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Seasonale (Levonorgestrel / Ethinyl Estradiol) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Seasonale® (levonorgestrel/ethinyl estradiol tablets) is an extended-cycle oral contraceptive consisting of 84 pink active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 white inert tablets (without hormones). The chemical formula of levonorgestrel USP is 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17(alpha))-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17(alpha))-. The structural formulas are as follows:

Each pink active tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP. Each white inert tablet contains the following inactive ingredients: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.

INTRODUCTION

Any woman who considers using oral contraceptives ("the birth control pill" or "the pill") should understand the benefits and risks of using this form of birth control. Although oral contraceptives have important advantages over other methods of contraception, they have certain risks that no other method has, and some of these risks may continue after you have stopped using the oral contraceptive. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use Seasonale® properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with your healthcare provider, both when you first start taking Seasonale® and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on Seasonale®.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or "the birth control pill" or "the pill" are used to prevent pregnancy and are more effective than most other nonsurgical methods of birth control. The chance of becoming pregnant is approximately 1.0% per year (1 pregnancy per 100 women per year of use) when the pills are used correctly, and no pills are missed. Typical failure rates are approximately 5.0% per year when women who miss pills are included. The chance of becoming pregnant increases with each missed pill during the menstrual cycle.

In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:

No methods: 85%

Vaginal sponge: 20 to 40%

Cervical cap: 20 to 40%

Spermicides alone: 26%

Periodic abstinence: 25%

Condom (female): 21%

Diaphragm with spermicides: 20%

Withdrawal: 19%

Condom (male): 14%

Female sterilization: 0.5%

IUD: 0.1 to 2.0%

Injectable progestogen: 0.3%

Male sterilization: 0.15%

Norplant system: 0.05%

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.

Some women should not use the pill. You should not use the pill if you have any of the following conditions:

  • A history of heart attack or stroke
  • A history of blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
  • A history of blood clots in the deep veins of your legs
  • Chest pain (angina pectoris)
  • Known or suspected breast cancer or cancer of the lining of the uterus, cervix, vagina, or certain hormonally-sensitive cancers
  • Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare provider)
  • Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill
  • Liver tumor (benign or cancerous)
  • Known or suspected pregnancy
  • Heart valve or heart rhythm disorders that may be associated with formation of blood clots
  • Diabetes affecting your circulation
  • Uncontrolled high blood pressure
  • Active liver disease with abnormal liver function tests
  • Allergy or hypersensitivity to any of the components of Seasonale®
  • A need for surgery with prolonged bedrest

Tell your healthcare provider if you have any of the above conditions. Your healthcare provider can recommend a safer method of birth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES

Tell your healthcare provider if you or any family member has ever had:

  • Breast nodules, fibrocystic disease of the breast, an abnormal breast X-ray or mammogram
  • Diabetes
  • Elevated cholesterol or triglycerides
  • High blood pressure
  • Migraine or other headaches or epilepsy
  • Depression
  • Gallbladder, liver, heart or kidney disease
  • History of scanty or irregular menstrual periods

Women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives. Also, be sure to inform your healthcare provider if you smoke or are on any medications.

RISKS OF TAKING ORAL CONTRACEPTIVES

If you use Seasonale® you will receive more exposure to hormones on a yearly basis than if you used a conventional 28-day cycle oral contraceptives containing a similar amount of estrogen and progestin (an additional 9 weeks exposure per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with Seasonale have not suggested an increased risk of these disorders.

  1. Risk of Developing Blood Clots
    Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare provider about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill (See also the section on Breastfeeding in " GENERAL PRECAUTIONS ".)
    The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills (containing 50 micrograms or higher of ethinyl estradiol) and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44, it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers.
  2. Heart Attacks and Strokes
    Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease.
    Women with migraine (especially migraine with aura) who take oral contraceptives also may be at higher risk of stroke.
  3. Gallbladder Disease
    Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens.
  4. Liver Tumors
    In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers in two studies in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers in general are extremely rare and the chance of developing liver cancer from using the pill is thus even rarer.
  5. Cancer of the Breast and Reproductive Organs
    Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram.
    Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.
    Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.
  6. Lipid Metabolism and Inflammation of the Pancreas
    In patients with inherited defects of the lipid metabolism, there have been reports of significant elevations of plasma triglycerides during estrogen therapy. This has led to pancreatitis in some cases.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY

All methods of birth control and pregnancy are associated with a risk of developing certain diseases, which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.

ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE
Method of control AGE
and outcome 15-19 20-24 25-29 30-34 35-39 40-44
No fertility -
control methods *
7.0 7.4 9.1 14.8 25.7 28.2
Oral contraceptives
non-smoker **
0.3 0.5 0.9 1.9 13.8 31.6
Oral contraceptives
smoker **
2.2 3.4 6.6 13.5 51.1 117.2
IUD ** 0.8 0.8 1.0 1.0 1.4 1.4
Condom * 1.1 1.6 0.7 0.2 0.3 0.4
Diaphragm/
spermicide *
1.9 1.2 1.2 1.3 2.2 2.8
Periodic
abstinence *
2.5 1.6 1.6 1.7 2.9 3.6
* Deaths are birth related
** Deaths are method related

In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group.

The suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older high-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks. Older women, as all women who take oral contraceptives, should take an oral contraceptive that contains the least amount of estrogen and progestin that is compatible with the individual patient needs.

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 changes in the endometrium (which reduce the likelihood of implantation).

PHARMACOKINETICS

ABSORPTION

No specific investigation of the absolute bioavailability of Seasonale® in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 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 approximately 43%.

Table 1: Mean ± SD Pharmacokinetic Parameters Following A Single Dose Administration of Two Tablets of Seasonale® in Healthy Female Subjects Under Fasting Conditions
Analyte AUCt (mean ± SD) Cmax (mean ± SD) Tmax (mean ± SD) T1/2 (mean ± SD)
Levonorgestrel 60.8 ± 25.6 ng*hr/mL 5.6 ± 1.5 ng/mL 1.4 ± 0.3 hours 29.8 ± 8.3 hours
Ethinyl estradiol 1307 ± 361 pg*hr/mL 145 ± 45 pg/mL 1.6 ± 0.5 hours 15.4 ± 3.2 hours

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Seasonale® has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5-99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95-97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17(beta)-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3(alpha),5(beta)-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3(alpha),5(alpha)-tetrahydrolevonorgestrel and 16(beta)-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. 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.

First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonale® was about 30 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Seasonale® was found to be about 15 hours.

SPECIAL POPULATIONS

Race

No formal studies on the effect of race on the pharmacokinetics of Seasonale® were conducted.

Hepatic Insufficiency

No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale®. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale®.

DRUG-DRUG INTERACTIONS

See PRECAUTIONS section - Drug Interactions.

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