
Magnetic Resonance Imaging (MRI) Safety Information: Inform the patient that Kyleena can be safely scanned with MRI only under specific conditions [see Warnings and Precautions (5.11)]. Instruct patients who will have an MRI to tell their doctor that they have Kyleena.
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
© 2016, Bayer HealthCare Pharmaceuticals Inc.All rights reserved.

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