Mircette (Desogestrel, Ethinyl Estradiol and Ethinyl Estradiol): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

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

Description for Mircette

Mircette® (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl11- methylene-18,19-dinor-17 alpha-pregn- 4-en- 20-yn-17-ol), 0.02 mg ethinyl estradiol (19-nor17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, povidone, pregelatinized starch, stearic acid and vitamin E, followed by 2 inert light-green round tablets with the following inactive ingredients: FD&C blue no. 1 aluminum lake, FD &C yellow no. 6 aluminum lake, D&C yellow no. 10 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Mircette® also contains 5 yellow round tablets containing 0.01 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne3,17-diol) and inactive ingredients which include colloidal silicon dioxide, D&C yellow no. 10, aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, lactose monohydrate, polyethylene glycol, povidone, polysorbate 80, pregelatinized starch, stearic acid, titanium dioxide and vitamin E. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40 respectively. The structural formulas are as follows:

Uses for Mircette

Mircette 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 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.

TABLE II: Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year, United States.

Dosage for Mircette

To achieve maximum contraceptive effectiveness, Mircette must be taken exactly as directed and at intervals not exceeding 24 hours. Mircette may be initiated using either a Sunday start or a Day 1 start.

NOTE: Each cycle pack dispenser is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen. Six different “day label strips” are provided with each cycle pack dispenser in order to accommodate a Day 1 start regimen. In this case, the patient should place the self-adhesive “day label strip” that corresponds to her starting day over the preprinted days.

IMPORTANT: The possibility of ovulation and conception prior to initiation of use of Mircette should be considered.

The use of Mircette for contraception may be initiated 4 weeks postpartum in women who elect not to breast-feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for Nursing mothers).

If the patient starts on Mircette postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white tablet has been taken daily for 7 days.

Sunday Start

When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

Using a Sunday start, tablets are taken daily without interruption as follows: The first white tablet should be taken on the first Sunday after menstruation begins (if menstruation begins on Sunday, the first white tablet is taken on that day). One white tablet is taken daily for 21 days, followed by 1 light-green (inert) tablet daily for 2 days and 1 yellow (active) tablet daily for 5 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (Sunday) after taking the last yellow tablet. [If switching from a Sunday start oral contraceptive, the first Mircette (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablet should be taken on the second Sunday after the last tablet of a 21 day regimen or should be taken on the first Sunday after the last inactive tablet of a 28 day regimen.]

If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should keep taking 1 white tablet daily until the next Sunday. On Sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

Day 1 Start

Counting the first day of menstruation as “Day 1”, tablets are taken without interruption as follows: One white tablet daily for 21 days, one light-green (inert) tablet daily for 2 days followed by 1 yellow (ethinyl estradiol) tablet daily for 5 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last yellow tablet. [If switching directly from another oral contraceptive, the first white tablet should be taken on the first day of menstruation which begins after the last ACTIVE tablet of the previous product.]

If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. If the patient misses 2 consecutive white tablets in the third week or if the patient misses 3 or more white tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

All Oral Contraceptives

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagin*, non­functional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagin*, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If both pregnancy and pathology have been excluded, time or a change to another preparation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period:

1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued until pregnancy is ruled out.
2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

HOW SUPPLIED

Mircette (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets contain 21 round white tablets, 2 round green tablets and 5 round yellow tablets in a blister card within a recyclable plastic dispenser. Each white tablet (debossed with “ dp” on one side and “021” on the other side) contains 0.15 mg desogestrel and 0.02 mg ethinyl estradiol. Each green tablet (debossed with “ dp” on one side and “331” on the other side) contains inert ingredients. Each yellow tablet (debossed with “dp” on one side and “457” on the other side) contains 0.01 mg ethinyl estradiol.

Boxes of 6 NDC 51285-114-58

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

REFERENCES

1. Hatcher RA, Trussell J, Stewart F et al. Contraceptive Technology: Seventeenth Revised Edition, New York: Irvington Publishers, 1998, in press.

2. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612–618.

3. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672–677.

36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral-contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405–411.

37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer risk in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926–929.

38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723–725.

39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863–868.

40. Olson H, Olson KL, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 2:748–749.

41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653–660.

42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733–761.

46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930.

47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long-term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339–344.

52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437–440.

53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355–1357.

54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357–1361.

79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast Cancer in relation to early use of oral contraceptives 1988; 259:1828–1833.

80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oral contraceptive use and breast cancer. JNCI 1984; 72:39–42.

81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br. J. Cancer 1986; 54:311–317.

82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use in breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650–654.

83. Kay CR, Hannaford PC. Breast cancer and the pill—A further report from the Royal College of General Practitioners’ oral contraception study. Br. J. Cancer 1988; 58:675–680.

84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287–299.

85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am. J. Epidemiol 1989; 129:269–280.

86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973–982.

87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1–38.

88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br. J. Cancer 1989; 59:613–617.

89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br. J. Cancer 1989; 59:618–621.

90. Godsland, I et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323:1375–81.

93. Data on file, Organon Inc.

94. Fotherby, K. Oral contraceptives, lipids and cardiovascular diseases. Contraception, 1985; Vol. 31; 4:367–94.

95. Lawrence, DM et al. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clinical Endocrinology, 1981; 15:87–91.

105. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a doubleblind,placebo-controlled trial. Epilepsia 2007;48(3):484­489.

Manufactured for: Teva Pharmaceuticals Parsippany, NJ 07054. Revised Jan 2023

Side Effects for Mircette

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

Post Marketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 -1.12 (Figure 2) (64-68).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2) (64, 67,69). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 -1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

FIGURE 2: RELEVANT STUDIES OF RISK OF BREAST CANCER WITH COMBINED ORAL CONTRACEPTIVES

RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

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
• vagin*l 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

Drug Interactions for Mircette

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin, and tetracyclines (72).

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Concomitant Use With Hepatitis C Virus (HCV) Combination Therapy - Liver Enzyme Elevation

Co-administration of Mircette with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations (see CONTRAINDICATIONS and WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT). Co-administration of Mircette and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

Consult the labeling of the concurrently-used drug to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Interactions With laboratory tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
2. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
3. Other binding proteins may be elevated in serum.
4. Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.
5. High-density lipoprotein cholesterol (HDL-C) and triglycerides may be increased, while low-density lipoprotein cholesterol (LDL-C) and total cholesterol (Total-C) may be decreased or unchanged.
6. Glucose tolerance may be decreased.
7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

REFERENCES

64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335–341.

65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045–1049.

66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by Bardin CW, Milgrom E, Mauvis-Jarvis P. New York, Raven Press, 1983 pp. 395–410.

67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857– 864.

68. Royal College of General Practitioners’ Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.

69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499–2503.

72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143.

Warnings for Mircette

Cigarette smoking increases the risk of seriouscardiovascular side effects from oral contraceptive use. This risk increaseswith age and with heavy smoking (15 or more cigarettes per day) and is quite markedin women over 35 years of age. Women who use oral contraceptives should bestrongly advised not to smoke.

The use of oral contraceptives is associated with increasedrisks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk ofserious morbidity or mortality is very small in healthy women withoutunderlying risk factors. The risk of morbidity and mortality increasessignificantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

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

The information contained in this package insert isprincipally based on studies carried out in patients who used oralcontraceptives with formulations of higher doses of estrogens and progestogensthan those in common use today. The effect of long-term use of the oralcontraceptives with formulations of lower doses of both estrogens andprogestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported areof two types: retrospective or case control studies and prospective or cohortstudies. Case control studies provide a measure of the relative risk of adisease, namely, a ratio of the incidence of a disease among oral contraceptiveusers to that among non-users. The relative risk does not provide informationon the actual clinical occurrence of a disease. Cohort studies provide ameasure of attributable risk, which is the difference in the incidence ofdisease between oral contraceptive users and non-users. The attributable riskdoes provide information about the actual occurrence of a disease in thepopulation (Adapted from refs. 2 and 3 with the author's permission). Forfurther information, the reader is referred to a text on epidemiologic methods.

Thromboembolic disorders and other vascular problems

Thromboembolism

An increased risk of thromboembolic and thrombotic diseaseassociated with the use of oral contraceptives is well established. Casecontrol studies have found the relative risk of users compared to non-users tobe 3 for the first episode of superficial venous thromboembolic disease, 4 to11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women withpredisposing conditions for venous thromboembolic disease (2,3,19–24). Cohortstudies have shown the relative risk to be somewhat lower, about 3 for newcases and about 4.5 for new cases requiring hospitalization (25). The risk ofthromboembolic disease associated with oral contraceptives is not related tolength of use and disappears after pill use is stopped (2).

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

A two- to four-fold increase in relative risk ofpost-operative thromboembolic complications has been reported with the use oforal contraceptives (9,26). The relative risk of venous thrombosis in women whohave predisposing conditions is twice that of women without such medicalconditions (9,26). If feasible, oral contraceptives should be discontinued atleast four weeks prior to and for two weeks after elective surgery of a typeassociated with an increase in risk of thromboembolism and during and followingprolonged immobilization. Since the immediate postpartum period is alsoassociated with an increased risk of thromboembolism, oral contraceptivesshould be started no earlier than four weeks after delivery in women who electnot to breast-feed.

Myocardial infarction

An increased risk of myocardial infarction has been attributedto oral contraceptive use. This risk is primarily in smokers or women withother underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heartattack 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.

Smoking in combination with oral contraceptive use has beenshown to contribute substantially to the incidence of myocardial infarction inwomen in their mid-thirties or older with smoking accounting for the majorityof excess cases (11). Mortality rates associated with circulatory disease havebeen shown to increase substantially in smokers, over the age of 35 andnonsmokers over the age of 40 (Table III) among women who use oralcontraceptives.

TABLE III: CIRCULATORY DISEASE MORTALITY RATES PER100,000 WOMANYEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE

Adapted from P.M. Layde and V. Beral, ref. #12.

Oral contraceptives may compoundthe effects of well-known risk factors, such as hypertension, diabetes,hyperlipidemias, age and obesity (13). In particular, some progestogens areknown to decrease HDL cholesterol and cause glucose intolerance, whileestrogens may create a state of hyperinsulinism (14–18). Oral contraceptiveshave been shown to increase blood pressure among users (see WARNINGS).Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women withcardiovascular disease risk factors.

Cerebrovascular diseases

Oral contraceptives have beenshown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk isgreatest among older (>35 years), hypertensive women who also smoke.Hypertension was found to be a risk factor for both users and non-users, forboth types of strokes, while smoking interacted to increase the risk for hemorrhagicstrokes (27–29).

In a large study, the relativerisk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (30). The relative risk ofhemorrhagic stroke is reported to be 1.2 for non-smokers who used oralcontraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 forsmokers who used oral contraceptives, 1.8 for normotensive users and 25.7 forusers with severe hypertension (30). The attributable risk is also greater in olderwomen (3).

Dose-related risk of vascular disease from oral contraceptives

A positive association has beenobserved between the amount of estrogen and progestogen in oral contraceptivesand the risk of vascular disease (31–33). A decline in serum high-densitylipoproteins (HDL) has been reported with many progestational agents (14–16). Adecline in serum high-density lipoproteins has been associated with an increasedincidence of ischemic heart disease. Because estrogens increase HDLcholesterol, the net effect of an oral contraceptive depends on a balanceachieved between doses of estrogen and progestogen and the nature and absoluteamount of progestogens used in the contraceptives. The amount of both hormonesshould be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogenand progestogen is in keeping with good principles of therapeutics. For anyparticular estrogen/progestogen combination, the dosage regimen prescribedshould be one which contains the least amount of estrogen and progestogen thatis compatible with a low failure rate and the needs of the individual patient.New acceptors of oral contraceptive agents should be started on preparationscontaining 0.035 mg or less of estrogen.

Persistence of risk of vascular disease

There are two studies which haveshown persistence of risk of vascular disease for ever-users of oralcontraceptives. In a study in the United States, the risk of developingmyocardial infarction after discontinuing oral contraceptives persists for atleast 9 years for women 40 to 49 years old who had used oral contraceptives forfive or more years, but this increased risk was not demonstrated in other agegroups (8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation oforal contraceptives, although excess risk was very small (34). However, bothstudies were performed with oral contraceptive formulations containing 50micrograms or more of estrogen.

Estimates of mortality from contraceptive use

One study gathered data from avariety of sources which have estimated the mortality rate associated withdifferent methods of contraception at different ages (Table IV). Theseestimates include the combined risk of death associated with contraceptivemethods plus the risk attributable to pregnancy in the event of method failure.Each method of contraception has its specific benefits and risks. The studyconcluded that with the exception of oral contraceptive users 35 and older whosmoke and 40 and older who do not smoke, mortality associated with all methodsof birth control is low and below that associated with childbirth.

The observation of a possibleincrease in risk of mortality with age for oral contraceptive users is based ondata gathered in the 1970's - but not reported until 1983 (35). However,current clinical practice involves the use of lower estrogen formulationscombined with careful consideration of risk factors.

Because of these changes inpractice and, also, because of some limited new data which suggest that therisk of cardiovascular disease with the use of oral contraceptives may now beless than previously observed (100,101), the Fertility and Maternal HealthDrugs Advisory Committee was asked to review the topic in 1989. The Committeeconcluded that although cardiovascular disease risks may be increased with oralcontraceptive use after age 40 in healthy non-smoking women (even with thenewer low-dose formulations), there are also greater potential health risksassociated with pregnancy in older women and with the alternative surgical andmedical procedures which may be necessary if such women do not haveaccess to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits oflow-dose oral contraceptive use by healthy non-smoking women over 40 mayoutweigh the possible risks. Of course, older women, as all women who take oralcontraceptives, should take the lowest possible dose formulation that iseffective.

TABLE IV: ANNUAL NUMBER OF BIRTH-RELATED ORMETHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

Carcinoma of the reproductive organs and breasts

Numerous epidemiologic studieshave been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. While there are conflictingreports, most studies suggest that the use of oral contraceptives is notassociated with an overall increase in the risk of developing breast cancer.Some studies have reported an increased relative risk of developing breastcancer, particularly at a younger age. This increased relative risk appears tobe related to duration of use (36–43, 79–89).

Some studies suggest that oralcontraceptive use has been associated with an increase in the risk of cervical intra-epithelial neoplasia in some populations of women (45–48). However, therecontinues to be controversy about the extent to which such findings may be dueto differences in sexual behavior and other factors.

Hepatic neoplasia

Benign hepatic adenomas areassociated with oral contraceptive use, although the incidence of benign tumorsis rare in the United States. Indirect calculations have estimated theattributable risk to be in the range of 3.3 cases/100,000 for users, a riskthat increases after four or more years of use especially with oralcontraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas maycause death through intra-abdominal hemorrhage (50,51).

Studies from Britain have shown anincreased risk of developing hepatocellular carcinoma (52– 54) in long-term(>8 years) oral contraceptive users. However, these cancers are extremelyrare in the US and the attributable risk (the excess incidence) of livercancers in oral contraceptive users approaches less than one per million users.

Ocular lesions

There have been clinical casereports of retinal thrombosis associated with the use of oral contraceptives.Oral contraceptives should be discontinued if there is unexplained partial orcomplete loss of vision; onset of proptosis or diplopia; papilledema; orretinal vascular lesions. Appropriate diagnostic and therapeutic measuresshould be undertaken immediately.

Oral contraceptive use before or during early pregnancy

Extensive epidemiologic studieshave revealed no increased risk of birth defects in women who have used oralcontraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defectsare concerned (55,56,58,59), when oral contraceptives are taken inadvertentlyduring early pregnancy.

The administration of oralcontraceptives to induce withdrawal bleeding should not be used as a test forpregnancy. Oral contraceptives should not be used during pregnancy to treatthreatened or habitual abortion. It is recommended that for any patient who hasmissed two consecutive periods, pregnancy should be ruled out before continuingoral contraceptive use. If the patient has not adhered to the prescribedschedule, the possibility of pregnancy should be considered at the first missedperiod. Oral contraceptive use should be discontinued until pregnancy is ruled out.

Gallbladder disease

Earlier studies have reported anincreased lifetime relative risk of gallbladder surgery in users of oralcontraceptives and estrogens (60,61). More recent studies, however, have shownthat the relative risk of developing gallbladder disease among oralcontraceptive users may be minimal (62–64). The recent findings of minimal riskmay be related to the use of oral contraceptive formulations containing lowerhormonal doses of estrogens and progestogens.

Carbohydrate and lipid metabolic effects

Oral contraceptives have beenshown to cause a decrease in glucose tolerance in a significant percentage ofusers (17). Oral contraceptives containing greater than 75 micrograms ofestrogens cause hyperinsulinism, while lower doses of estrogen cause lessglucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents(17,66). However, in the non-diabetic woman, oral contraceptives appear to haveno effect on fasting blood glucose (67). Because of these demonstrated effects,prediabetic and diabetic women should be carefully monitored while taking oralcontraceptives.

A small proportion of women willhave persistent hypertriglyceridemia while on the pill. As discussed earlier(see WARNINGS), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

Elevated blood pressure

An increase in blood pressure has been reported in womentaking oral contraceptives (68) and this increase is more likely in older oralcontraceptive users (69) and with continued use (61). Data from the RoyalCollege of General Practitioners (12) and subsequent randomized trials haveshown that the incidence of hypertension increases with increasing quantitiesof progestogens.

Women with a history of hypertension or hypertension-relateddiseases, or renal disease (70) should be encouraged to use another method ofcontraception. If women elect to use oral contraceptives, they should bemonitored closely and if significant elevation of blood pressure occurs, oralcontraceptives should be discontinued. For most women, elevated blood pressurewill return to normal after stopping oral contraceptives (69), and there is nodifference in the occurrence of hypertension between ever- and never-users(68,70,71).

Headache

The onset or exacerbation of migraine or development ofheadache with a new pattern which is recurrent, persistent, or severe requiresdiscontinuation of oral contraceptives and evaluation of the cause.

Bleeding irregularities

Breakthrough bleeding and spotting are sometimes encounteredin patients on oral contraceptives, especially during the first three months ofuse. Non-hormonal causes should be considered and adequate diagnostic measurestaken to rule out malignancy or pregnancy in the event of breakthroughbleeding, as in the case of any abnormal vagin*l bleeding. If pathology hasbeen excluded, time or a change to another formulation may solve the problem.In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

Ectopic pregnancy

Ectopic as well as intrauterine pregnancy may occur incontraceptive failures.

Precautions for Mircette

General

Patients should be counseled that this product does notprotect against HIV infection (AIDS) and other sexually transmitted diseases.

Physical examination and follow up

It is good medical practice for all women to have annualhistory and physical examinations, including women using oral contraceptives.The physical examination, however, may be deferred until after initiation oforal contraceptives if requested by the woman and judged appropriate by theclinician. The physical examination should include special reference to bloodpressure, breasts, abdomen, and pelvic organs, including cervical cytology, andrelevant laboratory tests. In case of undiagnosed, persistent or recurrentabnormal vagin*l bleeding, appropriate measures should be conducted to rule outmalignancy. Women with a strong family history of breast cancer or who havebreast nodules should be monitored with particular care.

Lipid disorders

Women who are being treated for hyperlipidemias should befollowed closely if they elect to use oral contraceptives. Some progestogensmay elevate LDL levels and may render the control of hyperlipidemias moredifficult.

Liver function

If jaundice develops in any woman receiving such drugs, themedication should be discontinued. Steroid hormones may be poorly metabolizedin patients with impaired liver function.

Fluid retention

Oral contraceptives may cause some degree of fluidretention. They should be prescribed with caution, and only with carefulmonitoring, in patients with conditions which might be aggravated by fluidretention.

Emotional disorders

Women with a history of depression should be carefullyobserved and the drug discontinued if depression recurs to a serious degree.

Contact lenses

Contact lens wearers who develop visual changes or changesin lens tolerance should be assessed by an ophthalmologist.

Carcinogenesis

See WARNINGS section.

Pregnancy

Pregnancy Category X (see CONTRAINDICATIONS and WARNINGSsections).

Nursing mothers

Small amounts of oral contraceptive steroids have beenidentified in the milk of nursing mothers and a few adverse effects on thechild have been reported, including jaundice and breast enlargement. Inaddition, oral contraceptives given in the postpartum period may interfere withlactation by decreasing the quantity and quality of breast milk. If possible,the nursing mother should be advised not to use oral contraceptives but to useother forms of contraception until she has completely weaned her child.

Pediatric use

Safety and efficacy of Mircette® (desogestrel/ethinyl estradiol and ethinyl estradiol)Tablets have been established in women of reproductive age. Safety and efficacyare expected to be the same for postpubertal adolescents under the age of 16and for users 16 years and older. Use of this product before menarche is notindicated.

Information For The Patient

See Patient Labeling

REFERENCES

1. Hatcher RA, Trussell J, Stewart F et al. Contraceptive Technology: Seventeenth Revised Edition, New York: Irvington Publishers, 1998,in press.

2. Stadel BV. Oral contraceptives and cardiovasculardisease. (Pt. 1). N Engl J Med 1981; 305:612–618.

3. Stadel BV. Oral contraceptives and cardiovasculardisease. (Pt. 2). N Engl J Med 1981; 305:672–677.

4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns.Br J Obstet and Gynecol 1981; 88:838–845.

5. Mann JI, Inman WH. Oral contraceptives and death frommyocardial infarction. Br Med J 1975; 2(5965):245–248.

6. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptivepractice. Br Med J 1975; 2(5956):241–245.

7. Royal College of General Practitioners' Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541–546.

8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current anddiscontinued use of oral contraceptives. N Engl J Med 1981; 305:420–424.

9. Vessey MP. Female hormones and vascular disease—anepidemiological overview. Br J Fam Plann 1980; 6:1–12.

10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, UnitedStates, 1976–80. Prevent Med 1986; 15:352–362.

11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the UnitedStates. JAMA 1987; 258:1339–1342.

12. Layde PM, Beral V. Further analyses of mortality in oral contraceptive users: Royal College General Practitioners' Oral ContraceptionStudy. (Table 5) Lancet 1981; 1:541–546.

13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement):913–921.

14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983;145:446–452.

15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoproteincholesterol. N Engl J Med 1983; 308:862–867.

16. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high-density lipoproteins. Am J ObstetGynecol 1982; 142:766–771.

17. Wynn V, Godsland I. Effects of oral contraceptives and carbohydrate metabolism. J Reprod Med 1986; 31 (9) (Supplement):892–897.

18. LaRosa JC. Atherosclerotic risk factors incardiovascular disease. J Reprod Med 1986; 31 (9) (Supplement):906–912.

19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearingage. Br Med J 1968; 2 (5599):193–199.

20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report.Am J Epidemiol 1979; 110 (2):188–195.

21. Pettiti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptiveestrogens, and other factors. JAMA 1979; 242:1150–1154.

22. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2(5599):199–205.

23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J1969; 2 (5658):651– 657.

24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and nonfatal vascular disease—recent experience. ObstetGynecol 1982; 59 (3):299–302.

25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: aninterim report. Biosocial Sci 1976; 8:375–427.

26. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract1978; 28:393–399.

27. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia orthrombosis. N Engl J Med 1973; 288:871–878.

28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234–236.

29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2 (6203):1468–70.

30. Collaborative Group for the Study of Stroke in Young Women: Oral contraceptives and stroke in young women: associated risk factors.JAMA 1975; 231:718–722.

31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. Areport to the Committee on Safety of Drugs. Br Med J 1970; 2:203–209.

32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280(6224):1157–1161.

33. Kay CR. Progestogens and arterial disease—evidence from the Royal College of General Practitioners' Study. Am J Obstet Gynecol 1982;142:762–765.

34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983;33:75–82.

35. Ory HW. Mortality associated with fertility andfertility control: 1983. Family Planning Perspectives 1983; 15:50–56.

36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral-contraceptive use and the risk of breast cancer. N Engl J Med1986; 315:405–411.

37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer risk in young women and use of oral contraceptives: possible modifyingeffect of formulation and age at use. Lancet 1983; 2:926–929.

38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723–725.

39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oralcontraceptive use. Obstet Gynecol 1986; 68:863–868.

40. Olson H, Olson KL, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet1985; 2:748–749.

41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653–660

42. Huggins GR, Zucker PF. Oral contraceptives andneoplasia: 1987 update. Fertil Steril 1987; 47:733–761.

43. McPherson K, Drife JO. The pill and breast cancer: whythe uncertainty? Br Med J 1986; 293:709–710.

45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW.Contraceptive choice and prevalence of cervical dysplasia and carcinoma insitu. Am J Obstet Gynecol 1976; 124:573–577.

46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasiaof the cervix uteri and contraception: a possible adverse effect of the pill.Lancet 1983; 2:930.

47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA,Trapido E, Rosenthal J, Hoover R. Long-term use of oral contraceptives and riskof invasive cervical cancer. Int J Cancer 1986; 38:339–344.

48. WHO Collaborative Study of Neoplasia and SteroidContraceptives: Invasive cervical cancer and combined oral contraceptives. BrMed J 1985; 209:961–965.

49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR,Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oralcontraceptive use. JAMA 1979; 242:644–648.

50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage frombenign hepatic tumors secondary to oral contraceptives. Br J Surg 1977;64:433–435.

51. Klatskin G. Hepatic tumors: possible relationship to useof oral contraceptives. Gastroenterology 1977; 73:386–394.

52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL,Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983;48:437–440.

53. Neuberger J, Forman D, Doll R, Williams R. Oralcontraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355–1357.

54. Forman D, Vincent TJ, Doll R. Cancer of the liver andoral contraceptives. Br Med J 1986; 292:1357– 1361.

55. Harlap S, Eldor J. Births following oral contraceptivefailures. Obstet Gynecol 1980; 55:447–452.

56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards oforal contraceptives analyzed in a national malformation register. Am J ObstetGynecol 1981; 140:521–524.

57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptivesand birth defects. Am J Epidemiol 1980; 112:73–79.

58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA,Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology1980; 21:225–239.

59. Rothman KJ, Fyler DC, Goldbatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heartdisease. Am J Epidemiol 1979; 109:433–439.

60. Boston Collaborative Drug Surveillance Program: Oralcontraceptives and venous thromboembolic disease, surgically confirmedgallbladder disease, and breast tumors. Lancet 1973; 1:1399–1404.

61. Royal College of General Practitioners: Oralcontraceptives and health. New York, Pittman, 1974.

62. Layde PM, Vessey MP, Yeates D. Risk of gallbladderdisease: a cohort study of young women attending family planning clinics. JEpidemiol Community Health 1982; 36:274–278.

63. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adultfemale population. Am J Epidemiol 1984; 119:796–805.

64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL,Stolley PD, Jones JK. Oral contraceptives and other risk factors forgallbladder disease. Clin Pharmacol Ther 1986; 39:335–341.

65. Wynn V, Adams PW, Godsland IF, Melrose J,Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of differentcombined oral-contraceptive formulations on carbohydrate and lipid metabolism.Lancet 1979; 1:1045–1049.

66. Wynn V. Effect of progesterone and progestins oncarbohydrate metabolism. In Progesterone and Progestin. Edited by Bardin CW,Milgrom E, Mauvis-Jarvis P. New York, Raven Press, 1983 pp. 395–410.

67. Perlman JA, Roussell-Briefel RG, Ezzati TM, LieberknechtG. Oral glucose tolerance and the potency of oral contraceptive progestogens. JChronic Dis 1985; 38:857–864.

68. Royal College of General Practitioners' OralContraception Study: Effect on hypertension and benign breast disease ofprogestogen component in combined oral contraceptives. Lancet 1977;

69. Fisch IR, Frank J. Oral contraceptives and bloodpressure. JAMA 1977; 237:2499– 2503.

70. Laragh AJ. Oral contraceptive induced hypertension—nineyears later. Am J Obstet Gynecol 1976; 126:141–147.

71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT.Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort.In Pharmacology of Steroid Contraceptive Drugs. Garattini S, Berendes HW. Eds.New York, Raven Press, 1977 pp. 277–288. (Monographs of the Mario NegriInstitute for Pharmacological Research, Milan).

73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983;249:1596–1599.

79. Schlesselman J, Stadel BV, Murray P, Lai S. BreastCancer in relation to early use of oral contraceptives 1988; 259:1828–1833.

80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C,Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oralcontraceptive use and breast cancer. JNCI 1984; 72:39–42.

81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, GentileA, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of thebreast and of the female genital tract. Interim results from a case-control study.Br. J. Cancer 1986; 54:311–317.

82. Meirik O, Lund E, Adami H, Bergstrom R, ChristoffersenT, Bergsjo P. Oral contraceptive use in breast cancer in young women. A JointNational Case-control study in Sweden and Norway. Lancet 1986; 11:650–654.

83. Kay CR, Hannaford PC. Breast cancer and the pill—Afurther report from the Royal College of General Practitioners' oralcontraception study. Br. J. Cancer 1988; 58:675–680.

84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oralcontraceptives and premenopausal breast cancer in nulliparous women.Contraception 1988; 38:287–299.

85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, WarshauerME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: NewFindings. Am. J. Epidemiol 1989; 129:269–280.

86. The UK National Case-Control Study Group, Oralcontraceptive use and breast cancer risk in young women. Lancet 1989;1:973–982.

87. Schlesselman JJ. Cancer of the breast and reproductivetract in relation to use of oral contraceptives. Contraception 1989; 40:1–38.

88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D.Oral contraceptives and breast cancer: latest findings in a large cohort study.Br. J. Cancer 1989; 59:613–617.

89. Jick SS, Walker AM, Stergachis A, Jick H. Oralcontraceptives and breast cancer. Br. J. Cancer 1989; 59:618–621.

100. Porter JB, Hunter J, Jick H et al. Oral contraceptivesand nonfatal vascular disease. Obstet Gynecol 1985; 66:1–4.

101. Porter JB, Jick H, Walker AM. Mortality among oralcontraceptive users. Obstet Gynecol 1987; 7029–32.

102. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C.Risk of idiopathic cardiovascular death and non-fatal venous thromboembolism inwomen using oral contraceptives with differing progestagen components. Lancet,1995; 346:1589–93.

103. World Health Organization Collaborative Study ofCardiovascular Disease and Steroid Hormone Contraception. Effect of differentprogestagens in low oestrogen oral contraceptives on venous thromboembolicdisease. Lancet, 1995; 346:1582–88.

104. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M,MacRae KD on behalf of Transnational Research Group on Oral Contraceptives andHealth of Young Women. Third generation oral contraceptives and risk of venousthromboembolic disorders: An international case-control study. Br Med J, 1996;312:83–88.

105. Christensen J, Petrenaite V, Atterman J, et al. Oralcontraceptives induce lamotrigine metabolism: evidence from adoubleblind,placebo-controlled trial. Epilepsia 2007;48(3):484-489.

Overdose Information for Mircette

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.

Non-Contraceptive Health Benefits

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic 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

Contraindications for Mircette

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 diagnosis of, or history of, breast cancer, which may be hormone-sensitive
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Hepatic adenomas or carcinomas
• Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT)

REFERENCES

73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596–1599.

74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796–800.

75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68–69.

76. Ory HW, Cole P, Macmahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419–422.

77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182–184.

78. Ory HW, Forrest JD, Lincoln R. Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1.

Clinical Pharmacology for Mircette

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.

Pharmaco*kinetics

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%. Mircette (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 Mircette 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 Mircette tablets following oral administration has not been evaluated.

The pharmaco*kinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Mircette 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 pharmaco*kinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Mircette tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMAco*kINETIC PARAMETERS OF Mircett® OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=17). Etonogestrel

Ethinyl Estradiol

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).

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., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-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 pharmaco*kinetics of Mircette.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Mircette.

Renal Insufficiency

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

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).

REFERENCES

91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception, 1988; 38:325–32.

92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim. Forsch./Drug Res., 1983; 33(l),2:231–6.

96. Cullberg, G et al. Effects of a low-dose desogestrel-ethinyl estradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome. Acta Obstet Gynecol Scand, 1985; 64:195–202.

97. Jung-Hoffmann, C and Kuhl, H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. AJOG, 1987; 156:199–203.

98. Hammond, G et al. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil. Steril., 1984; 42:44–51.

99. Palatsi, R et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol, 1984; 64:517–23.

Patient Information for Mircette

Mircette®
(desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets

This product (like all oral contraceptives) is intendedto prevent pregnancy. It does not protect against HIV infection (AIDS) andother sexually transmitted diseases.

PLEASE NOTE: This labeling is revised from time to timeas important new medical information becomes available. Therefore, pleasereview this labeling carefully.

DESCRIPTION

The following oral contraceptive product contains acombination of a progestin and estrogen, the two kinds of female hormones:

Each white tablet contains 0.15 mg desogestrel and 0.02 mgethinyl estradiol. Each light-green tablet contains inert ingredients and eachyellow tablet contains 0.01 mg ethinyl estradiol.

INTRODUCTION

Any woman who considers using oral contraceptives (the birthcontrol pill or the pill) should understand the benefits and risks of usingthis form of birth control. This leaflet will give you much of the informationyou will need to make this decision and will also help you determine if you areat risk of developing any of the serious side effects of the pill. It will tellyou how to use the pill properly so that it will be as effective as possible.However, this leaflet is not a replacement for a careful discussion between youand your doctor or healthcare provider. You should discuss the informationprovided in this leaflet with him or her, both when you first start taking thepill and during your revisits. You should also follow your doctor's or healthcareprovider's advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or “birth control pills” or “the pill”are used to prevent pregnancy and are more effective than other non-surgical methodsof birth control. When they are taken correctly, the chance of becomingpregnant is less than 1% (1 pregnancy per 100 women per year of use) when usedperfectly, without missing any pills. Typical failure rates are actually 5% peryear. The chance of becoming pregnant increases with each missed pill during amenstrual cycle.

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

WHO SHOULD NOT TAKE ORALCONTRACEPTIVES

Cigarette smoking increases therisk of serious cardiovascular side effects from oral contraceptive use. Thisrisk 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 oralcontraceptives are strongly advised not to smoke.

Some women should not use thepill. For example, you should not take the pill if you are pregnant or thinkyou may be pregnant. You should also not use the pill if you have any of thefollowing conditions:

• A history of heart attack or stroke
• 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 or vagin*
• Unexplained vagin*l bleeding (until a diagnosis is reached by your doctor)
• 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.

Tell your doctor or healthcareprovider if you have ever had any of these conditions. Your doctor orhealthcare provider can recommend another method of birth control.

OTHER CONSIDERATIONS BEFORETAKING ORAL CONTRACEPTIVES

Tell your doctor or healthcareprovider if you have:

• 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
• Mental depression
• Gallbladder, heart, or kidney disease
• History of scanty or irregular menstrual periods.

Women with any of these conditionsshould be checked often by their doctor or healthcare provider if they choose to use oral contraceptives.

Also, be sure to inform yourdoctor or healthcare provider if you smoke or are on any medications.

RISKS OF TAKING ORALCONTRACEPTIVES

1. Risk of developing bloodclots

Blood clots and blockage of bloodvessels are one of the most serious side effects of taking oral contraceptivesand can cause death or serious disability. In particular, a clot in the leg cancause thrombophlebitis and a clot that travels to the lungs can cause a suddenblockage of the vessel carrying blood to the lungs. The risks of these sideeffects may be greater with desogestrelcontaining oral contraceptives such asMircette® than with certainother low-dose pills. Rarely, clots occur in the blood vessels of the eye andmay cause blindness, double vision, or impaired vision.

If you take oral contraceptivesand need elective surgery, need to stay in bed for a prolonged illness or haverecently delivered a baby, you may be at risk of developing blood clots. Youshould consult your doctor or healthcare provider about stopping oralcontraceptives three to four weeks before surgery and not taking oralcontraceptives for two weeks after surgery or during bed rest. You should alsonot take oral contraceptives soon after delivery of a baby. It is advisable towait for at least four weeks after delivery if you are not breast-feeding orfour weeks after a second trimester abortion. If you are breast-feeding, youshould wait until you have weaned your child before using the pill (see Breast-Feedingin GENERAL PRECAUTIONS).

The risk of circulatory disease inoral contraceptive users may be higher in users of high dose pills and may begreater with longer duration of oral contraceptive use. In addition, some ofthese increased risks may continue for a number of years after stopping oralcontraceptives. The risk of venous thromboembolic disease associated with oralcontraceptives does not increase with length of use and disappears after pilluse is stopped. The risk of abnormal blood clotting increases with age in bothusers and non-users of oral contraceptives, but the increased risk from theoral contraceptive appears to be present at all ages. For women aged 20 to 44it is estimated that about 1 in 2,000 using oral contraceptives will behospitalized each year because of abnormal clotting. Among non-users in thesame age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptiveusers in general, it has been estimated that in women between the ages of 15and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 peryear, whereas for non-users the rate is about 1 in 50,000 per year. In the agegroup 35 to 44, the risk is estimated to be about 1 in 2,500 per yearfor 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 developstrokes (stoppage or rupture of blood vessels in the brain) and angina pectorisand heart attacks (blockage of blood vessels in the heart). Any of theseconditions can cause death or serious disability.

Smoking greatly increases the possibility of suffering heartattacks and strokes. Furthermore, smoking and the use of oral contraceptivesgreatly increase the chances of developing and dying of heart disease.

3. Gallbladder disease

Oral contraceptive users probably have a greater risk thannon-users of having gallbladder disease, although this risk may be related topills containing high doses of estrogens.

4. Liver tumors

In rare cases, oral contraceptives can cause benign butdangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association hasbeen found with the pill and liver cancers in two studies, in which a few womenwho developed these very rare cancers were found to have used oralcontraceptives for long periods. However, liver cancers are extremely rare. Thechance of developing liver cancer from using the pill is thus even rarer.

5. Cancer of the reproductive organs and breasts

There is conflict among studies regarding breast cancer andoral contraceptive use. Some studies have reported an increase in the risk ofdeveloping breast cancer, particularly at a younger age. This increased riskappears to be related to duration of use. The majority of studies have found nooverall increase in the risk of developing breast cancer.

Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, thisfinding may be related to factors other than the use of oral contraceptives.There is insufficient evidence to rule out the possibility that pills may causesuch cancers.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD ORPREGNANCY

All methods of birth control and pregnancy are associatedwith a risk of developing certain diseases which may lead to disability ordeath. An estimate of the number of deaths associated with different methods ofbirth control and pregnancy has been calculated and is shown in the followingtable.

ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHSASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BYFERTILITY CONTROL METHOD ACCORDING TO AGE

In the above table, the risk ofdeath from any birth control method is less than the risk of childbirth, exceptfor oral contraceptive users over the age of 35 who smoke and pill users overthe age of 40 even if they do not smoke. It can be seen in the table that forwomen aged 15 to 39, the risk of death was highest with pregnancy (7 to 26deaths per 100,000 women, depending on age). Among pill users who do not smoke,the risk of death is always lower than that associated with pregnancy for anyage group, although over the age of 40, the risk increases to 32 deaths per100,000 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 ofdeaths exceeds those for other methods of birth control. If a woman is over theage 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 40who do not smoke should not take oral contraceptives is based on informationfrom older, high-dose pills and on less selective use of pills than ispracticed today. An Advisory Committee of the FDA discussed this issue in 1989and recommended that the benefits of oral contraceptive use by healthy,non-smoking women over 40 years of age may outweigh the possible risks.However, all women, especially older women, are cautioned to use the lowestdose pill that is effective.

WARNING SIGNALS

If any of these adverse effectsoccur while you are taking oral contraceptives, call your doctor or healthcareprovider immediately:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or healthcare provider to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems).

SIDE EFFECTS OF ORALCONTRACEPTIVES

1. vagin*l bleeding

Irregular vagin*l bleeding or spotting may occur while youare taking the pills. Irregular bleeding may vary from slight staining betweenmenstrual periods to breakthrough bleeding which is a flow much like a regularperiod. Irregular bleeding occurs most often during the first few months oforal contraceptive use, but may also occur after you have been taking the pillfor some time. Such bleeding may be temporary and usually does not indicate anyserious problems. It is important to continue taking your pills on schedule. Ifthe bleeding occurs in more than one cycle or lasts for more than a few days,talk to your doctor or healthcare provider.

2. Contact lenses

If you wear contact lenses and notice a change in vision oran inability to wear your lenses, contact your doctor or healthcare provider.

3. Fluid retention

Oral contraceptives may cause edema (fluid retention) withswelling of the fingers or ankles and may raise your blood pressure. If youexperience fluid retention, contact your doctor or healthcare provider.

4. Melasma

A spotty darkening of the skin is possible, particularly ofthe face.

5. Other side effects

Other side effects may include nausea and vomiting, changein appetite, headache, nervousness, depression, dizziness, loss of scalp hair,rash, and vagin*l infections.

If any of these side effects bother you, call your doctor orhealthcare provider.

GENERAL PRECAUTIONS

1. Missed periods and use of oral contraceptives beforeor during early pregnancy

There may be times when you may not menstruate regularlyafter you have completed taking a cycle of pills. If you have taken your pillsregularly and miss one menstrual period, continue taking your pills for thenext cycle but be sure to inform your doctor or healthcare provider beforedoing so. If you have not taken the pills daily as instructed and missed amenstrual period, or if you missed two consecutive menstrual periods, you maybe pregnant. Check with your doctor or healthcare provider immediately todetermine whether you are pregnant. Do not continue to take oral contraceptivesuntil you are sure you are not pregnant, but continue to use another method ofcontraception.

There is no conclusive evidence that oral contraceptive useis associated with an increase in birth defects, when taken inadvertentlyduring early pregnancy. Previously, a few studies had reported that oralcontraceptives might be associated with birth defects, but these studies havenot been confirmed. Nevertheless, oral contraceptives or any other drugs shouldnot be used during pregnancy unless clearly necessary and prescribed by yourdoctor or healthcare provider. You should check with your doctor or healthcareprovider about risks to your unborn child of any medication taken duringpregnancy.

2. While breast-feeding

If you are breast-feeding, consult your doctor or healthcareprovider before starting oral contraceptives. Some of the drug will be passedon to the child in the milk. A few adverse effects on the child have beenreported, including yellowing of the skin (jaundice) and breast enlargement. Inaddition, oral contraceptives may decrease the amount and quality of your milk.If possible, do not use oral contraceptives while breast-feeding. You shoulduse another method of contraception since breast-feeding provides only partialprotection from becoming pregnant and this partial protection decreasessignificantly as you breast-feed for longer periods of time.

You should consider starting oral contraceptives only afteryou have weaned your child completely.

3. Laboratory tests

If you are scheduled for any laboratory tests, tell yourdoctor or healthcare provider you are taking birth control pills. Certain bloodtests may be affected by birth control pills.

4. Drug interactions

Certain drugs may interact with birth control pills to makethem less effective in preventing pregnancy or cause an increase inbreakthrough bleeding. Such drugs include rifampin, drugs used for epilepsysuch as barbiturates (for example, phenobarbital), phenytoin (Dilantin® is one brand of this drug), phenylbutazone(Butazolidin® is one brand),and possibly certain antibiotics. You may need to use additional contraceptionwhen you take drugs which can make oral contraceptives less effective.

Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, soyour physician may need to adjust the dose of lamotrigine.

Some medicines may make birth control pill less effective,including:

• Barbiturates
• Bosentan
• Carbamazepine
• Felbamate
• Griseofulvin
• Oxcarbazepine
• Phenytoin
• Rifampin
• St. John's wort
• Topiramate

As with all prescription products, you should notify yourhealthcare provider of any other medicines and herbal products you are taking.You may need to use a barrier contraceptive when you take drugs or productsthat can make birth control pills less effective.

5. Sexually transmitted diseases

This product (like all oral contraceptives) is intendedto prevent pregnancy. It does not protect against transmission of HIV (AIDS) andother sexually transmitted diseases such as chlamydia, genital herpes, genitalwarts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERYDAY AT THE SAME TIME.

If you miss pills you could get pregnant. This includesstarting the pack late.

The more pills you miss, the more likely you are to getpregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEELSICK TO THEIR STOMACH DURING THE FIRST 1 TO 3 PACKS OF PILLS.

If you feel sick to your stomach, do not stop taking thepill. The problem will usually go away. If it doesn't go away, check with yourdoctor or healthcare provider.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING,even when you make up these missed pills.

On the days you take 2 pills to make up for missed pills,you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IFYOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work aswell.

Use a back-up method (such as condoms, foam, or sponge)until you check with your doctor or healthcare provider.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talkto your doctor or healthcare provider about how to make pill-taking easier orabout using another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THEINFORMATION IN THIS LEAFLET, call your doctor or healthcare provider.

BEFORE YOU START TAKING YOUR PILLS

8. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

It is important to take it at about the same time every day.

8. LOOK AT YOUR PILL PACK: IT WILL HAVE 28 PILLS:

This 28-pill pack has 26 “active” [white and yellow] pills(with hormones) and 2 “inactive” [light-green] pills (without hormones).

10. ALSO FIND:

1) where on the pack to start taking the pills,

2) in what order to take the pills (follow the arrows) and

3) the week numbers as shown in the picture below.

11. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as condoms, foam, orsponge) to use as a back-up in case you miss pills.

AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your firstpack of pills. Decide with your doctor or healthcare provider which is the bestday for you. Pick a time of day which will be easy to remember.

DAY 1 START

12. Pick the day label strip that starts with the first dayof your period (this is the day you start bleeding or spotting, even if it isalmost midnight when the bleeding begins).

13. Place this day label strip in the cycle tablet dispenserover the area that has the days of the week (starting with Sunday) imprinted.

Note: If the first day of yourperiod is a Sunday, you can skip steps #1 and #2.

14. Take the first “active” [white] pill of thefirst pack during the first 24 hours of your period.

15. You will not need to use a back-up method of birthcontrol, since you are starting the pill at the beginning of your period.

SUNDAY START

16. Take the first “active” [white] pill of the first packon the Sunday after your period starts, even if you are still bleeding. If yourperiod begins on Sunday, start the pack that same day.

17. Use another method of birth control as a back-up methodif you have sex anytime from the Sunday you start your first pack until thenext Sunday (7 days). Condoms, foam, or the sponge are good back-up methods ofbirth control.

WHAT TO DO DURING THE MONTH

18. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACKIS EMPTY.

Do not skip pills even if you arespotting or bleeding between monthly periods or feel sick to your stomach(nausea).

Do not skip pills even if you donot have sex very often.

19. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

21 pills: Wait 7 days to start the next pack.You will probably have your period during that week. Be sure that no more than7 days pass between 21-day packs.

28 pills: Start the next pack on the day afteryour last pill. Do not wait any days between packs.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 “active” [white] pill:

20. Take it as soon as you remember. Take the next pill atyour regular time. This means you take 2 pills in 1 day.

21. You do not need to use a back-up birth control method ifyou have sex. If you MISS 2 “active” [white] pills in a row in WEEK 1 OR WEEK 2of your pack:

22. Take 2 pills on the day you remember and 2 pills thenext day.

23. Then take 1 pill a day until you finish the pack.

24. You MAY BECOME PREGNANT if you have sex in the 7 days afteryou miss pills. You MUST use another birth control method (such as condoms,foam, or sponge) as a backup method for those 7 days.

If you MISS 2 “active” [white] pills in a row in WEEK 3:

25. If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a newpack of pills that same day.

26. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call your doctoror healthcare provider because you might be pregnant.

27. You MAY BECOME PREGNANT if you have sex in the 7 days afteryou miss pills. You MUST use another birth control method (such as condoms,foam, or sponge) as a back-up method for those 7 days.

If you MISS 3 OR MORE “active” [white] pills in a row(during the first 3 weeks):

28. If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a newpack of pills that same day.

29. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call your doctoror healthcare provider because you might be pregnant.

30. You MAY BECOME PREGNANT if you have sex in the 7 days afteryou miss pills. You MUST use another birth control method (such as condoms,foam, or sponge) as a back-up method for those 7 days.

A REMINDER FOR THOSE ON 28-DAY PACKS

If you forget any of the 2 [light-green] or 5 [yellow] pillsin Week 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THEPILLS YOU HAVE MISSED

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE “ACTIVE” [WHITE] PILL EACH DAY until you canreach your doctor or healthcare provider.

PREGNANCY DUE TO PILL FAILURE

The incidence of pill failure resulting in pregnancy isapproximately one percent (i.e., one pregnancy per 100 women per year) if takenevery day as directed, but more typical failure rates are about 5%. If failuredoes occur, the risk to the fetus is minimal.

PREGNANCY AFTER STOPPING THE PILL

There may be some delay in becoming pregnant after you stopusing oral contraceptives, especially if you had irregular menstrual cyclesbefore you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pilland desire pregnancy.

There does not appear to be any increase in birth defects innewborn babies when pregnancy occurs soon after stopping the pill.

OVERDOSAGE

Serious ill effects have not been reported followingingestion of large doses of oral contraceptives by young children. Overdosagemay cause nausea and withdrawal bleeding in females. In case of overdosage,contact your doctor, healthcare provider or pharmacist.

OTHER INFORMATION

Your doctor or healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. Thephysical examination may be delayed to another time if you request it and yourdoctor or the healthcare provider believes that it is a good medical practiceto postpone it. You should be reexamined at least once a year. Be sure toinform your doctor or healthcare provider if there is a family history of anyof the conditions listed previously in this leaflet. Be sure to keep allappointments with your doctor or healthcare provider, because this is a time todetermine if there are early signs of side effects of oral contraceptive use.

Do not use the drug for any condition other than the one forwhich it was prescribed. This drug has been prescribed specifically for you; donot give it to others who may want birth control pills.

HEALTH BENEFITS FROM ORAL CONTRACEPTIVES

In addition to preventing pregnancy, use of combination oralcontraceptives may provide certain benefits. They are:

• menstrual cycles may become more regular.
• blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.
• pain or other symptoms during menstruation may be encountered less frequently.
• ectopic (tubal) pregnancy may occur less frequently.
• non-cancerous cysts or lumps in the breast may occur less frequently.
• acute pelvic inflammatory disease may occur less frequently.
• oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.

If you want more information about birth control pills, askyour doctor, healthcare provider, or pharmacist. They have a more technicalleaflet called the Prescribing Information which you may wish to read.