The following product is a combination oral contraceptive containing the progestational compound norgestimate USP and the estrogenic compound ethinyl estradiol USP.
Norgestimate and Ethinyl Estradiol Tablets USP:
Each white to off white tablet contains 0.18 mg of the progestational compound, norgestimate USP (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 USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.
Each light blue tablet contains 0.215 mg of the progestational compound norgestimate USP (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 USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2, lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.
Each blue tablet contains 0.25 mg of the progestational compound norgestimate USP (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 USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2, lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.
Each light green tablet contains only inert ingredients, as follows: D&C Yellow No. 10, FD&C Blue No. 2, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc.
Norgestimate and Ethinyl Estradiol - 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).
Acne
Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.
Pharmacokinetics
AbsorptionNorgestimate (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 Norgestimate and Ethinyl Estradiol tablets.. Accumulation following multiple dosing of the 250 μg NGM / 35 μg 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 μg to 250 μg. 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.
Table 1. Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.
| Mean (SD) Pharmacokinetic Parameters of Norgestimate and Ethinyl Estradiol tablets during a Three Cycle Study |
| Analyte |
Cycle |
Day |
Cmax |
tmax (h) |
AUC 0-24h |
t 1/2 (h) |
| NGMN |
3 |
7 |
1.80 (0.46) |
1.42 (0.73) |
15.0 (3.88) |
NC |
|
|
14 |
2.12 (0.56) |
1.21 (0.26) |
16.1 (4.97) |
NC |
|
|
21 |
2.66 (0.47) |
1.29 (0.26) |
21.4 (3.46) |
22.3 (6.54) |
| NG |
3 |
7 |
1.94 (0.82) |
3.15 (4.05) |
34.8 (16.5) |
NC |
|
|
14 |
3.00 (1.04) |
2.21 (2.03) |
55.2 (23.5) |
NC |
|
|
21 |
3.66 (1.15) |
2.58 (2.97) |
69.3 (23.8) |
40.2 (15.4) |
| EE |
3 |
7 |
124 (39.5) |
1.27 (0.26) |
1130 (420) |
NC |
|
|
14 |
128 (38.4) |
1.32 (0.25) |
1130 (324) |
NC |
|
|
21 |
126 (34.7) |
1.31 (0.56) |
1090 (359) |
15.9 (4.39) |
C max = peak serum concentration, t max = time to reach peak serum concentration,
AUC 0-24h = area under serum concentration vs time curve from 0 to 24 hours, t 1/2 = elimination half-life, NC = not calculated. |
| NGMN and NG: C max = ng/mL, AUC 0-24h=h•ng/mL |
| EE: C max=pg/mL, AUC 0-24h=h•pg/mL |
The effect of food on the pharmacokinetics of Norgestimate and Ethinyl Estradiol tablets has not been studied.
DistributionNorelgestromin 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.
MetabolismNorgestimate 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.
ExcretionThe 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, 17α-dihydroxy-13-ethyl, (17α), various hydroxylated metabolites and conjugates of these metabolites.
Special PopulationsThe effects of body weight, body surface area or age on the pharmacokinetics of Norgestimate and Ethinyl Estradiol tablets has not been studied.
Hepatic ImpairmentThe effects of hepatic impairment on the pharmacokinetics of Norgestimate and Ethinyl Estradiol tablets has not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).
Renal ImpairmentThe effects of renal impairment on the pharmacokinetics of Norgestimate and Ethinyl Estradiol tablets have not been studied.
Drug-Drug InteractionsNo formal drug-drug interaction studies were conducted with Norgestimate and Ethinyl Estradiol tablets. 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 Norgestimate and Ethinyl Estradiol
Norgestimate and Ethinyl Estradiol tablets USP are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Norgestimate and Ethinyl Estradiol tablets USP are indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Norgestimate and Ethinyl Estradiol tablets USP should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
Oral contraceptives are highly effective for pregnancy prevention.Table 2 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.
Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.
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 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. |
|
|
% 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 |
|
| Cap |
|
|
|
| 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 |
|
| Condom |
|
|
|
| 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 |
Norgestimate and Ethinyl Estradiol tablets USP have not been studied for and is not indicated for use in emergency contraception.
In four clinical trials with Norgestimate and Ethinyl Estradiol tablets USP , a total of 4,756 subjects completed 45,244 cycles, and the use-efficacy pregnancy rate was approximately 1 pregnancy per 100 women-years.
Norgestimate and Ethinyl Estradiol tablets USP were evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. 221 patients received Norgestimate and Ethinyl Estradiol tablets USP and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changes from 55 to 31 (42% reduction) in patients treated with Norgestimate and Ethinyl Estradiol tablets USP and from 54 to 38 (27% reduction) in patients similarly treated with placebo.
Table 3 summarizes the changes in lesion count for each type of lesion in the ITT population. Based on the investigator’s global assessment conducted at the final visit, patients treated with Norgestimate and Ethinyl Estradiol tablets USP showed a statistically significant improvement in total lesions compared to those treated with placebo.
Table 3: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials. Observed Means at Six Months (LOCF) and at Baseline. Intent-to-Treat Population.
|
|
Norgestimate and Ethinyl Estradiol tablets USP
(N=221)
|
Placebo
(N=234) |
Difference in counts between Norgestimate and Ethinyl Estradiol tablets USP and Placebo at 6 Months
|
| # of Lesions |
Counts |
% Reduction |
Counts |
%
Reduction |
|
INFLAMMATORY
LESIONS |
|
|
|
|
|
| Baseline Mean |
19 |
|
19 |
|
|
| Sixth Month Mean |
10 |
48% |
13 |
30% |
3(95% CI: -1.2, 5.1) |
NON-INFLAMMATORY
LESIONS |
|
|
|
|
|
| Baseline Mean |
36 |
|
35 |
|
|
| Sixth Month Mean |
22 |
34% |
25 |
21% |
3(95% CI: -0.2, 7.8) |
| TOTAL LESIONS |
|
|
|
|
|
| Baseline Mean |
55 |
|
54 |
|
|
| Sixth Month Mean |
31 |
42% |
38 |
27% |
7 (95% CI: 2.0, 11.9) |
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 InfarctionAn 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.
Figure 1. Circulatory Disease Mortality Rates Per 100,000 Women-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.
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. ThromboembolismAn 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 breast feed.
c. Cerebrovascular DiseasesOral 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 ContraceptivesA 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 DiseaseThere 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 4 ). 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 nonsmoking 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.
Table 4: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Non-Sterile Women, by Fertility Control Method According to Age
| 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 |
0.3 |
0.5 |
0.9 |
1.9 |
13.8 |
31.6 |
|
