norgestimate and ethinyl estradiol
Dosage Form: tablets
MonoNessa® Tablets
(norgestimate and ethinyl estradiol)
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
MonoNessa Description
The following product is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.
MonoNessa® Tablets
Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide.
Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium dioxide.
Norgestimate
Ethinyl Estradiol
MonoNessa - Clinical Pharmacology
ORAL CONTRACEPTION
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 and humans, have shown that norgestimate and 17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity.90–93 Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone.90,91,94
PHARMACOKINETICS
Absorption
Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration. Norgestimate is rapidly and completely metabolized by firstpass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of MonoNessa®. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding globulin), which limits its biological activity.
| Mean (SD) Pharmacokinetic Parameters of MonoNessa® During a Three Cycle Study | ||||||
|---|---|---|---|---|---|---|
| Analyte | Cycle | Day | Cmax | tmax (h) | AUC0–24h | t1/2 (h) |
| Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0–24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated. | ||||||
| NGMN and NG: Cmax = ng/mL, AUC0–24h=h∙ng/mL | ||||||
| EE: Cmax=pg/mL, AUC0–24h=h∙pg/mL | ||||||
| NGMN | 1 | 1 | 1.78 (0.397) | 1.19 (0.250) | 9.90 (3.25) | 18.4 (5.91) |
| 3 | 21 | 2.19 (0.655) | 1.43 (0.680) | 18.1 (5.53) | 24.9 (9.04) | |
| NG | 1 | 1 | 0.649 (0.49) | 1.42 (0.69) | 6.22 (2.46) | 37.8 (14.0) |
| 3 | 21 | 2.65 (1.11) | 1.67 (1.32) | 48.2 (20.5) | 45.0 (20.4) | |
| EE | 1 | 1 | 92.2 (24.5) | 1.2 (0.26) | 629 (138) | 10.1 (1.90) |
| 3 | 21 | 147 (41.5) | 1.13 (0.23) | 1210 (294) | 15.0 (2.36) | |
The effect of food on the pharmacokinetics of MonoNessa® has not been studied.
Distribution
Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.
Metabolism
Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Excretion
The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45–49%) and 37% (16–49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged norgestimate was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate have been identified in human urine following administration of radiolabeled norgestimate. These include 18,19 - Dinor - 17 - pregn - 4 - en - 20 - yn - 3 - one,17 - hydroxy - 13 - ethyl,(17α) - ( - );18,19 - Dinor - 5β - 17 - pregnan - 20 - yn,3α,17β - dihydroxy - 13 - ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.
Special Populations
The effects of body weight, body surface area or age on the pharmacokinetics of MonoNessa® have not been studied.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of MonoNessa® have not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).
Renal Impairment
The effects of renal impairment on the pharmacokinetics of MonoNessa® have not been studied.
Drug-Drug Interactions
No formal drug-drug interaction studies were conducted with MonoNessa®. Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS).
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki).
Indications and Usage for MonoNessa
MonoNessa® is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective for pregnancy prevention. 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, the IUD, and the Norplant® System, 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* | ||
|---|---|---|---|
| Method | Typical Use† | Perfect Use‡ | |
| (1) | (2) | (3) | (4) |
| Hatcher et al, 1998, Ref. # 1. | |||
| Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.§ | |||
| Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶ | |||
| Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. | |||
| |||
| Chance# | 85 | 85 | |
| SpermicidesÞ | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-Thermalß | 2 | ||
| Post-Ovulation | 1 | ||
| Capà | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Diaphragmà | 20 | 6 | 56 |
| Withdrawal | 19 | 4 | |
| Condomè | |||
| 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 |
| Norplant® and Norplant-2® | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.10 | 100 |
MonoNessa® has not been studied for and is not indicated for use in emergency contraception.
In clinical trials with MonoNessa®, 1,651 subjects completed 24,272 cycles and the overall use-efficacy (typical user efficacy) pregnancy rate was approximately 1 pregnancy per 100 women-years. This rate includes patients who did not take the drug correctly.
Contraindications
Oral contraceptives should not be used in women who currently have the following conditions:
- Thrombophlebitis or thromboembolic disorders
- A past history of deep vein thrombophlebitis or thromboembolic disorders
- Cerebral vascular or coronary artery disease (current or past history)
- Valvular heart disease with complications
- Severe hypertension
- Diabetes with vascular involvement
- Headaches with focal neurological symptoms
- Major surgery with prolonged immobilization
- Known or suspected carcinoma of the breast or personal history of breast cancer
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with prior pill use
- Acute or chronic hepatocellular disease with abnormal liver function
- Hepatic adenomas or carcinomas
- Known or suspected pregnancy
- Hypersensitivity to any component of this product
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 higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations 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. 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 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, and in nonsmokers over the age of 40 among women who use oral contraceptives.
(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.
Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater.97
b. 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 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.2,3,19–24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2
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 breastfeed.
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 activity of the progestogen used in the contraceptives. The activity and 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 40–49 years 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 50 micrograms 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 IV). 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 risks 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.
| Method of control and outcome | 15–19 | 20–24 | 25–29 | 30–34 | 35–39 | 40–44 |
|---|---|---|---|---|---|---|
| Adapted from H.W. Ory, ref. #35. | ||||||
| ||||||
| 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. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives (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 found a small increase in risk for women who first use COCs before age 20. 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 oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had 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 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. In spite of many studies of the relationship between 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 especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51
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. 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 concerned55,56,58,59, when 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. 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
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 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 have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular 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 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
In clinical studies with MonoNessa® there were no clinically significant changes in fasting blood glucose levels. No statistically significant changes in mean fasting blood glucose levels were observed over 24 cycles of use. Glucose tolerance tests showed minimal, clinically insignificant changes from baseline to cycles 3, 12, and 24.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal contraception.98 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 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 disease70 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, and there is no difference in the occurrence of hypertension between former and never users.68–71 It should be noted that in two separate large clinical trials (N=633 and N=911), no statistically significant changes in mean blood pressure were observed with MonoNessa®.
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. Non-hormonal 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 preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
Precautions
1. General
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
2. 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.
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.
4. 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.
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
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
8. Drug Interactions
Changes in contraceptive effectiveness associated with co-administration of other products
Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered 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, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan.
Several of the anti-HIV protease inhibitors have been studied with co-administration 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 co-administration of anti-HIV protease inhibitors. Healthcare 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 P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
Concurrent use of bosentan and ethinyl estradiol-containing products may result in decreased concentrations of these contraceptive hormones, thereby increasing the risk of unintended pregnancy and unscheduled bleeding.
Increase in plasma levels associated with co-administered drugs
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estrad
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