XULANE (Page 6 of 11)

7.4 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use hormonal contraceptives during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose hormonal contraceptives prior to conception or during early pregnancy.

The administration of hormonal contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Hormonal contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

The effects of Xulane in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. Estrogen-containing CHCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

Safety and efficacy of norelgestromin and ethinyl estradiol transdermal system have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use

Xulane has not been studied in postmenopausal women and is not indicated in this population.

8.6 Hepatic Impairment

No studies with Xulane have been conducted in women with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of combined hormonal contraceptive use until markers of liver function return to normal and combined hormonal contraceptive causation has been excluded. [See Contraindications (4) and Warnings and Precautions (5.3).]

8.7 Renal Impairment

No studies with Xulane have been conducted in women with renal impairment.

8.8 Women with Weight ≥ 198 lbs (90 kg)

Xulane may be less effective in preventing pregnancy in women who weigh 198 lbs (90 kg) or more.

10 OVERDOSAGE

Overdosage may cause nausea and vomiting, and withdrawal bleeding may occur in females. In case of suspected overdose, all Xulane patches should be removed and symptomatic treatment given.

11 DESCRIPTION

Xulane is a transdermal system with a contact surface area of 14 cm². It contains 4.86 mg norelgestromin, USP (NGMN) and 0.53 mg ethinyl estradiol, USP (EE), and its delivery rate is approximately 150 mcg of NGMN and 35 mcg of EE per day. Systemic exposures (as measured by area under the curve [AUC] and steady state concentration [Css ]) of NGMN and EE during use of norelgestromin and ethinyl estradiol transdermal system are higher and the Cmax is lower than those produced by an oral contraceptive containing NGM 250 mcg / EE 35 mcg. [See Boxed Warning and Clinical Pharmacology (12.3).]

Xulane is a thin, matrix-type transdermal system consisting of three layers. The backing layer is composed of a peach flexible film consisting of a pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutene adhesive, crospovidone, mineral oil, non-woven polyester fabric, oleyl alcohol and dipropylene glycol as inactive components. The active components in this layer are the hormones, NGMN and EE. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyester film with a fluoropolymer coating on the side that is in contact with the middle adhesive layer.

The outside of the backing layer is printed with “Xulane® (norelgestromin and ethinyl estradiol) 150/35 mcg per day” in brown ink.

Xulane transdermal systems are packaged with additional pieces of protective film above and below the system within each pouch. These pieces of protective film are removed and discarded at the time of use.

The structural formulas of the components are:

Norelgestromin and Ethinyl Estradiol Structural Formulas
(click image for full-size original)

Molecular weight, NGMN: 327.47

Molecular weight, EE: 296.41

Chemical name for NGMN: 18, 19-dinorpregn-4-en-20-yn-3-one, 13-ethyl-, 17-hydroxy, 3-oxime, (17α)-

Chemical name for EE: 19-Norpregna-1,3,5(10)-trien-20-yne-3, 17β-diol, (17α)-

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

NGMN is the active progestin largely responsible for the progestational activity that occurs in women following application of norelgestromin and ethinyl estradiol transdermal system. NGMN is also the primary active metabolite produced following oral administration of NGM, the progestin component of some oral contraceptive products.

Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

12.2 Pharmacodynamics

One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post-therapy.

12.3 Pharmacokinetics

Absorption

The systemic delivery rate of NGMN and EE from norelgestromin and ethinyl estradiol transdermal system is approximately 150 mcg of NGMN and 35 mcg of EE per day based on a comparative analysis with intravenous (IV) data. Following a single application of norelgestromin and ethinyl estradiol transdermal system, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady state is reached within 2 weeks of application. In one of the clinical studies, Css concentrations across all subjects ranged from 0.305 to 1.53 ng/mL for NGMN and from 23 to 137 pg/mL for EE.

Absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.

The mean (%CV) PK parameters Css and AUC0-168 for NGMN and EE following a single buttock application of norelgestromin and ethinyl estradiol transdermal system are summarized in Table 5.

In multiple dose studies, AUC0-168 for NGMN and EE was found to increase over time (Table 5). In a three-cycle study, these PK parameters reached steady state conditions during Cycle 3 (Figures 3 and 4). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days.

Table 5: Mean (%CV *) PK Parameters of NGMN and EE Following Three Consecutive Cycles of Norelgestromin and Ethinyl Estradiol Transdermal System Wear on the Buttock
nc = not calculated
*
%CV is % of Coefficient of variation = 100 (standard deviation/mean)

Analyte

Parameter

Cycle 1

Cycle 3

Cycle 3

Cycle 3

Week 1

Week 1

Week 2

Week 3

NGMN

Css (ng/mL)

0.70 (39.4)

0.70 (41.8)

0.80 (28.7)

0.70 (45.3)

AUC0-168 (ng·h/mL)

107 (44.2)

105 (43.2)

132 (43.4)

120 (43.9)

t1/2 (h)

nc

nc

nc

32.1 (40.3)

EE

Css (pg/mL)

46.4 (38.5)

47.6 (36.4)

59.0 (42.5)

49.6 (54.4)

AUC0-168 (pg·h/mL)

6796 (39.3)

7160 (40.4)

10054 (41.8)

8840 (58.6)

t1/2 (h)

nc

nc

nc

21.0 (43.2)

Figure 3: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)

Figure 3:  Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)
(click image for full-size original)

Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Norelgestromin and Ethinyl Estradiol Transdermal System on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)

Figure 4: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Xulane on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)
(click image for full-size original)

The absorption of NGMN and EE following application of norelgestromin and ethinyl estradiol transdermal system was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN, there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.

Results from a study of consecutive norelgestromin and ethinyl estradiol transdermal system wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations.

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