norethindrone acetate and ethinyl estradiol and ferrous fumarate
Dosage Form: tablets
ESTROSTEP Fe
(Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets*)
*Ferrous fumarate tablets are not USP for dissolution and assay.
ESTROSTEP® Fe
(Each white triangular tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each white square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each white round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol; each brown tablet contains 75 mg ferrous fumarate.)
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Estrostep Fe Description
ESTROSTEP® Fe is a graduated estrophasic oral contraceptive providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen.
Estrostep Fe provides for a continuous dosage regimen consisting of 21 oral contraceptive tablets and seven ferrous fumarate tablets. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose.
Each white triangle-shaped tablet contains 1 mg norethindrone acetate [(17 alpha)-17-(acetyloxy)-19-norpregna-4-en-20-yn-3-one] and 20 mcg ethinyl estradiol [(17 alpha)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol]; each white square-shaped tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; and each white round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each tablet also contains calcium stearate; lactose; microcrystalline cellulose; and starch.
The structural formulas are as follows:
Each brown tablet contains microcrystalline cellulose; ferrous fumarate; magnesium stearate; povidone; sodium starch glycolate; sucrose with modified dextrins.
Each Estrostep Fe tablet dispenser contains five white triangular tablets, seven white square tablets, nine white round tablets, and seven brown tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, then one square tablet each day for seven days, followed by one round tablet each day for nine days, and then one brown tablet each day for seven days.
Estrostep Fe - 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).
In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of Estrostep Fe, serum SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity.
ACNE
Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol 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
Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours post-dose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.
Administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food.
Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of Estrostep Fe to 17 women are shown below (Figure 1). Mean steady-state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose-dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1).
FIGURE 1. Mean Steady-State Plasma Ethinyl Estradiol and Norethindrone Concentrations Following Chronic Administration of Estrostep Fe
| |||||
| Norethindrone Acetate/ Ethinyl Estradiol Dose | Cycle Day | Cmax | AUC | CL/F | SHBG† |
| Norethindrone | |||||
| mg/μg | ng/mL | ng·hr/mL | mL/min | nmol/L | |
| 1/20 | 5 | 10.8 | 81.1 | 220 | 120 |
| (3.9) | (28.5) | (137) | (33) | ||
| 1/30 | 12 | 12.7 | 102 | 166 | 139 |
| (4.1) | (32) | (85) | (42) | ||
| 1/35 | 21 | 12.7 | 109 | 152 | 163 |
| (4.1) | (32) | (73) | (40) | ||
| Ethinyl Estradiol | |||||
| mg/μg | pg/mL | pg·hr/mL | mL/min | nmol/L | |
| 1/20 | 5 | 61.0 | 661 | 549 | |
| (16.8) | (190) | (171) | |||
| 1/30 | 12 | 92.4 | 973 | 546 | |
| (26.9) | (293) | (199) | |||
| 1/35 | 21 | 113 | 1149 | 568 | |
| (44) | (372) | (219) | |||
No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of Estrostep Fe to 119 postmenarchal women ages 15 to 48 years.
Distribution
Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Estrostep Fe increases serum SHBG concentrations two- to three-fold (Table 1).
Metabolism
Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.
Excretion
Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of Estrostep Fe are approximately 13 hours and 19 hours, respectively.
Special Population
Race:
The effect of race on the disposition of Estrostep Fe has not been evaluated.
Renal Insufficiency
The effect of renal disease on the disposition of Estrostep Fe has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.
Hepatic Insufficiency
The effect of hepatic disease on the disposition of Estrostep Fe has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.
Drug-Drug Interactions
Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.
Indications and Usage for Estrostep Fe
Estrostep Fe is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Estrostep Fe is indicated for the treatment of moderate acne vulgaris in females, ≥15 years of age, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, and are unresponsive to topical anti-acne medications. Estrostep Fe should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control and plans to stay on it for at least 6 months.
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, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| ||||
| 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. | ||||
| % 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) | |
| Chance§ | 85 | 85 | ||
| Spermicides¶ | 26 | 6 | 40 | |
| Periodic Abstinence | 25 | 63 | ||
| Calendar | 9 | |||
| Ovulation Method | 3 | |||
| Symptothermal# | 2 | |||
| Post-ovulation | 1 | |||
| CapÞ | ||||
| Parous Women | 40 | 26 | 42 | |
| Nulliparous Women | 20 | 9 | 56 | |
| Sponge | ||||
| Parous Women | 40 | 20 | 42 | |
| Nulliparous Women | 20 | 9 | 56 | |
| DiaphragmÞ | 20 | 6 | 56 | |
| Withdrawal | 19 | 4 | ||
| Condomß | ||||
| Female (Reality) | 21 | 5 | 56 | |
| Male | 14 | 3 | 61 | |
| Pill | 5 | 71 | ||
| Progestin Only | 0.5 | |||
| Combined | 0.1 | |||
| IUD | ||||
| Progesterone T | 2.0 | 1.5 | 81 | |
| Copper 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 | |
| Emergency Contraceptives Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.à Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.è Source: Trussell J, The Essentials of Contraception. 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. | ||||
Estrostep Fe was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28-day) cycle studies. A total of 296 patients received Estrostep Fe and 295 received placebo. Mean age at enrollment for both groups was 24 years. At six months each study demonstrated a statistically significant difference between Estrostep Fe and placebo for mean change from baseline in lesion counts (see Table 3 and Figure 2). Each study also demonstrated overall treatment success in the investigator’s global evaluation. Patients with severe androgen excess were not studied.
| ||||||
Acne Vulgaris Indication Pooled Data 376-403 and 376-404 Observed at Six Months and at Baseline* Intent To Treat Population | ||||||
Estrostep Fe N = 296 | Placebo N = 295 | Difference in Counts Between Estrostep Fe and Placebo at Six Months (95% CI)† | ||||
| Number of Lesions | Counts | % reduction | Counts | % reduction | ||
| INFLAMMATORY LESIONS | ||||||
| Baseline Mean | 29 | 29 | ||||
| Six Month Mean | 14 | 52% | 17 | 41% | 3 (±2) | |
| NON-INFLAMMATORY LESIONS | ||||||
| Baseline Mean | 44 | 43 | ||||
| Six Month Mean | 27 | 38% | 32 | 25% | 5 (±3.5) | |
| TOTAL LESIONS | ||||||
| Baseline Mean | 74 | 72 | ||||
| Six Month Mean | 42 | 43% | 49 | 32% | 7 (±5) | |
Estrostep Fe users who started with about 74 acne lesions had about 42 lesions after 6 months of treatment. Placebo users who started with about 72 acne lesions had about 49 lesions after the same duration of treatment.
Figure 2. Mean Percent Reduction in Total Lesion Counts From Baseline to Each 28-Day Cycle and Mean Total Lesion Counts at Each Cycle Following Administration of Estrostep Fe and Placebo (Statistically significant differences were not found in both studies individually until cycle 6)
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
- Known or suspected carcinoma of the breast
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with prior pill use
- Hepatic adenomas or carcinomas
- Known or suspected pregnancy
Warnings
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with 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 References 8 and 9 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. 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 non-smokers over the age of 40 (Figure 3) among women who use oral contraceptives.
FIGURE 3. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
Adapted from P.M. Layde and V. Beral
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 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.
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. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and 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 4 weeks prior to and for 2 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 4 to 6 weeks after delivery in women who elect not to breastfeed.
c. Cerebrovascular disease
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 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. The attributable risk is also greater in older women.
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 progestin and the nature of the progestin used in the contraceptives. The amount and activity 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 oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the 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 5 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 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 ri
No comments:
Post a Comment