Zenchent

ZENCHENT — norethindrone and ethinyl estradiol
Physicians Total Care, Inc.

Rx only

Revised: November 2007 14624-1

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Zenchent® tablets provide a continuous regimen for oral contraception derived from 21 orange tablets composed of norethindrone and ethinyl estradiol to be followed by 7 white tablets of inert ingredients. The structural formulas are:

Norethindrone and ethinyl estradiol structural formulas
(click image for full-size original)

C20 H26 O2 Molecular Weight: 298.42 C20 H24 O2 Molecular Weight: 296.40

The orange active tablets each contain 0.4 mg norethindrone and 0.035 mg ethinyl estradiol, and contain the following inactive ingredients: dibasic calcium phosphate dihydrate, lactose monohydrate, sodium starch glycolate, magnesium stearate, povidone, FD&C yellow #6 aluminum lake 15-18%, D&C yellow #10 aluminum lake 15-20%

The white tablets in the 28-Day regimen contain only inert ingredients as follows: lactose anhydrous, magnesium stearate, and microcrystalline cellulose.

CLINICAL PHARMACOLOGY

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).

INDICATIONS AND USAGE

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table 1 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, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 1: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD
% of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Method Lowest
Expected* Typical**
Reproduced with permission of the Population Council from J. Trussell, et al: Contraceptive failure in the United States: An update. Studies in Family Planning, 21(1), January-February 1990.
*The authors’ best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any reason other than pregnancy.
**This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any reason other than pregnancy.
***Combined typical rate for both combined and progestin only.
#Combined typical rate for both medicated and nonmedicated IUD.
(No contraception) (85) (85)
Oral contraceptives
combined 0.1 3***
progestin only 0.5 3***
Diaphragm with spermicidal
cream or jelly 6 18
Spermicides alone (foam, creams,
jellies and vaginal suppositories) 3 21
Vaginal sponge
nulliparous 6 18
multiparous 9 28
IUD 0.8-2.0 3#
Condom without spermicides 2 12
Periodic abstinence (all methods) 1-9 20
Injectable progestogen 0.3-0.4 0.3-0.4
Implants
6 capsules 0.04 0.04
2 rods 0.03 0.03
Female sterilization 0.2 0.4
Male sterilization 0.1 0.15

CONTRAINDICATIONS

Oral contraceptives should not be used in women who currently have the following conditions:

  • Thrombophlebitis or thromboembolic disorders

  • A past history of deep vein thrombophlebitis or thromboembolic disorders

  • Cerebrovascular or coronary artery disease

  • Known or suspected carcinoma of the breast

  • 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

  • Known or suspected pregnancy

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) 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 risk of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations 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 a 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.

*Adapted from Stadel BB: Oral contraceptives and cardiovascular disease. N Engl J Med, 1981; 305: 612-618, 672-677; with author’s permission.

1. Thromboembolic Disorders and Other Vascular Problems:

The physician should be alert to the earliest manifestations of thromboembolic thrombotic disorders as discussed below. Should any of these occur or be suspected the drug should be discontinued immediately.

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 infarctions 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 1) among women who use oral contraceptives.

Figure 1
(click image for full-size original)

Layde PM, Beral V: Further analyses of mortality in oral contraceptive users: Royal College of General Practitioners’ oral contraception study. (Table 5) Lancet 1981;1:541-546.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Such increases in risk factors have been associated with an increased risk of heart disease and the risk increases with the number of risk factors present. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breastfeed.

c. Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risk of cerebrovascular events (thrombotic and hemorrhagic strokes); although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.

d. Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.05 mg or less of estrogen.

e. Persistence of risk

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

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