LYLLANA Dailymed

7 Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice may increase plasma concentrations of estrogens and may result in adverse reactions.


Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration.(7)

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

LYLLANA is not indicated for use in pregnancy. There are no data with the use of LYLLANA in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2Lactation

Risk Summary

Estrogens are present in human milk and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LYLLANA and any potential adverse effects on the breastfed child from LYLLANA or from the underlying maternal condition.

8.4 Pediatric Use

LYLLANA is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing LYLLANA to determine whether those over 65 years of age differ from younger subjects in their response to LYLLANA.

The Women’s Health Initiative Studies

In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.3)].

In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Warnings and Precautions (5.1), and  Clinical Studies (14.3)].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.3), and Clinical Studies (14.4)].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women⁸ [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

10 Overdosage

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of LYLLANA therapy with institution of appropriate symptomatic care.

11 Description

LYLLANA (estradiol transdermal system, USP), contains estradiol, USP in a multipolymeric adhesive. The system is designed to release estradiol, USP continuously upon application to intact skin.

Five dosage strengths of LYLLANA are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol, USP per day via the skin. Each corresponding system has an active surface area of 1.89, 2.83, 3.78, 5.66, or 7.55 cm² and contains 0.314, 0.470, 0.627, 0.940, or 1.253 mg of estradiol USP, respectively.

The composition of the systems per unit area is identical.

Estradiol, USP is a white to practically white powder, chemically described as estra-1,3,5 (10)-triene-3,17β-diol.

The structural formula is

 

The molecular formula of estradiol, USP is C₁₈H₂₄0₂. The molecular weight is 272.39

LYLLANA is comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) polyester and ethylene vinyl acetate copolymer film (2) an adhesive formulation containing estradiol, USP, acrylic adhesive, silicone adhesive, oleyl alcohol, NF, povidone, USP and dipropylene glycol, and (3) a polyester release liner which is attached to the adhesive surface and must be removed before the system can be used.

 

The active component of the system is estradiol, USP. The remaining components of the system are pharmacologically inactive.

Meets USP Dissolution Test 6.

12 Clinical Pharmacology

12.1 Mechanism of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated concentrations of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to LYLLANA nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3 Pharmacokinetics

Absorption

In a single-dose, two way-crossover clinical study conducted in 96 healthy, non-smoking postmenopausal women under fed condition, LYLLANA (0.1 mg per day) was bioequivalent to Vivelle (0.1 mg per day) based on estradiol exposure (AUC_0-84) and estradiol peak concentration (C_max) following a single-dose on the lower abdomen for 84 hours.

Estradiol pharmacokinetics were characterized in a separate open-label, single-center, randomized, single-dose, three-way crossover study conducted in 36 healthy, non-smoking postmenopausal women (aged 40 to 65 years). LYLLANA transdermal systems delivering nominal estradiol of approximately 0.025 mg, 0.05 mg, and 0.1 mg per day were applied to the lower abdomen under fed state in a crossover fashion for 84 hours. The mean estradiol pharmacokinetics parameters are summarized in Table 2. AUC and C_max are dose proportional from 0.025 mg to 0.1 mg per day.

Table 2: Mean (SD) Serum Pharmacokinetic Parameters of Baseline-Uncorrected Estradiol following a Single Dose of LYLLANA (N=36)

Parameter	0.1 mg/day	0.05 mg/day	0.025 mg/day
AUC84 (pg·hr/mL)	5875 (1857)	3057 (980)	1763 (600)
AUC120 (pg·hr/mL)	6252 (1938)	3320 (1038)	1979 (648)
Cmax (pg/mL)	117 (39.3)	56.6 (17.6)	30.3 (11.1)
Tmax (hr)a	24 (8 to 60)	24 (8 to 60)	36 (8 to 84)

^a Median (minimum-maximum)

Figure 1 illustrates the mean baseline-uncorrected estradiol serum concentrations of LYLLANA at three different strengths.

Figure 1: Mean Baseline-Uncorrected Estradiol Serum Concentration-Time Profiles Following a Single Dose of LYLLANA 0.1 mg per day (Treatment A), 0.05 mg per day (Treatment B), and 0.025 mg per day (Treatment C) (N=36)

  

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The mean half-life values of estradiol calculated from treatment groups in the bioequivalence study and dose-proportionality study after dosing with LYLLANA ranged from 6.2 to 7.9 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline concentrations within 24 hours.

Adhesion and Adhesive Residue

Based on combined data from bioequivalence and dose proportionality studies consisting of 208 LYLLANA observations, approximately 98 percent of the observations had an adhesion score of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour wear period. One woman had a complete detachment during the wear period. Approximately 65 percent of the transdermal systems evaluated in these studies were with LYLLANA 0.1 mg per day (6.6 cm² active surface area).

After removal of LYLLANA, woman had either no adhesive residue (score of 0) or light adhesive residue (score of 1). No woman had medium adhesive residue. Of the 208 LYLLANA observations, 54 percent had light adhesive residue and 46 percent had no adhesive residue.

14.1 Effects on Vasomotor SymptomsinPostmenopausal Women

There have been no efficacy and safety trials conducted with LYLLANA. In a pharmacokinetic study, LYLLANA was shown to be bioequivalent to Vivelle.

In two controlled clinical trials with Vivelle, in a total of 356 women, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Weeks 4, 8 and 12 of treatment. In these studies, the 0.0375 and 0.05 mg doses did not differ from placebo at Week 4, therefore, a third 12-week placebo-controlled study in 255 women was performed with Vivelle to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 women was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in Figure 2.

Figure 2: Mean (SD) change from baseline in mean daily number of hot flushes for Vivelle 0.0375 mg versus Placebo in a 12-week trial.

  

The 0.0375 mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Weeks 4, 8 and 12 of treatment.

14.2 Effects on Bone Mineral DensityinPostmenopausal Women

There have been no bone efficacy and safety trials conducted with LYLLANA. In a pharmacokinetic study, LYLLANA was shown to be bioequivalent to Vivelle.

Efficacy and safety of Vivelle in the prevention of postmenopausal osteoporosis have been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within 5 years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within 2 standard deviations of average peak bone mass, i.e., ≥0.0827 g/cm²) were enrolled in this study; 194 women were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 women to placebo. Over 2 years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.

The study population comprised naturally (82 percent) or surgically (18 percent) menopausal, hysterectomized (61 percent) or non-hysterectomized (39 percent) women with a mean age of 52 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89 percent) randomized women (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Women were given supplemental dietary calcium (100 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at 6 months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically significant differences in pairwise comparisons among the three lower doses (See Figure 3).

Figure 3: Bone mineral density – AP Lumbar spine   

Least squares means of percentage change from baseline

All randomized women with at least one post-baseline assessment available with last post-baseline observation carried forward

  

Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant and non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three lower doses at this skeletal site (see Figure 4).

Figure 4: Bone mineral density – Femoral neck   

Least squares means of percentage change from baseline

All randomized women with at least one post-baseline assessment available with last post-baseline observation carried forward

14.3 Womens Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 3.

Table 3: Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHI^a

Event	Relative Risk CE vs. Placebo (95% nCIb)	CE n = 5,310	Placebo n = 5,429
		Absolute Risk per 10,000 Women-Years
CHD eventsc Non-fatal MIc CHD deathc	0.95 (0.78 to 1.16) 0.91 (0.73 to 1.14) 1.01 (0.71 to 1.43)	54 40 16	57 43 16
All strokesc Ischemic strokec	1.33 (1.15 to 1.68) 1.55 (1.19 to 2.01)	45 38	33 25
Deep vein thrombosisc,d	1.47 (1.06 to 2.06)	23	15
Pulmonary embolismc	1.37 (0.90 to 2.07)	14	10
Invasive breast cancerc	0.80 (0.62 to 1.04)	28	34
Colorectal cancere	1.08 (0.75 to 1.55)	17	16
Hip fracturec	0.65 (0.45 to 0.94)	12	19
Vertebral fracturesc,d	0.64 (0.44 to 0.93)	11	18
Lower arm/wrist fracturesc,d	0.58 (0.47 to 0.72)	35	59
Total fracturesc,d	0.71 (0.64 to 0.80)	144	197
Death due to other causese,f	1.08 (0.88 to 1.32)	53	50
Overall mortalityc,d	1.04 (0.88 to 1.22)	79	75
Global Indexg	1.02 (0.92 to 1.13)	206	201

^a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. ^b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ^c Results are based on centrally adjudicated data for an average follow-up of 7.1 years. ^d Not included in “global index”. ^e Results are based on an average follow-up of 6.8 years. ^f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. ^g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.⁹ The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.¹⁰

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36­ to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 4: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years^a,b

Event	Relative Risk CE/MPA vs. Placebo (95% nCIc)	CE/MPA (n = 8,506)	Placebo (n = 8, 102)
		Absolute Risk per 10,000 Women-Years
CHD events Non-fatal MI CHD death	1.23 (0.99 to 1.53) 1.28 (1 to 1.63) 1.10 (0.70 to 1.75)	41 31 8	34 25 8
All strokes Ischemic stroke	1.31 (1.03 to 1.68) 1.44 (1.09 to 1.90)	33 26	25 18
Deep vein thrombosisd	1.95 (1.43 to 2.67)	26	13
Pulmonary embolism	2.13 (1.45 to 3.11)	18	8
Invasive breast cancere	1.24 (1.01 to 1.54)	41	33
Colorectal cancer	0.61 (0.42 to 0.87)	10	16
Endometrial cancerd	0.81 (0.48 to 1.36)	6	7
Cervical cancerd	1.44 (0.47 to 4.42)	2	1
Hip fracture	0.67 (0.47 to 0.96)	11	16
Vertebral fracturesd	0.65 (0.46 to 0.92)	11	17
Lower arm/wrist fracturesd	0.71 (0.59 to 0.85)	44	62
Total fracturesd	0.76 (0.69 to 0.83)	152	199
Overall mortalityf	1 (0.83 to 1.19)	52	52
Global Indexg	1.13 (1.02 to 1.25)	184	165

^a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. ^b Results are based on centrally adjudicated data. ^c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ^d Not included in “global index”. ^e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. ^f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. ^g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified for age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44 to 1.07)].

14.4 Womens Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].