Desolett Desogen 21 Tablets Merck Sharp & Dohme

Desolett Desogen 21 Tablets Merck Sharp & Dohme

Brand:MSD Pharmaceuticals
Product Code:196
Availability:In Stock

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.

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

DESCRIPTION

DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP) provides an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Inactive ingredients include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. DESOGEN® also contains 7 green round tablets containing the following inert ingredients: lactose, corn starch, magnesium stearate, FD&C Blue No. 2 aluminum lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40, respectively. The structural formulas are as follows:

Chemical Structure

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).

Receptor-binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of etonogestrel, is approximately 84%.

In the third cycle of use after a single dose of DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP), maximum concentrations of etonogestrel of 2805±1203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0–∞) is 33,858±11,043 pg/mL∙hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5840±1667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of etonogestrel at steady state are 1400±560 pg/mL. The AUC0–24 at steady state is 52,299±17,878 pg/mL∙hr. The mean AUC0–∞ for etonogestrel at single dose is significantly lower than the mean AUC0–24 at steady state. This indicates that the kinetics of etonogestrel are non-linear due to an increase in binding of etonogestrel to SHBG in the cycle, attributed to increased SHBG levels which are induced by the daily administration of ethinyl estradiol. SHBG levels increased significantly in the third treatment cycle from day 1 (150±64 nmol/L) to day 21 (230±59 nmol/L).

Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of DESOGEN®, the relative bioavailability is approximately 83%.

In the third cycle of use after a single dose of DESOGEN®, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0–∞ is 1471±268 pg/mL∙hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141±48 pg/mL are reached at about 1.4±0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24±8.3 pg/mL. The AUC0–24, at steady state is 1117±302 pg/mL∙hr. The mean AUC0–∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0–24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99).

Metabolism

Desogestrel

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β-13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OHdesogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl estradiol

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. The elimination half-life of etonogestrel is approximately 38±20 hours at steady state. The elimination half-life of ethinyl estradiol is 26±6.8 hours at steady state.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP).

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of DESOGEN®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of DESOGEN®.

Drug–Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with DESOGEN® (seePRECAUTIONS).

INDICATIONS AND USAGE

DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP) is 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 unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

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

·         Cerebral vascular or coronary artery disease (current or history)

·         Valvular heart disease with thrombogenic complications

·         Severe hypertension

·         Diabetes with vascular involvement

·         Headaches with focal neurological symptoms

·         Major surgery with prolonged immobilization

·         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 hormonal contraceptive use

·         Hepatic tumors (benign or malignant) or active liver disease

·         Known or suspected pregnancy

·         Heavy smoking (≥15 cigarettes per day) and over age 35

·         Hypersensitivity to any of the components of DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP)

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 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 thrombophilias, 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 formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic 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 non-users. 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 non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors' permission). For further information, the reader is referred to a text on epidemiologic methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

a. 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 (2,3,19–24). 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 (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2).

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102–104). In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional 1–2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). 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 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 breast-feed.

b. 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 (4–10). The risk is very low in women under the age of 30.

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