Mercilon

Category:Oral Contraceptives
Brand names: Alesse, Brevicon, Cyclessa, Demulen, Desogen, Levlen, Levlite, Loestrin, Lo/Ovral, Low-Ogestrel, Micronor, Modicon, Necon, Nordette, Norinyl, Ogestrel, Ortho-Cept, Ortho-Cyclen, Ortho-Novum, Ortho Tri-Cyclen, Ovcon, Ovral, Tri-Norinyl, Triphasil, Trivora, Yasmin, Zovia

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DESCRIPTION

Mercilon (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide 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), 0.02 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc, followed by 2 green round tablets with the following inactive ingredients: lactose, corn starch, magnesium stearate, FD&C Blue No. 2 aluminum lake, yellow ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc. Mercilon also contains 5 yellow round tablets containing 0.01 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc, and yellow ferric oxide. The molecular weight for desogestrel and ethinyl estradiol are 310.48 and 296.41 respectively. The structural formulas are as follows:

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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).

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 compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Mercilon (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the yellow tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Mercilon combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [yellow] is 99%. The effect of food on the bioavailability of Mercilon tablets following oral administration has not been evaluated.
The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Mercilon tablets were determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by Day 21. The AUC (0-24) for etonogestrel at steady-state on Day 21 was approximately 2.2 times higher than AUC (0-24) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Mercilon tablets are summarized in Table 1.

Distribution
Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly 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).

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Metabolism
Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3 alpha -OH-desogestrel, 3 beta -OH-desogestrel, and 3 alpha -OH-5 alpha -H-desogestrel) with no pharmacologic actions 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 excreted in urine, bile and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. For the 0.01 mg ethinyl estradiol tablet [yellow], the elimination half-life at steady state, Day 28, is 18.9±8.3 hours.
Special Populations

Race
There is no information to determine the effect of race on the pharmacokinetics of Mercilon (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets.

Hepatic Insufficiency
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Mercilon.

Renal Insufficiency
No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mercilon.

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 (see PRECAUTIONS section).

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INDICATIONS AND USAGE

Mercilon (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets 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 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, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

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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
- 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 of carcinomas
- Known or suspected pregnancy

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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 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 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, 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 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 author's permission). For further information, the reader is referred to a text on epidemiological methods.

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INFORMATION FOR THE PATIENT

See Patient Labeling Printed Below

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ADVERSE REACTIONS

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):
- Thrombophlebitis and venous thrombosis with or without embolism
- Arterial thromboembolism
- Pulmonary embolism
- Myocardial infarction
- Cerebral hemorrhage
- Cerebral thrombosis
- Hypertension
- Gallbladder disease
- Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of oral contraceptives:
- Mesenteric thrombosis
- Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:
- Nausea
- Vomiting
- Gastrointestinal symptoms (such as abdominal cramps and bloating)
- Breakthrough bleeding
- Spotting
- Change in menstrual flow
- Amenorrhea
- Temporary infertility after discontinuation of treatment
- Edema
- Melasma which may persist
- Breast changes: tenderness, enlargement, secretion
- Change in weight (increase or decrease)
- Change in cervical erosion and secretion
- Diminution in lactation when given immediately postpartum
- Cholestatic jaundice
- Migraine
- Rash (allergic)
- Mental depression
- Reduced tolerance to carbohydrates
- Vaginal candidiasis
- Change in corneal curvature (steepening)
- Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:
- Pre-menstrual syndrome
- Cataracts
- Changes in appetite
- Cystitis-like syndrome
- Headache
- Nervousness
- Dizziness
- Hirsutism
- Loss of scalp hair
- Erythema multiforme
- Erythema nodosum
- Hemorrhagic eruption
- Vaginitis
- Porphyria
- Impaired renal function
- Hemolytic uremic syndrome
- Acne
- Changes in libido
- Colitis
- Budd-Chiari Syndrome

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OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

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NON-CONTRACEPTIVE HEALTH BENEFITS

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (73-78). Effects on menses:
- increased menstrual cycle regularity
- decreased blood loss and decreased incidence of iron deficiency anemia
- decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
- decreased incidence of functional ovarian cysts
- decreased incidence of ectopic pregnancies
Effects from long-term use:
- decreased incidence of fibroadenomas and fibrocystic disease of the breast
- decreased incidence of acute pelvic inflammatory disease
- decreased incidence of endometrial cancer
- decreased incidence of ovarian cancer