of LOETTE of LOETTE

To improve the tolerability and reduce the occurrence of adverse effects associated with the initially high doses of estrogen and progestin, the doses of the hormones that comprise combination oral contraceptive (COC) preparations have steadily decreased since their introduction in the U.S. more than 40 years ago. Clinical experience has

demonstrated that low-dose levonorgestrel (LNG)/ethinyl estradiol (EE) combinations in a 5:1 ratio provide good contraceptive efficacy with an acceptable safety profile.¹For example, the first oral contraceptive containing EE and norgestrel (the parent compound of LNG) introduced in 1968 contained 50 mcg of EE and 500 mcg of norgestrel (equivalent to 250 mcg of LNG). However, by 1974, these dosages had been reduced to 30 mcg of EE and 150 mcg of LNG; and today, with the introduction of LOETTE, these dosages have successfully been reduced to 20 mcg EE and 100 mcg LNG.² Although low-dose COCs are the most widely prescribed form of contraception today and have a low failure rate, approximately 50% of all women who begin taking oral contraceptives discontinue their use within one year.³Among the factors attributed to noncompliance and/

or premature discontinuation of a COC preparation, poor cycle control (i.e., spotting, breakthrough bleeding, and amenorrhea) is the most frequently cited reason for

discontinuation.^3,4Headache, weight gain, and breast tenderness are also frequently cited reasons for early COC discontinuation.^3,4 As demonstrated by the data presented in the Clinical Experience, Clinical Safety and Tolerability, and Laboratory Parameters sections of this monograph, the LNG- containing COC preparation LOETTE

effectively combines LNG 100 mcg with EE 20 mcg to provide high contraceptive reliability with good cycle control, minimal changes in metabolic functions, and a low incidence of nuisance side effects.

Combination oral contraceptives (COCs) are not appropriate for all women. Serious as well as minor adverse reactions have been reported with the use of all COCs. Cigarette smoking increases the risk of serious cardiovascular side effects from COC use. Women who use COCs should be strongly advised not to smoke. COCs do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Please see LOETTE prescribing information at the end of this document.

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COCs such as LOETTE act as a contraceptive by suppressing gonadotropins.^5-7Although the primary mechanism of action is the inhibition of ovulation, other alterations include changes in the cervical mucus (i.e., thickening, which increases the difficulty of sperm penetration into the uterus) and in the endometrium (i.e., relative atrophy, which reduces the likelihood of implantation).^5,6,8-10When COCs are taken consistently and correctly, the failure rate is 0.1%; however, the failure rate during typical use of all types of oral contraceptives is approximately 5%.^11-13Like many other contraceptive methods, the efficacy of COCs depends upon consistent adherence to usage guidelines.

Levonorgestrel is a potent 19-nortestosterone- derived progestogen that has been used as an oral contraceptive (OC) agent, either alone or in combination with EE in different concentrations.⁶It is the parent compound of gestodene, desogestrel, and norgestimate (Figure 1). Like gestodene, LNG is an active progestogen, in contrast to other progestogens such as desogestrel and norgestimate, which are prodrugs. Table 1 summarizes the pharmacologic properties of LNG compared with those of 3-keto-desogestrel (the active metabolite of pharmacologically inactive desogestrel) and gestodene.^14,15

of LOETTE of LOETTE

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Figure 1

Chemical structures of the new progestogens gestodene, desogestrel, and norgestimate, and the parent compound levonorgestrel.

OH C CH

O

OH

O

C CH

H₂C OH

C CH

HON

OCOCH₃ C CH Levonorgestrel

Gestodene

Desogestrel

Norgestimate

Table 1 Summary of the pharmacologic properties of levonorgestrel, gestodene, and desogestrel.^* Pharmacologic Property Levonorgestrel^a Gestodene 3-Keto-Desogestrel^b Progestogenic Activity

Progesterone receptor binding affinity +++ ++ +++

(human uterine receptors)

Inhibition of ovulation +++ +++ +++

Transformation of endometrium + ++ + to ++

Estrogenic/Antiestrogenic Activity

Estrogen receptor binding affinity 0 0 0

CBG binding affinity 0 0 0

Effects on CBG levels 0 to + 0 to + 0 to +

Antiestrogenic effects ++ + +

Androgenic/Antiandrogenic Activity

Androgen receptor binding affinity + + +

(rat prostate receptors)

SHBG binding affinity + to ++ ++ + to ++

Effects on SHBG levels^c 0 to + ++ ++

Antiandrogenic effects 0 0 0

* Adapted from Wilde and Balfour¹⁴

a Levonorgestrel, levonorgestrel acetate, and levonorgestrel oxime are major metabolites of the prodrug norgestimate, and levonorgestrel accounts for at least part of the pharmacologic activity of norgestimate. Because norgestimate is rapidly metabolized in vivo, its in vitro activity is unlikely to be clinically relevant; therefore, norgestimate-specific data have not been provided.

b 3-keto-desogestrel is the active metabolite of the prodrug desogestrel.

c Effects on SHBG levels are a result of both the progestogen and estrogen components.

Abbreviations:CBG: corticosteroid-binding globulin; SHBG: sex hormone-binding globulin; +++: marked effect;

++: moderate effect; +: minimal effect; 0: no effect.

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Absorption, Metabolism, and Elimination of Levonorgestrel

No specific investigation of the absolute bioavailability of LNG 100 mcg/EE 20 mcg in humans has been conducted. However, a review of the literature indicates that LNG is rapidly and completely absorbed after oral administration and is not subject to appreciable first-pass metabolism. Consequently, the absolute bioavailability of LNG is approximately 100%

following oral administration. Moreover, its peak serum concentration is reached about 1.5 hours after ingestion.¹⁶Unlike norgestimate and desogestrel, which are prodrugs, LNG does not have to be metabolized into an active form in the liver. Instead, LNG is active in its present form, a characteristic that may lead to more predictable blood levels (Figure 2).^17,18

LNG is primarily bound to sex hormone- binding globulin (SHBG) and, to a lesser degree, serum albumin. The compound

possesses a particularly high affinity for specific binding to SHBG. After a single dose of

LOETTE under fasting conditions, maximum serum concentrations of LNG are 2.8 ± 0.9 ng/mL. At steady state, from day 19 onward, maximum LNG concentrations of 6.0 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose.

The minimum serum levels of LNG at steady state are 1.9 ± 1.0 ng/mL. Observed LNG concentrations increase from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively. Unbound LNG

concentrations increase from day 1 to days 6 and 21 by 25% and 83%, respectively.¹⁶

of LOETTE of LOETTE

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Levonorgestrel (approx. 100%)

Levonorgestrel Norgestimate and other metabolites

LiverLiver

Norgestimate 100%

Levonorgestrel

GutGut

Norgestimate acetate (small %) Levonorgestrel oxime

3-Keto-desogestrel (40% to 100%)

Bioavailability of Levonorgestrel, Norgestimate, and Desogestrel Figure 2

Unlike norgestimate and desogestrel, which are prodrugs, levonorgestrel and gestodene are active in their present forms, a characteristic that may lead to more predictable blood levels.¹⁴

The most important metabolic pathway of LNG involves the reduction of the ∆4-3-oxo group, hydroxylation at positions 2α, 1β, and 16β, and subsequent conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonogestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent LNG also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals, and this may account in part for the wide variation observed in LNG concentrations among users. LNG and its metabolites are primarily excreted in the urine (40% to 68%) and approximately 16% to 48% are excreted in feces.¹⁶

Absorption, Metabolism, and Elimination of Ethinyl Estradiol

EE is rapidly and almost completely absorbed from the gastrointestinal tract.¹⁹It undergoes extensive first-pass metabolism, and its absolute bioavailability is approximately 38%-48%.¹⁶ Ethinyl estradiol is highly bound to albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG.^20-22 After single oral administration in a study of 22 women, peak plasma concentrations of EE were reached at 1.5 ± 0.5 hours. At steady state, from day 6 onward, maximum concentrations of EE were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of EE at steady state were 10.5 ± 5.1 pg/mL. Ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21.¹⁶

Ethinyl estradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free

metabolites and as conjugates with glucuronide and sulfate.^19,23-25The major oxidative reaction is 2-hydroxylation by cytochrome P450

enzymes.^26-28The metabolites of EE are not pharmacologically active. Ethinyl estradiol is subject to presystemic conjugation (i.e., small- bowel mucosa, and in the liver) and

enterohepatic circulation.^23,24,28

Serum EE levels decrease in two phases, and their terminal half-life is approximately 16-18 hours during repeated administration.^29,30Active metabolites of EE are excreted to a greater extent in the feces than in the urine.²⁶The elimination half-life of EE is 18 ± 4.7 hours at steady state.¹⁶

Peak Plasma Levels and Half-Life of Levonorgestrel and Ethinyl Estradiol

After administration of a single oral dose of LOETTE, peak plasma levels of LNG (approximately 3 ng/mL) are reached in approximately 1.5 hours. The half-life of the terminal disposition phase of LNG in the plasma is approximately 36 ± 13 hours at steady state; the elimination half-life of EE is 18 ± 4.7 hours at steady state.¹⁶

5

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Inhibition of Ovulation

Results of three different clinical trials involving 65 women between 20 and 35 years of age have demonstrated that ovarian activity, as reflected by mean serum progesterone levels and mean follicular size, is effectively suppressed during treatment with LOETTE (Figure 3).^31-33Further, results of these studies demonstrated that ovulation returned during the posttreatment period.

Contraceptive Efficacy

The first study to demonstrate the contraceptive efficacy of a formulation equivalent to LNG 100 mcg/EE 20 mcg was conducted in Brazil during the early 1970s. This study evaluated 438 subjects (3,424 cycles) over an average of 8 months. The Pearl Index was 0.38, with 1 pregnancy occurring in a user who had “used it inadequately.”³⁴Since then, five published studies conducted in Germany and in North America of the LNG 100 mcg/EE 20 mcg formulation have demonstrated similarly high contraceptive efficacies with Pearl Indices ranging from 0.29 to 0.88 (Table 2).^2,35-38 The interim and final results of the pivotal phase-III U.S. study were published in 1997 and 1999, respectively.^2,36The study evaluated a total of 1,708 North American women between

17 and 49 years of age (and 26,554 evaluable cycles) over a 36-month period.³⁶After 1 year, the Pearl Index (1,477 subjects and 7,720 cycles) for method-failure was 0.84, with 5 pregnancies attributed to method-failure and 5 attributed to user-failure (i.e., stopping the study medication or missing >3 consecutive days of active study medication).²At the end of 3 years, the Pearl Index for method-failure was 0.88, with 12 pregnancies attributed to method- failure and 6 due to user-failure (i.e., missing ≥1 pills in the cycle in which conception occurred or the cycle just before conception occurred).³⁶ A postpublication data analysis yielded an additional pregnancy due to method-failure and a revised Pearl Index of 0.93.

A large-scale phase-IV German study subsequently reported high contraceptive efficacy. In this study, 12,843 evaluable women (average age of 24.1 years) provided 70,796 evaluable cycles in a 6-month period. The Pearl Index for method-failure was 0.44, with 8 pregnancies attributed to method-failure and 16 attributed to user-failure.³⁵

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5 6 7

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Table 2 Summary of contraceptive efficacy of LNG 100 mcg/EE 20 mcg.

Clinical Trial No. of Efficacy Evaluable Mean Age No. of Pregnancies Pearl

Patients/Cycles (Years) MF* UF^† Index^‡

Hite et al. 1999³⁵ 12,843/70,796 24.1 8 16 0.44

Archer et al. 1999³⁶ 1,708/26,554 27.2 12 (13)^§ 6 0.88 (0.93)^§

Archer et al. 1997² 1,477/7,720 27.0 5 5 0.84

Boerrigter et al. 1999³⁷ 1,560/7,960 26 4 2 0.65

Bannemerschult et al. 1997³⁸ 805/4,400 25.6 1 0 0.29

* Pregnancies due to method-failure.

† Pregnancies due to user-failure (e.g., missed pills or discontinuation of study medication).

‡ For method-failure only; the Pearl Index for user failure was not provided.

§ Postpublication data analysis

2 4 6 8 10 12 14 16 18 20 22 24 26 28

Cycle Day 0

5 10 15 20

Postcycle

3rd treatment cycle 2nd treatment cycle Precycle

1st treatment cycle

▼ mm

Figure 3

Mean diameters of follicle-like structures prior to, during, and after treatment with 100 mcg levonorgestrel plus 20 mcg ethinyl estradiol.

2 4 6 8 10 12 14 16 18 20 22 24 26 28

Cycle Day 0

5 10 15 20

▼ mm

Cycle Control

A certain percentage of women taking low-dose oral contraceptives will experience intermenstrual bleeding, which varies in intensity and can be characterized as spotting (i.e., scanty intermenstrual bleeding during treatment not requiring sanitary protection) or breakthrough bleeding (i.e., normal to heavy intermenstrual bleeding requiring sanitary protection with or without scanty bleeding during treatment). Clinical trials with LNG 100 mcg/EE 20 mcg have demonstrated that, as with other low-dose oral contraceptives, bleeding irregularities occur most often during the first few cycles of use and decrease considerably thereafter.^2,35-41This trend is best exemplified by the results of the largest clinical trial to date. In a 6-month phase-IV study which evaluated a total of 10,736 evaluable subjects (n=70,796 cycles) over a 6-month period, the incidence of breakthrough bleeding using LNG 100 mcg/EE 20 mcg peaked at cycle 1 (approximately 8%), was markedly decreased by cycle 3 (approximately 4%), and was only 2% at cycle 6.³⁵

The results of LOETTE studies also suggest that the intensity of the intermenstrual bleeding among LOETTE users is usually light and scant.^2,36-41 Intermenstrual spotting generally accounts for the majority of all reported intermenstrual bleeding and/or spotting (Table 3 and Figure 4). In two studies involving a total of 2,513 women (and 31,411 cycles), spotting alone accounted for 10.1%-12.4% of all intramenstrual bleeding and/or spotting compared to 3.4%-4.5% for bleeding alone.^36,38

The incidence of spotting reported among users of LOETTE from these studies was generally

<10.0% following cycle 4. The incidence of amenorrhea was <2.5% among women treated with LOETTE for at least 6 cycles.^35-38Results from both noncomparative and comparative LOETTE studies suggest a decrease both in the duration and intensity of withdrawal bleeding episodes.^35-41

Several comparative studies have compared the tolerability and safety of LOETTE with either norethindrone (NET triphasic) at 500 mcg, 750 mcg, and 1,000 mcg for 7 days each combined with 35 mcg EE for 21 days^39,41or with NETA/EE 1,000 mcg /20 mcg.⁴⁰In two of these studies, the frequency and duration of withdrawal bleeding episodes were lower in the LOETTE group compared with the NET/EE group (Table 4).^39,41The incidence of breakthrough bleeding and/or spotting was similar in both treatment groups in two of the studies,^39,41while the incidence was significantly lower in the LOETTE group compared to the NETA/EE group in the third study.⁴⁰These studies suggest that treatment with LOETTE results in more favorable bleeding profiles compared to treatment with NETA/EE,⁴⁰ and bleeding comparable to a triphasic norethindrone compound. Furthermore, in one study, amenorrhea occurred in 10.0% of all cycles with NETA/EE compared to only 1.1% of all cycles with LOETTE (Figure 5).⁴⁰ 5

6 7 8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Table 3 Summary of cycle control of LNG 100 mcg/EE 20 mcg in noncomparative trials.

Cycle Control

Clinical Trial Treatment No. of Evaluable Study Breakthrough Withdrawal Bleeding Duration Patients/Cycles Design Bleeding/Spotting

Breakthrough bleeding alone:

Incidence ranged from 2% (Cycle 4) to 8%

(Cycle 1) Spotting alone:

Incidence ranged from 4.7% (Cycle 6) to 22.7%

(Cycle 1)

Bleeding and/or spot- ting occurred mainly in Cycle 1 (30.4%) and decreased to 6.0% by the end of Cycle 6

Amenorrhea:1.1% of all cycles

Duration of withdrawal bleeding: mean 4-4.5 days Hite et al. 1999³⁵ 6 cycles 12,843/70,796 o, mc

Breakthrough bleeding alone:

Incidence ranged from 2.6% (Cycle 24) to 5.4%

(Cycle 3) Spotting alone:

Incidence ranged from 7.9% (Cycle 18) to 16.8%

(Cycle 1) Bleeding and/or spotting:

Incidence ranged from 16.5% (Cycle 30) to 30.6% (Cycle 1)

Amenorrhea: 1.9%

(all cycles except Cycle 1)

Duration of withdrawal bleeding:

mean 4.7 days Intensity of withdrawal bleeding:mean intensity 1.92* (all cycles) [*2=light bleeding]

Archer et al. 1999³⁶ 36 cycles 1,708/25,554 o, mc

Breakthrough bleeding alone:

Incidence ranged from 2.2% (Cycle 5) to 4.0%

(Cycle 2) Spotting alone:

Incidence ranged from 9.1% (Cycle 5) to 26%

(Cycle 1) Bleeding and/or spotting: Incidence ranged from 2.9% (Cycle 5) to 4.4% (Cycle 3)

Amenorrhea: 6.3%

(all cycles except Cycle 1)

Duration of withdrawal bleeding:

median 5 days Boerrigter et al. 6 cycles 1,590/8,016 o, mc

1999³⁷

Key

o: Open-label; mc: Multicenter

5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Table 3 (cont.)

Cycle Control

Clinical Trial Treatment No. of Evaluable Study Breakthrough Withdrawal Bleeding Duration Patients/Cycles Design Bleeding/Spotting

Breakthrough bleeding alone:

Incidence ranged from 3.3% (Cycle 9) to 4.6%

(Cycle 3) Spotting alone:

Incidence ranged from 7.8% (Cycle 12) to 11.1%

(Cycle 3) Bleeding and/or spotting:

Incidence ranged from 6.5% (Cycle 12) to 11.3%

(Cycle 9)

Amenorrhea:1.6% (all cycles except Cycle 1) Duration of withdrawal bleeding:4.8 days Intensity of withdrawal bleeding:mean intensity

<2* (all cycles) [*2=light bleeding]

Archer et al. 1997² 12 cycles 1,477/7,720 o, mc

Key

o: Open-label; mc: Multicenter

Breakthrough bleeding alone:

Occurred alone or in combination with spot- ting was reported most frequently in Cycle 3 (8.0%) and decreased progressively to Cycle 5 (3.2%)

Spotting alone:

Spotting alone or in combination with break- through bleeding was reported most frequent- ly in Cycle 1 (25.8%) and decreased progressive- ly to Cycle 5 (8.4%) Spotting alone or in combination was reported in 13.8% of all cycles vs. breakthrough bleeding alone or in combination (5.9%)

Amenorrhea:2.4%

(Cycle 6)

Duration of withdrawal bleeding:3-5 days Intensity of withdrawal bleeding:“scanty or normal” in 95.6% of cycles.

Bannemerschult 6 cycles 805⁄4,440 o, mc

et al. 1997³⁸

Figure 4. Incidence of intermenstrual bleeding (% of users) from 26,554 evaluable cycles of LOETTE use over 30 months.36

[FIGURE 5 HERE]

Figure 5. Percentage of amenorrheic cycles by treatment groups and cycle over 4 months. 40

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12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Table 4 Summary of cycle control of LOETTE in comparative trials.

Cycle Control

Clinical Trial Treatment No. of Evaluable Study Breakthrough Withdrawal Bleeding Patients/Cycles Design Bleeding/Spotting

Overall, the percent- ages of cycles with intermenstrual bleeding were similar between the two treatment groups.

Overall, the percent- ages of normal men- strual cycles were simi- lar between the two treatment groups.

In the LNG group, there was a statistically sig- nificantly longer latent period with statistically significant shorter withdrawal bleeding episodes.

Reisman et al. LOETTE^ax 4 102⁄453 o, r, mc

1999³⁹ cycles

triphasic

NET/EE^bx 4 118⁄506 cycles

The LNG/EE group achieved a lower rate of breakthrough bleeding and/or spotting than the NETA/EE group (34.8%

vs. 56.3% in Cycle 3, respectively; P<0.05).

Overall, the LNG/EE group achieved a con- sistently higher per- centage of normal men- strual cycles than the NETA/EE group (63.8%

vs. 41.9%, respectively;

P<0.005) in Cycle 4.

Of the total cycles in the NETA/EE group, 10%

were amenorrheic, compared with 1.1% in the LNG/EE group.

DelConte et al. LOETTE^ax 4 84⁄274 o, r, mc

1999⁴⁰ cycles

89⁄289 monophasic

NETA/EE^cx 4 cycles

In individual cycles, consistently lower occurrences of inter- menstrual bleeding (including spotting) occurred in the LNG/EE group, although these differences were not statistically significant.

For all treatment cycles, the percentage of cycles classified as nor- mal were consistently higher in the LNG/EE group than the NET/EE group.

By Cycle 4, approxi- mately 70% of cycles with LNG/EE were nor- mal compared with 54%

with NET/EE (P<0.05).

Chavez et al. LOETTE^ax 4 93/384 o, r, mc

1999⁴¹ cycles

98/400 triphasic 4

NET/EE^bx 4 cycles Comparative Trials

a LNG 100 mcg/EE 20 mcg

b NET 500 mcg, 750 mcg, and 1,000 mcg for 7 days each/EE 35 mcg for 21 days

c NETA/EE 1,000 mcg/20 mcg

Abbreviations:o: open-label; r: randomized; mc: multicenter; LNG: levonorgestrel; EE: ethinyl estradiol;

NETA: norethindrone acetate; NET: norethindrone

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13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Amenorrheic Cycles (% of Total Cycles)

*

LNG/EE 100 mcg/20 mcg NETA/EE 1,000 mcg/20 mcg 25%

20%

15%

10%

5%

0%

Cycle 1 Cycle 2 Cycle 3 Cycle 4 All Cycles

*

Figure 4 Incidence of

intermenstrual bleeding (% of users) from 26,554 evaluable cycles of LOETTE use over 30 months.³⁶

Percent of Users

Breakthrough bleeding only Breakthrough bleeding and/or spotting

Spotting only Amenorrhea 40

30

20

10

0

Cycle 1 Cycle 6 Cycle 12 Cycle 24 Cycle 30 All Cycles (Excluding Cycle 1)

Figure 5 Percentage of amenorrheic cycles by treatment groups and cycle over 4 months.⁴⁰

*P<0.05 between groups.

Androgenic Effects

Although numerous studies have evaluated the effects of COC preparations on lipid

metabolism and thromboembolic disorders, only a few studies have assessed changes in the levels of androgen markers.^42-44

In two comparative clinical trials involving 41 and 58 healthy women, respectively, LOETTE had a greater suppressive effect on ovarian androgen production compared with NETA/EE 1,000 mcg/20 mcg.^43,44

In a study involving 41 women using LOETTE or NETA/EE for 3 months, SHBG increased 234% from baseline to cycle 3 in the NETA/EE group (n=20) compared to 100% in the

LOETTE group (n=21), while total testosterone levels were reduced (-21%) in only the

LOETTE group.⁴³DHEAS, dihydrotestosterone, and 3α-androstanediol glucuronide were

similarly and significantly reduced from baseline to cycle 3 (reduced approximately 20%, 20%, and up to 37%, respectively) in both treatment groups.⁴³

In a study involving 58 women (Table 5), LNG 100 mcg/EE 20 mcg reduced adrenal, ovarian, and peripheral androgens compared with NETA/EE, which reduced only adrenal and peripheral androgens.⁴⁴Despite a 2.2-fold greater relative increase in SHBG with NETA/EE than LNG/EE, bioavailable

testosterone was reduced by the same amount using either progestin/EE combination. Acne was improved in both treatment groups as well.⁴⁴These data demonstrate that LOETTE has substantial antiandrogenic effects with respect to androgen production when administered orally.^43,44

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14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Table 5 Biochemistry measures at baseline and end of therapy.

LOETTE (n=21)

Variable Baseline End of Therapy Change (%)

DHEAS (mcg/mL) 2.57 ± 1.17 1.81 ± 0.69 -18.9 ± 40.2*

A (ng/mL) 1.39 ± 0.43 0.85 ± 0.41 -36.9 ± 26.7*

Total T (ng/dL) 34.6 ± 9.3 24.9 ± 8.9 -27.0 ±21.5*

Bioavailable T (ng/dL) 7.19 ± 2.79 4.69 ± 2.22 -30.7 ± 35.5*

DHT (ng/dL) 20.7 ± 7.3 16.9 ± 7.1 -16.8 ± 23.2*

3α-diol G (ng/mL) 4.08 ± 2.06 2.27 ± 1.32 -38.8 ± 36.1*

SHBG (nmol/L) 25.2 ± 11.8 46.0 ± 16.1 106 ± 89*

Values are mean ± standard deviation.

DHEAS: dehydroepiandrosterone sulfate; A: androstenedione; Total T: total testosterone; Bioavailable T: bioavailable testosterone;

DHT: dihydrotestosterone; 3α-diol G: 3α-androstanediol glucuronide; SHBG: sex hormone-binding globulin.

*P< 0.05, baseline vs. end of therapy.

Table adapted from Thorneycroft et al⁴⁴

LOETTE is well tolerated, as demonstrated by a low incidence of adverse events (AEs) including common COC side effects. The incidence of common COC side effects in women who have received LOETTE for at least 12 months follows a well-known and expected pattern. Typically, the incidence of side effects is increased during the initial cycles (cycles 1 and 2); decreases notably between cycles 3 and 4;

and minimal or negligible side effects are reported during cycles 5 and 6. A review of 5 clinical trials involving more than 16,000 women who received LNG 100 mcg/EE 20 mcg for 6 to 36 cycles has consistently shown that headache, breast pain, and nausea were the most commonly reported adverse events, followed by less common events including nervousness, vomiting, depression, and acne.^2,35-38As previously noted, the incidence of these side effects was negligible by cycle 6. This safety profile is particularly well demonstrated in the largest study to date involving 12,843 women over 6 months (Table 6).³⁵

Only 17% of 1,708 volunteers treated with LOETTE during a 3-year clinical trial withdrew due to adverse events, and no single adverse event accounted for more than 2% of all reported adverse events (Table 7).³⁶ 5

6 7 8 9 10 11 12 13 14

15 16 17 18 19 20 21 22 23 24 25 26 27

Tolerability Tolerability

Table 7 Adverse events most frequently attributed to withdrawal of ≥10 subjects who received LOETTE.³⁶

Subjects Affected (n=1,708)

Adverse Event No. %*

Any adverse event^† 290 17

Metrorrhagia 41 2

Headache 33 2

Weight gain 17 <1

Amenorrhea 17 <1

Emotional lability 14 <1

Depression 13 <1

Hypertension 12 <1

Nausea 12 <1

Acne 11 <1

Hypercholesteremia 11 <1

Migraine 11 <1

Table 6 Adverse events most frequently reported among 12,843 women who received LNG 100 mcg/EE 20 mcg over 6 cycles.³⁵

Subjects Affected (n=12,843)

Adverse Event No. %*

Any adverse event^† 1579 12.3

Intracyclic bleeding 450 3.5

Metrorrhagia 244 1.9

Headache 167 1.3

Skin irritation 141 1.1

Amenorrhea 141 1.1

Weight gain 115 0.9

Nausea/vomiting 115 0.9

Acne 103 0.8

Dysmenorrhea 77 0.6

Mood disorders 51 0.4

Breast tension 13 0.1

Thrombosis 2 0.02

*Subjects could report ≥2 different AEs in the same body system. Percentages are based on the total number of subjects enrolled.

† 9.8% withdrew because of AEs.

Adapted from Hite et al³⁵

In a 3-year study involving 1,708 women, no cases of venous thromboembolism were reported.³⁶However, one myocardial infarction was reported in a 38-year-old woman who smoked 20 cigarettes per day.

Thrombotic events were rare occurrences in six other published studies involving more than 14,000 women who used LNG 100 mcg/EE 20 mcg for 4 to 6 cycles.^35,37-41In these trials, only 2 cases were reported and these women had a positive family history of thrombosis.³⁵ Venous thromboembolism (VTE) risk is increased with the use of all OCs.

Please see LOETTE prescribing information at the end of this document.

Changes in Weight

In the analysis of a placebo-controlled study, changes in mean body weight from baseline were similar between participants taking LOETTE and placebo.⁴⁵

The LOETTE and placebo groups displayed comparable changes in weight from baseline over six cycles of treatment. The results of placebo-controlled trials that examined the

effects of LOETTE on measured weight are shown in Figure 6. No difference in mean weight change between the LOETTE and placebo groups was observed at any time point.

Blood Pressure

Although the use of any COC is contraindicated in women with uncontrolled hypertension, and increases in blood pressure have been reported in women taking COCs,¹⁶blood pressure has been shown to be largely unaffected by LOETTE use. In studies involving more than 16,000 women receiving LNG 100 mcg/EE 20 mcg over 4 to 36 cycles, no clinically significant changes in mean systolic or diastolic blood pressure were reported.^2,35-41In a 3-year study of 1,708 women, a total of 64 women (4.0%) had an elevated systolic blood pressure of ≥140 mmHg or an elevated diastolic blood pressure of ≥90 mmHg at least once during the study.³⁶ However, of these 64 women, 52 of them (81.3%) either remained in the study with no additional episodes of elevated clinical hypertension or withdrew from the study for other reasons. In only 12 cases (<1%), elevated blood pressure was the reason for study withdrawal.³⁶

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16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Figure 6

Changes in body weight from baseline among 704 women who used LOETTE or placebo over 6 cycles (% of users)⁴⁵

% of Women

LOETTE Placebo 80%

60%

40%

20%

0%

Weight Loss (≥1 kg) Weight Change (<1 kg) Weight Gain (≥1 kg)

Data from clinical trials have demonstrated that, overall, LNG-containing COCs exert no clinically significant changes in most laboratory parameters.^39,46Several studies indicate that LNG 100 mcg/EE 20 mcg has minimal impact on metabolic parameters.^39,46,47

Lipid Metabolism

It is well known that the effects of COC preparations on lipid profiles are based upon the dosage and type of estrogen and progestogen components, the selectivity of the progestogen, and the overall ratio of estrogenicity/antiestrogenicity.⁴⁸

Data from a clinical study of 28 women using LOETTE for 24-cycles (Table 8) indicate that users were shown to have a favorable lipid profile, with no subjects having “...clinically important changes” in their lipid profiles during treatment, according to the study’s authors.⁴⁶

Additionally, by the end of cycle 24, all lipid values that had increased during earlier cycles had returned to pretreatment levels.⁴⁶Although this study had a restrictive sample size, these results demonstrate that LOETTE has an effect similar to that of other low-dose COC

preparations on plasma lipids.^39,46

It should be noted that in patients with elevated triglycerides, estrogen-containing preparations may be associated with rare but large elevations of plasma triglycerides that may lead to

pancreatitis.^16,49,50

Carbohydrate Metabolism

Glucose intolerance has been reported in COC users.^16,51-53However, an open label, randomized study in 48 women lasting 13 cycles compared the influence of a LNG 100 mcg/EE 20 mcg COC on carbohydrate metabolism variables to that of a LNG 150 mcg/ EE 30 mcg COC. Data from the 48 subjects (Table 9) indicated that fasting levels for glucose and insulin were decreased in the 20 mcg EE group and either minimally elevated or unchanged in the 30 mcg EE group. The differences between the two groups from baseline were statistically significant for insulin levels. The authors concluded that the “...20 EE preparation appears to have a more favorable effect on the carbohydrate profile compared to the higher- dosed OC.”⁴⁷

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18 19 20 21 22 23 24 25 26 27 28 29 30 Table 8 Pretreatment values and mean percentage changes of serum lipid and apolipoprotein

concentrations during treatment with LOETTE⁴⁶

Lipid Variable N Pretreatment Cycle 3 Cycle 6 Cycle 12 Cycle 18 Cycle 24 (% Change) (% Change) (% Change) (% Change) (% Change) Triglyceride 28 0.79 ± 0.41 40.21 ± 7.93* 33.09 ± 8.86* 36.84 ± 7.98* 31.46 ± 8.93† 20.65 ± 10.3 concentration

L (mmol/L)

Total cholesterol 28 4.60 ± 0.85 5.83 ± 3.0 4.98 ± 3.21 6.22 ± 3.19 5.66 ± 3.76 7.28 ± 3.82 concentration

(mmol/L)

High-density 25 1.28 ± 0.36 0.02 ± 3.79 -0.04 ± 3.81 0.77 ± 3.23 1.04 ± 3.33 3.32 ± 3.91 lipoprotein

cholesterol concentration (mmol/L )

Low-density 28 2.95 ± 0.62 9.13 ± 3.88‡ 10.94 ± 3.89† 10.56 ± 4.39‡ 1.27 ± 4.52 4.60 ± 4.83 lipoprotein

cholesterol concentration (mmol/L)

High-density 23 0.41 ± 0.18 -5.15 ± 7.43 -3.51 ± 12.3 5.90 ± 12.3 5.11 ± 12.6 2.27 ± 11.9 lipoprotein

subfraction 2 concentration (mmol/L)

High-density 23 0.91 ± 0.21 5.41 ± 3.36 7.36 ± 3.79 4.49 ± 2.97 4.51 ± 4.02 7.15 ± 3.18‡

lipoprotein subfraction 3 concentration (mmol/L)

Apolipoprotein A-I 27 1.48 ± 0.31 0.79 ± 3.63 -0.65 ± 4.07 -1.94 ± 4.26 -0.38 ± 4.77 -6.88 ± 3.36 concentration (g/L)

Apolipoprotein B 27 1.01 ± 0.23 22.29 ± 5.27* 24.94 ± 5.49* 25.01 ± 4.60* 6.08 ± 5.53 -4.68 ± 5.05 concentration (g/L)

Ratio of total to 24 3.71 ± 0.93 7.78 ± 2.73† 6.57 ± 3.80 7.70 ± 3.64‡ 6.82 ± 3.42 6.54 ± 4.38 high-density

lipoprotein cholesterol

Ratio of low- 24 2.43 ± 0.85 10.62 ± 3.62† 12.75 ± 4.70‡ 12.94 ± 5.30‡ 2.74 ± 4.65 4.66 ± 5.82 density lipoprotein

to high-density lipoprotein cholesterol

Ratio of high- 23 0.44 ± 0.15 -10.5 ± 5.69 -11.4 ± 9.72 1.36 ± 11.2 9.02 ± 19.3 -6.17 ± 9.13 density lipoprotein

subfractions 2 and 3

Ratio of 26 0.70 ± 0.17 22.81 ± 4.06* 27.26 ± 4.16* 32.66 ± 6.56* 7.81 ± 5.63 3.31 ± 4.26 apolipoproteins

B and A-I

Hemostasis

Oral contraceptives are known to influence the hemostatic system by increasing procoagulant and fibrinolytic activity. A comparative study involving 30 women taking LOETTE over 12 cycles was undertaken to evaluate its effects on various hemostatic factors.⁵⁴Factor X, plasminogen antigen and activity, and D-dimer levels were significantly increased during all 3 cycle periods (Cycles 3, 6, and 12).

Antithrombin antigen and protein S total antigen were significantly decreased at Cycles 3, 6, and 12, whereas Factor VII and protein S activity were significantly decreased at Cycle 3 and at Cycles 3 and 6, respectively (see Table 10).

Overall, the authors concluded that LOETTE had effects on hemostasis consistent with those of other low-dose COCs. In addition, they stated, “Most individual values remained within the reference range, however, and no clinically important effects on hemostatic balance were noted.”⁵⁴

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Table 10 Hemostatic changes in 30 subjects who received LOETTE over 12 cycles.⁵⁴

% Change from Baseline

Parameter Cycle 6 Cycle 12

Prothrombin time(s) -0.1 0.0

Partial thromboplastin time(s) 0.2 0.0 Procoagulant factors:

Factor VII (%) -5.5 -8.6

Factor X (%) 9.4^† 7.8^‡

TAT complexes (mcg/L) 0.0 -0.2

Anticoagulant factors:

Protein S activity (%) -10.4* -4.9 Total protein S antigen (%) -13.1^† -13.2^† Free protein S antigen (%) -1.6 -2.1 Antithrombin antigen (%) -5.8^† -11.0^† Antithrombin activity (%) 1.8 1.4 Fibrinolytic factors:

Fibrinogen level (g/L) -0.05 0.04

Plasminogen antigen (mg/L) 26.4^† 29.3^† Plasminogen activity (%) 23.0^† 26.8^†

D-dimer (mcg/L) 60.0^‡ 48.9*

*Denotes statistically significant percentage change from base-

Table 9 Carbohydrate profile, fasting, and AUCs (0-3h) (median and interquartile ranges)⁴⁷

Unit Baseline Cycle 6 Cycle 13 % change baseline PValue

to cycle 13*

20 EE 30 EE 20 EE 30 EE 20 EE 30 EE 20 EE 30 EE

Glucose mmcl/L 4.7 (0.3) 4.6 (0.7) 4.6 (0.3) 4.5 (0.4) 4.5 (0.6) 4.6 (0.3) -1.96 (12.4) 2.00 (6.6) n.s.

Insulin pmcl/L 50 (28) 42 (15) 48 (49) 45 (14) 48 (30) 43 (13) -8.23 (46) 5.26 (69) n.s.

C-peptide pmcl/L 462 (183) 437 (166) 462 (188) 479 (100) 429 (141) 438 (143) -5.88 (41) 5.62 (50) n.s.

Free fatty acids µmcl/L 420 (190) 420 (31) 440 (150) 410 (300) 490 (280) 370 (180) -9.38 (72) 0.00 (67) n.s.

AUC(0-3b) absolute change baseline

to cycle 13*

Glucose mmcl/L x 907 (102) 900 (186) 987 (220) 924 (309) 962 (137) 992 (183) 41.25 (110) 73.5 (159) n.s.

min

Insulin pmcl/L x 39930 37380 47145 44100 40275 49530 -1635 11797 0.0491

min (17595) (23340) (30810) (17895) (18030) (21232) (18125) (24112)

*It should be noted that this column presents the median of the individual changes, which is in general not equal to the change of the medians for each time point presented in the columns on the left hand side.

The following noncontraceptive health benefits related to the use of COCs are supported by epidemiological studies that largely utilized COC formulations containing more than 35 mcg of EE or 50 mcg of mestranol. Since 20 mcg EE COCs are as effective as those containing 30 mcg or more of EE with regard to ovulation inhibition and atrophy of the endometrium (the mechanisms by which COCs elicit many of their noncontraceptive benefits), 20 mcg pills should offer the same benefits as those with higher estrogen doses.^31,55

Effects on Menses

• Improved menstrual cycle regularity^56,57

• Decreased blood loss and decreased incidence of iron-deficiency anemia^58,59

• Decreased incidence of dysmenorrhea⁶⁰

Effects Related to Inhibition of Ovulation

• Decreased incidence of functional ovarian cysts^61,62

• Decreased incidence of ectopic pregnancies^63,64 Other Effects

• Decreased incidence of fibroadenomas and fibrocystic disease of the breast^65,66

• Decreased incidence of acute pelvic inflammatory disease^67,68

• Decreased incidence of endometrial cancer^69,70

• Decreased incidence of ovarian cancer^70-73

• Decreased incidence and severity of acne^74,75

Health Benefits

Health Benefits

⁵

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Acne is a common condition that affects about 45 million people in the U.S. and accounts for approximately 5 million doctor visits a year.

Dermatologists are not the only health care providers treating acne. The proportion of visits for acne to nondermatologists has been

increasing each decade. The effects of acne can substantially impact quality of life. Although acne is not generally considered a reproductive issue, it is an appropriate subject for

gynecologists as well as for dermatologists because it involves hormonal aspects of a woman’s health and can occur throughout her reproductive lifespan. Women may be interested to know that combined oral contraceptives (COCs) can be used to treat acne. Moreover, if a woman experiences an improvement in her acne with the use of COCs, her satisfaction and compliance with the regimen may be enhanced.

Introduction

Acne vulgaris, the most common type of acne, is a disease of the pilosebaceous unit affecting primarily the face and, to a lesser degree, the back, chest, and shoulders. It has a multifactorial etiology, which encompasses the following^76-78

1. Follicular hyperkeratinization, with increased turnover, desquamation, and cohesiveness of follicular cells that obstruct the follicular canal

2. Increased sebum production

3. Proliferation of Propionibacterium acnes, promoted by an environment rich in sebum and desquamated follicular cells

4. Inflammation due to the irritant action of sebum leaking into the dermis and to chemotactic proinflammatory factors generated by P. acnes

Production of sebum by the sebaceous glands is controlled by androgens (Figure 7).^79-82

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Figure 7

Acne and Androgen Metabolism

Androgen receptor in sebaceous

gland Total testosterone

Sebum production

SHBG

5α-reductase Free testosterone

DHT

The sebaceous glands are stimulated by dihydrotestosterone (DHT), which is derived from free testosterone in the presence of 5a- reductase. The factors determining the level of free testosterone are total testosterone and sex hormone binding globulin (SHBG), which binds testosterone. SHBG is produced by the liver;

testosterone by the adrenal glands and, in females, by the ovaries. An increase in total testosterone or decrease in SHBG causes free testosterone to rise.

With hirsutism and alopecia, acne forms a triad of conditions associated with hyperandrogenici- ty. It is increased androgenic activity that accounts for the high frequency of acne during adolescence.

Using Low-Dose COCs to Treat Acne in Women How COCs Improve Acne

Combination oral contraceptives (COCs) improve acne by reducing the production of sebum.^83,84They achieve this effect by reducing the production of testosterone by the ovaries and adrenal glands and increasing the production of SHBG by the liver. These actions combine to reduce the level of free testosterone and its derivative, dihydrotestosterone, which is the substance that stimulates the sebaceous glands to produce sebum.^79-82

Efficacy of COCs in the Treatment of Acne The efficacy of COCs in the treatment of acne has been shown in numerous studies spanning 2 decades. Three were large observational studies—

one involving 3,000 women who, while taking COCs, showed a reduction in acne incidence of 96%⁸⁵; a second involving 11,605 women with acne who, after taking COCs for 6 cycles, showed the disappearance of acne in 80%⁸⁶; and a third (multicenter trial) involving 50,000 women who, after taking a monophasic OC for 6 cycles, showed acne improvement in 38%.⁸⁷ The efficacy of COCs in improving acne has also been shown in 2 open-label studies—one involving 271 women who took an OC for up to 11 months, showing a decrease in the incidence of pustular acne from 18% to 9%

and in papulopustular acne from 35% to 15%⁸⁸; and another, involving 41 acne patients, showing that 6 cycles of OC use reduced the number of comedones by about 80% in almost 70% of patients.⁷⁴

There have also been 7 nonplacebo-controlled, comparative studies, each involving 2 or 3 COCs.^89-95With subjects ranging in number from 54 to 162, some studies found significant differences between the COCs; others did not. The studies agreed that, regardless of composition, all COCs improve acne over baseline.

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