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PREVIFEM(norgestimate and ethinyl estradiol)kit
Cigarette smoking increases therisk of serious cardiovascular side effects from oral contraceptive use. Thisrisk increases with age and with heavy smoking (15 or more cigarettes perday) and is quite marked in women over 35 years of age. Women who use oralcontraceptives should be strongly advised not to smoke.
DESCRIPTION
Previfem® is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.
Eachblue tablet contains 0.25 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. 1 HT Aluminum Lake, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, and pregelatinized starch.
Each light-green tablet contains only inert ingredients, as follows: FD&C Blue No. 2, hypromellose, iron oxide yellow, lactose monohydrate, magnesium stearate, polyethylene glycol, and pregelatinized starch.
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
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 Previfem®. 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.
Table I. Summary of Norelgestromin, Norgestrel and Ethinyl Estradiol Pharmacokinetic Parameters.
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Mean (SD) Pharmacokinetic Parameters of Previfem® During a Three Cycle Study
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|
Analyte |
Cycle |
Day
|
Cmax
|
tmax (h)
|
AUC0-24h
|
t½ (h) |
|
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)
|
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, t½ = elimination half-life NGMN and NG: Cmax = ng/mL, AUC0-24h = h•ng/mL
EE: Cmax = pg/mL, AUC0-24h = h•pg/mL
The effect of food on the pharmacokinetics of Previfem® 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 to 49%) and 37% (16 to 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-5ß-17-pregnan-20-yn,3α,17ß-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 Previfem® have not been studied.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of Previfem® 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 Previfem® have not been studied.
Drug-Drug Interactions
No formal drug-drug interaction studies were conducted with Previfem®. 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
Previfem®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. TableII 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 II. Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.
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% of Women Experiencing an Unintended
Pregnancy within the
First Year of Use |
% of Women
Continuing Use at
One Year3
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Method (1) |
Typical Use1 (2) |
Perfect Use2 (3) |
(4) |
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Chance4 |
85 |
85 |
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Spermicides5
|
26 |
6 |
40 |
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Periodic abstinence |
25 |
|
63 |
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Calendar
|
|
9 |
|
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Ovulation Method
|
|
3 |
|
|
Sympto-Thermal6
|
|
2 |
|
|
Post-Ovulation |
|
1 |
|
|
Cap7
|
|
|
|
|
Parous Women
|
40 |
26 |
42 |
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Nulliparous Women
|
20 |
9 |
56 |
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Sponge
|
|
|
|
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Parous Women
|
40 |
20 |
42 |
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Nulliparous Women
|
20 |
9 |
56 |
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Diaphragm7
|
20 |
6 |
56 |
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Withdrawal
|
19 |
4 |
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Condom8
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|
|
|
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Female (Reality)
|
21 |
5 |
56 |
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Male
|
14 |
3 |
61 |
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Pill
|
5 |
|
71 |
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Progestin Only
|
|
0.5 |
|
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Combined
|
|
0.1 |
|
|
IUD |
|
|
|
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Progesterone T
|
2.0 |
1.5 |
81 |
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Copper T380A
|
0.8 |
0.6 |
78 |
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LNg 20
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0.1 |
0.1 |
81 |
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Depo-Provera
|
0.3 |
0.3 |
70 |
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Norplant and Norplant-2
|
0.05 |
0.05 |
88 |
|
Female Sterilization |
0.5 |
0.5 |
100 |
|
Male Sterilization
|
0.15 |
0.10 |
100 |
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%.9
Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception.10
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.
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 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills).
10 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 six months of age.
Previfem®has not been studied for and is not indicated for use in emergency contraception.
In clinical trials with norgestimate and ethinyl estradiol, 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:
WARNINGS
Cigarette smoking increases therisk of serious cardiovascular side effects from oral contraceptive use. Thisrisk increases with age and with heavy smoking (15 or more cigarettes perday) and is quite marked in women over 35 years of age. Women who use oralcontraceptives 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.
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 somewh |
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