Dosage Form: Tablets
Rx only
Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
DESCRIPTION
Each LO/OVRAL tablet, contains 0.3 mg of norgestrel (dl -13-beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.03 mg of ethinyl estradiol, (19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). The inactive ingredients present are cellulose, lactose, magnesium stearate, and polacrilin potassium.
CLINICAL PHARMACOLOGY
Mode of Action
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
INDICATIONS AND USAGE
Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table 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, the IUD, and implants depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| % of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year 3 | ||
|---|---|---|---|
| Method (1) | Typical Use 1 (2) | Perfect Use 2 (3) | (4) |
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.9 | |||
Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998. | |||
1. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. | |||
2. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. | |||
3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. | |||
4. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. | |||
5. Foams, creams, gels, vaginal suppositories, and vaginal film. | |||
6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. | |||
7. With spermicidal cream or jelly. | |||
8. Without spermicides. | |||
9. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. | |||
| Chance 4 | 85 | 85 | |
| Spermicides 5 | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-Thermal 6 | 2 | ||
| Post-Ovulation | 1 | ||
| Cap 7 | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Diaphragm 7 | 20 | 6 | 56 |
| Withdrawal | 19 | 4 | |
| Condom 8 | |||
| 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 T380A | 0.8 | 0.6 | 78 |
| LNg 20 | 0.1 | 0.1 | 81 |
| Depo-Provera® | 0.3 | 0.3 | 70 |
| Levonorgestrel Implants (Norplant®) | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.10 | 100 |
CONTRAINDICATIONS
Combination oral contraceptives should not be used in women with any of the following conditions:
- Thrombophlebitis or thromboembolic disorders
- A past history of deep-vein thrombophlebitis or thromboembolic disorders
- Cerebral-vascular or coronary-artery disease (current or history)
- Thrombogenic valvulopathies
- Thrombogenic rhythm disorders
- Major surgery with prolonged immobilization
- Diabetes with vascular involvement
- Headaches with focal neurological symptoms
- Uncontrolled hypertension
- Known or suspected carcinoma of the breast or personal history of breast cancer
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with prior pill use
- Hepatic adenomas or carcinomas, or active liver disease, as long as liver function has not returned to normal
- Known or suspected pregnancy
- Hypersensitivity to any of the components of Lo/Ovral
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with 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 disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders And Other Vascular Problems
a. Myocardial infarction
An increased risk of myocardial infarction has been attributed to oral-contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.
Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table II) among women who use oral contraceptives.
TABLE II. (Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.) |
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 inWARNINGS). 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.
b. Venous thrombosis and thromboembolism
An increased risk of venous 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 nonusers 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 approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped.
A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination.
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, while smoking interacted to increase the risk for hemorrhagic strokes.
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity.
Women with migraine (particularly migraine/headaches with focal neurological symptoms, see CONTRAINDICATIONS) who take combination oral contraceptives may be at an increased risk of stroke.
d. Dose-related risk of vascular disease from oral contraceptives
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral-contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.
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 who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral-contraceptive formulations containing 50 mcg or higher of estrogen.
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 less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral-contraceptive users is based on data gathered in the 1970's—but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral-contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular-disease risks may be increased with oral-contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are 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.
Therefore, the Committee recommended that the benefits of oral-contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
*Deaths are birth related | ||||||
**Deaths are method related | ||||||
Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983. | ||||||
| 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 nonsmoker** | 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 examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.
The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk for women who first use COCs at a younger age. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers.
Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.
Some studies suggest that oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between combination oral-contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.
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. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral-contraceptive users.
However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral-contraceptive users approaches less than one per million users.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. 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 infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section).
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 if pregnancy is confirmed.
7. Gallbladder Disease
Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. 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 glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS, 1a. and 1d.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users.
9. Elevated Blood Pressure
Women with uncontrolled hypertension should not be started on hormonal contraception. An increase in blood pressure has been reported in women taking oral contraceptives, and this increase is more likely in older oral-contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease, should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
10. Headache
The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c. and CONTRAINDICATIONS.)
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important. If bleeding persists or recurs, 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 some women withdrawal bleeding may not occur during the “tablet-free” or “inactive-tablet” interval. If the COC has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet-taking should be discontinued and a nonhormonal method of contraception should be used until the possibility of pregnancy is excluded.
Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was pre-existent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. General
Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
2. Physical Examination and Follow-Up
A periodic personal and family medical history and complete physical examination are appropriate for all women, 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 diagnostic 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.
3. 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. (See WARNINGS, 1a., 1d., and 8.)
In patients with defects of lipoprotein metabolism, estrogen-containing preparations may be associated with rare but significant elevations of plasma triglycerides which may lead to pancreatitis.
4. Liver Function
If jaundice develops in any woman receiving hormonal contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
5. 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.
6. Emotional Disorders
Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if significant depression occurs.
7. Contact Lenses
Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
8. Gastrointestinal
Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.
9. Drug Interactions
Changes in contraceptive effectiveness associated with coadministration of other products:
Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil.
Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines, possibly due to a decrease of enterohepatic recirculation of estrogens. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time.
Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health-care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.
Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
During concomitant use of ethinyl estradiol containing products and substances that may lead to decreased plasma steroid hormone concentrations, it is recommended that a nonhormonal back-up method of birth control be used in addition to the regular intake of Lo/Ovral. If the use of a substance which leads to decreased ethinyl estradiol plasma concentrations is required for a prolonged period of time, combination oral contraceptives should not be considered the primary contraceptive.
After discontinuation of substances that may lead to decreased ethinyl estradiol plasma concentrations, use of a nonhormonal back-up method of birth control is recommended for 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinyl estradiol concentrations. It may take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use, and rate of elimination of the inducing substance.
Increase in plasma levels associated with coadministered drugs:
Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. The mechanism of this interaction is unknown. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.
Changes in plasma levels of coadministered drugs:
Combination hormonal contraceptives containing some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.
The prescribing information of concomitant medications should be consulted to identify potential interactions.
10. 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 ie, corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids respectively. Free or biologically active hormone concentrations are unchanged.
- Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
- Glucose tolerance may
