Vienva TM: Package Insert and Label Information

VIENVA TM- levonorgestrel and ethinyl estradiol
Xiromed, LLC.

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Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DESCRIPTION

Each active, white tablet (21) contains 0.1 mg of levonorgestrel, d(-)-13β-ethyl-17α-ethinyl-17β-hydroxygon-4-en-3-one, a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol, 17α-ethinyl-1,3,5(10)-estratriene-3, 17β-diol.

The inactive ingredients present in the active tablet are: corn starch, crospovidone, lactose monohydrate, magnesium stearate, povidone, and pregelatinized starch.

The inactive ingredients present in the inert tablet are: corn starch, crospovidone, FD&C Red # 40 lake, D&C Yellow #10 lake, lactose anhydrous, magnesium stearate, povidone.

Structure
(click image for full-size original)

CLINICAL PHARMACOLOGY

Mode of Action

Combination oral 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).

Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is between 38% and 48%.

After a single dose of levonorgestrel and ethinyl estradiol to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady state are 1.9 ± 1 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (Figure 1). Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.

Following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of ethinyl estradiol at steady state are 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 (Figure 1).

FIGURE 1 Mean (SE) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving Levonorgestrel and ethinyl estradiol (100 mcg levonorgestrel and 20 mcg ethinyl estradiol)

Figure 1
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Table 1 provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF LEVONORGESTREL AND ETHINYL ESTRADIOL OVER A 21-DAY DOSING PERIOD Levonorgestrel

Cmax

Tmax

AUC

CL/F

Vλz/F

SHBG

Day

ng/mL

h

ng•h/mL

mL/h/kg

L/kg

nmol/L

1

2.75 (0.88)

1.6 (0.9)

35.2 (12.8)

53.7 (20.8)

2.66 (1.09)

57 (18)

6

4.52 (1.79)

1.5 (0.7)

46 (18.8)

40.80 (14.5)

2.05 (0.86)

81 (25)

21

6 (2.65)

1.5 (0.5)

68.3 (32.5)

28.4 (10.3)

1.43 (0.62)

93 (40)

Unbound Levonorgestrel

pg/mL

h

pg•h/mL

L/h/kg

L/kg

fu%

1

51.2 (12.9)

1.6 (0.9)

654 (201)

2.79 (0.97)

135.9 (41.8)

1.92 (0.30)

6

77.9 (22)

1.5 (0.7)

794 (240)

2.24 (0.59)

112.4 (40.5)

1.80 (0.24)

21

103.6 (36.9)

1.5 (0.5)

1177 (452)

1.57 (0.49)

78.6 (29.7)

1.78 (0.19)

Ethinyl Estradiol

pg/mL

h

pg•h/mL

mL/h/kg

L/kg

N/A

1

62 (20.5)

1.5 (0.5)

653 (227)

567 (204)

14.3 (3.7)

N/A

6

76.7 (29.9)

1.3 (0.7)

604 (231)

610 (196)

15.5 (4)

N/A

21

82.3 (33.2)

1.4 (0.6)

776 (308)

486 (179)

12.4 (4.1)

N/A

Distribution

Levonorgestrel in serum is primarily bound to SHBG. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

Metabolism

Levonorgestrel

The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α,5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

Ethinyl estradiol

Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.

Excretion

The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.

Special Populations

Race

Based on the pharmacokinetic study with levonorgestrel and ethinyl estradiol , there are no apparent differences in pharmacokinetic parameters among women of different races.

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol . However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel and ethinyl estradiol.

Drug-Drug Interactions

See PRECAUTIONS section-Drug Interactions

INDICATIONS AND USAGE

VienvaTM (levonorgestrel and ethinyl estradiol tablets, USP) is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant® System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

% of Women Experiencing an Unintended Pregnancy within the First Year of Use

% of Women Continuing Use at One Year3

Method

(1)

Typical Use1

(2)

Perfect Use2

(3)

(4)

Chance 4

85

85

Spermicides 5

26

6

40

Periodic abstinence

25

63

Calendar

9

Ovulation Method

3

Sympto-Thermal 6

2

Post-Ovulation

1

Cap7

Parous Women

40

26

42

Nulliparous Women

20

9

56

Sponge

Parous Women

40

20

42

Nulliparous Women

20

9

56

Diaphragm7

20

6

56

Withdrawal

19

4

Condom8

Female (Reality)

21

5

56

Male

14

3

61

Pill

5

71

Progestin only

0.5

Combined

0.1

IUD

Progesterone T

2

1.5

81

Copper T380A

0.8

0.6

78

LNg 20

0.1

0.1

81

Depo-Provera®

0.3

0.3

70

Levonorgestrel

Implants (Norplant®)

0.05

0.05

88

Female Sterilization

0.5

0.5

100

Male Sterilization

0.15

0.10

100

Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10

Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998.

1.
Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
2.
Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
3.
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4.
The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5.
Foams, creams, gels, vaginal suppositories, and vaginal film.
6.
Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7.
With spermicidal cream or jelly.
8.
Without spermicides.
9.
The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets.
10.
However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

In a clinical trial with levonorgestrel and ethinyl estradiol tablets, 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. This represents an overall pregnancy rate of 0.84 per 100 woman-years. This rate includes patients who did not take the drug correctly. One or more pills were missed during 1,479 (18.8%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. Of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the Pearl index due to the use of backup contraception and/or missing 3 or more consecutive pills.

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