«ALESSE® 28 Tablets (levonorgestrel and ethinyl estradiol tablets) Rx only Patients should be counseled that oral contraceptives do not protect ...»
ALESSE® 28 Tablets
(levonorgestrel and ethinyl estradiol tablets)
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.
21 pink active tablets each containing 0.10 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 are cellulose, hypromellose, iron oxide, lactose, magnesium stearate, polacrilin potassium, polyethylene glycol, titanium dioxide, and montanic ester wax.
7 light-green inert tablets, each containing cellulose, FD&C blue no. 1, hypromellose, iron oxide, lactose, magnesium stearate, polacrilin potassium, polyethylene glycol, titanium dioxide, and montanic ester wax.
CLINICAL PHARMACOLOGYMode 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 ALESSE 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 ALESSE 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 1 state, attained from day 19 onwards, maximum levonorgestrel 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 levonorgestrel at steady state are 1.9 ± 1.0 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 I).
FIGURE I: Mean (SE) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving ALESSE (100 μg levonorgestrel and 20 μg ethinyl estradiol) TABLE I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.
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.
3 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 ALESSE, 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 ALESSE.
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 ALESSE.
Drug-drug interactions See PRECAUTIONS section - Drug Interactions
INDICATIONS AND USAGEALESSE 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.
Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective 5 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 ALESSE (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
CONTRAINDICATIONSCombination oral contraceptives should not be used in women with any of the following
Thrombophlebitis or thromboembolic disorders A history of deep-vein thrombophlebitis or thromboembolic disorders Cerebrovascular or coronary artery disease (current or past history) Valvular heart disease with thrombogenic complications Thrombogenic rhythm disorders Hereditary or acquired thrombophilias Major surgery with prolonged immobilization Diabetes with vascular involvement Headaches with focal neurological symptoms Uncontrolled hypertension Known or suspected carcinoma of the breast or personal history of breast cancer Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Hepatic adenomas or carcinomas, or active liver disease Known or suspected pregnancy Hypersensitivity to any of the components of ALESSE
Cigarette smoking increases the risk of serious cardiovascular side effects from oralcontraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS).
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
7 The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial infarction An increased risk of myocardial infarction has been attributed to oral-contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.
Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (FIGURE II) among women who use oral contraceptives.