desogestrel and ethinyl estradiol
Dosage Form: tablets
Apri®
(desogestrel and ethinyl estradiol) Tablets
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
Rx only
Revised JANUARY 2009
11001429
Apri Description
Apri 28 Day Regimen blister cards for desogestrel and ethinyl estradiol tablets provide an oral contraceptive regimen of 21 round rose-colored tablets. Each rose-colored “active” desogestrel and ethinyl estradiol tablet for oral administration contains 0.15 mg desogestrel (13-ethyl-11- methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Inactive ingredients include colloidal silicon dioxide, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hydroxypropyl methylcellulose, lactose monohydrate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, stearic acid, titanium dioxide, and vitamin E.
Apri 28 Day Regimen blister cards also contain 7 white “inactive” tablets for oral administration, containing the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized starch.
DESOGESTREL C22H30O M.W.: 310.48
ETHINYL ESTRADIOL C20H24O2 M.W.: 296.41
The 21 rose-colored tablets meet USP Dissolution Test 2.
Apri - Clinical Pharmacology
Pharmacodynamics
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus, which increase the difficulty of sperm entry into the uterus, and changes in the endometrium which reduce the likelihood of implantation.
Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.
Pharmacokinetics
Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.
In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0-∞) is 33,858±11,043 pg/mL • hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840±1,667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400±560 pg/mL. The AUC0-24 at steady state is 52,299±17,878 pg/mL • hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150±64 nmol/L) to day 21 (230±59 nmol/L). The elimination half-life for 3-keto-desogestrel is approximately 38±20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3ß-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, the relative bioavailability is approximately 83%.
In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0-∞ is 1,471±268 pg/mL • hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141±48 pg/mL are reached at about 1.4±0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24±8.3 pg/mL. The AUC0-24, at steady state is 1,117±302 pg/mL • hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.
The elimination half-life is 26±6.8 hours at steady state. 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.
Indications and Usage for Apri
Apri (desogestrel and ethinyl estradiol) Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table I 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.
| Adapted from Hatcher et al, 1998, Ref #1. | |||
| |||
| % of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year* | ||
Method (1) | Typical Use† (2) | Perfect Use‡ (3) | (4) |
| Chance§ | 85 | 85 | |
| Spermicides¶ | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-Thermal# | 2 | ||
| Post-Ovulation | 1 | ||
| Withdrawal | 19 | 4 | |
| CapÞ | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| DiaphragmÞ | 20 | 6 | 56 |
| Condomß | |||
| Female (Reality) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| Progestin Only | 0.5 | ||
| Combined | 0.1 | ||
| IUD | |||
| Progesterone T | 2.0 | 1.5 | 81 |
| Copper T 380A | 0.8 | 0.6 | 78 |
| LNg 20 | 0.1 | 0.1 | 81 |
| Depo-Provera | 0.3 | 0.3 | 70 |
| Norplant and Norplant-2 | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.10 | 100 |
In a clinical trial with desogestrel and ethinyl estradiol tablets, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.
Contraindications
Oral contraceptives like Apri (desogestrel and ethinyl estradiol) tablets 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 or carcinomas
- Known or suspected pregnancy
Warnings
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased 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 nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Thromboembolism: An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.
Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-fold increase in risk.
A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (26). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast feed.
b. Myocardial infarction: An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (4-10). The risk is very low in women under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives. (See Table II)
TABLE II: Circulatory disease mortality rates per 100,000 woman-years by age, smoking status and oral contraceptive use (Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14-18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in 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 with cardiovascular disease risk factors.
c. Cerebrovascular diseases: Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke (27-29).
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension (30). The attributable risk is also greater in older women (3).
d. Dose-related risk of vascular disease from oral contraceptives: A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31-33). A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents (14-16). A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen.
e. Persistence of risk of vascular disease: There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (34). However, both studies were performed with oral contraceptive formulations containing 0.050 mg or higher of estrogens.
2. Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (TABLE III ). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.
The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s (35). Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.
Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. [See table below.]
| (Adapted from H.W. Ory, ref. #35.) | ||||||
| ||||||
| Method of control and outcome | 15-19 | 20-24 | 25-29 | 30-34 | 35-39 | 40-44 |
| No fertility control methods* | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
| Oral contraceptives non-smoker† | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
| Oral contraceptives smoker† | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
| IUD† | 0.8 | 0.8 | 1.0 | 1.0 | 1.4 | 1.4 |
| Condom* | 1.1 | 1.6 | 0.7 | 0.2 | 0.3 | 0.4 |
| Diaphragm/spermicide* | 1.9 | 1.2 | 1.2 | 1.3 | 2.2 | 2.8 |
| Periodic abstinence* | 2.5 | 1.6 | 1.6 | 1.7 | 2.9 | 3.6 |
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. While there are conflicting reports, most studies suggest that use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer particularly at a younger age. This increased relative risk has been reported to be related to duration of use (36-44, 79-89).
A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past 10 years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use (101).
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepitheal neoplasia in some populations of women (45-48). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (50,51).
Studies have shown an increased risk of developing hepatocellular carcinoma (52-54, 102) in oral contraceptive users. However, these cancers are rare in the U.S.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
6. Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (56-57). The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. 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. Oral contraceptive use should be discontinued until pregnancy is ruled out.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62-64). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
8. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users (17). This effect has been shown to be directly related to estrogen dose (65). In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
9. Elevated Blood Pressure
An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with extended duration of use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension among former and never users (68,70,71).
10. Headache
The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been 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.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
Precautions
1. Physical Examination and Follow-up
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
2. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.
3. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
4. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
5. Emotional Disorders
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
6. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
7. Drug Interactions
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).
8. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
- Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
- 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.
- Other binding proteins may be elevated in serum.
- 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.
- 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.
- Glucose tolerance may be decreased.
- 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.
9. Carcinogenesis
See WARNINGS section.
10. Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.
11. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.
12. Pediatric Use
Safety and efficacy of desogestrel and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.
13. Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
INFORMATION FOR THE PATIENT
See Patient Labeling Printed Below
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
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