Ferrous fumarate 75 MG Oral Tablet
Generic Name: NORETHINDRONE ACETATE AND ETHINYL ESTRADIOL
Brand Name: Tilia Fe
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 non-users.
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.
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 ).
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.
Mortality Rates 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 breast feed.
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 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 a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s but not reported until 1983.
However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al.
Oral contraceptives and nonfatal vascular disease.
Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM.
Mortality among oral contraceptive users.
Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989.
The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks.
Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
Table 4.
Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age 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 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 * Deaths are birth related.
** Deaths are method related.
Adapted from H.W.
Ory 3.
Carcinoma of the Reproductive Organs and Breasts Epidemiologic studies have been conducted examining the relationship between combination oral contraceptives and breast cancer.
Norethindrone acetate and ethinyl estradiol tablets were not included in these studies, and the majority of the combination oral contraceptives used by women in these studies have higher doses of estrogen than norethindrone acetate and ethinyl estradiol tablets.
These studies suggest that the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives; however, these studies do not provide evidence for causation.
The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of reasons.
The risk appears to decrease over time after combination oral contraceptive discontinuation, and by 10 years after cessation of combination oral contraceptive use, the additional risk disappears.
The risk does not appear to increase with duration of use and no consistent relationships have been found with age at first use or doses studied or type of steroid.
Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous combination 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 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.
However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
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 4 or more years of use.
Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.
However, these cancers are extremely rare in the US, 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 and During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.
Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.
Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.
If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period.
Oral contraceptive use should be discontinued if pregnancy is confirmed.
7.
Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.
More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.
The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
8.
Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users.
Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance.
Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.
However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.
Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill.
As discussed earlier (see , 1a.
and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
9.
Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use.
Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception.
If women 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 among ever and never users.
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 prolonged 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 pre-existent.
DRUG INTERACTIONS
8.
Drug Interactions Effects of Other Drugs on Oral Contraceptives Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin.
A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.
Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness.
Antibiotics: Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin.
However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.
Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.
St.
John’s Wort: 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 oral contraceptives.
This may also result in breakthrough bleeding.
Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.
Effects of Oral Contraceptives on Other Drugs Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds.
Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives.
In addition, oral contraceptives may induce the conjugation of other compounds.
Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children.
Overdosage may cause nausea, and withdrawal bleeding may occur in females.
NON-CONTRACEPTIVE HEALTH EFFECTS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.
Effects on menses: Increased menstrual cycle regularity Decreased blood loss and decreased incidence of iron deficiency anemia Decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: Decreased incidence of functional ovarian cysts Decreased incidence of ectopic pregnancies Effects from long-term use: Decreased incidence of fibroadenomas and fibrocystic disease of the breast Decreased incidence of acute pelvic inflammatory disease Decreased incidence of endometrial cancer Decreased incidence of ovarian cancer
DESCRIPTION
Tilia™ Fe is a graduated estrophasic providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen.
Tilia™ Fe provides for a continuous dosage regimen consisting of 21 oral contraceptive tablets and 7 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 tablet contains 1 mg norethindrone acetate, (17α) 17-(acetyloxy)-19-norpregn-4-en-20-yn-3-one, and 20 mcg ethinyl estradiol, (17α)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol.
The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone.
Each light-green tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol.
The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone.
The light-green tablets also contain D&C Yellow #10 and FD&C Blue #1.
Each green tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.
The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone.
The green tablets also contain D&C Yellow #10 and FD&C Blue #1.
The structural formulas are as follows: Norethindrone Acetate C22H28O3 M.W.
340.46 Ethinyl Es tradiol C20H24O2 M.W.
296.4 Each inactive, brown tablet contains microcrystalline cellulose, ferrous fumarate, magnesium stearate and sodium starch glycolate.
Ferrous fumarate tablets are not USP for dissolution and assay.
Each dispenser of Tilia™ Fe, contains 5 white tablets, 7 light-green tablets, 9 green tablets, and 7 brown tablets.
These tablets are to be taken in the following order: one white tablet each day for five days, then one light-green tablet each day for seven days, followed by one green tablet each day for nine days, and then one brown tablet each day for seven days.
Structural formulas of Norethindrone Acetate and Ethinyl Estradiol
HOW SUPPLIED
Tilia™ Fe (norethindrone acetate and ethinyl estradiol tablets USP and ferrous fumarate tablets*) is available in a 28 Tablet Dispenser, arranged in 3 rows of 7 active tablets and 1 row of 7 inert tablets, as follows: Five active, white, hexagonal tablets (each contain 1 mg of norethindrone acetate and 20 mcg of ethinyl estradiol) debossed with WATSON on one side and 0140 on the other side.
Seven active, light-green, hexagonal tablets (each contain 1 mg of norethindrone acetate and 30 mcg of ethinyl estradiol) debossed with WATSON on one side and 0141 on the other side.
Nine active, green, hexagonal tablets (each contain 1 mg of norethindrone acetate and 35 mcg of ethinyl estradiol) debossed with WATSON on one side and 0142 on the other side.
Seven inert, brown, round tablets (each contain 75 mg ferrous fumarate) debossed with WATSON 075 on one side.
One (1) dispenser of 28 tablets NDC 54868-6274-0 Store at 20°-25°C (68°-77°F).
[See USP controlled room temperature.] Manufactured By: Watson Laboratories, Inc.
Corona, CA 92880 USA Distributed By: Watson Pharma, Inc.
Corona, CA 92880 USA Issued: August 2010 192205-2 Relabeling and Repackaging by: Physicians Total Care, Inc.
Tulsa, OK 74146
GERIATRIC USE
14.
Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population.
INFORMATION FOR THE PATIENT See Patient Labeling printed below
INDICATIONS AND USAGE
Tilia™ Fe is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Tilia™ 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.
Tilia™ 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.
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).
% of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year 3 Emergency Contraceptives Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 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.
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 1 year.
4 The percentages 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 4 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 6 months of age.
Method Typical Use 1 Perfect Use 2 (1) (2) (3) (4) Chance4 85 85 Spermicides5 26 6 40 Periodic Abstinence 25 63 Calendar 9 Ovulation Method 3 Symptothermal6 2 Post-ovulation 1 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm7 20 6 56 Withdrawal 19 4 Condom8 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 Injectable progestogen 0.3 0.3 70 Implants 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Norethindrone acetate and ethinyl estradiol tablets were 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 295 patients received norethindrone acetate and ethinyl estradiol tablets and 296 received placebo.
Mean age at enrollment for both groups was 24 years.
At six months each study demonstrated a statistically significant difference between norethindrone acetate and ethinyl estradiol tablets 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.
Table 3: Acne Vulgaris Indication Pooled Data 376-403 and 376-404 Observed Means at Six Months and at Baseline* Intent To Treat Population Norethindrone Acetate and Ethinyl Estradiol Tablets N=296 Placebo N=295 Difference in Counts Between Norethindrone Acetate and Ethinyl Estradiol Tablets and Placebo at Six Months (95% CI)** Number of Lesions Counts % reduction Counts % reduction * Numbers rounded to nearest integer ** Limits for 95% Confidence Interval; not adjusted for baseline differences INFLAMMATORY LESIONS Baseline Mean 29 29 Sixth Month Mean 14 52% 17 41% 3 (± 2) NON-INFLAMMATORY Baseline Mean 44 43 Sixth Month Mean 27 38% 32 25% 5 (± 3.5) TOTAL LESIONS Baseline Mean 74 72 Sixth Month Mean 42 43% 49 32% 7 (± 5) Norethindrone acetate and ethinyl estradiol tablets 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.
Mean Percent Reduction vs.
Cycle Mean Total Lesion Counts: Norethindrone Acetate and Ethinyl Estradiol Tablets (N = 296) 74 62 56 52 48 46 42 Placebo (N = 295) 72 60 57 55 53 51 49
PEDIATRIC USE
13.
Pediatric Use Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age.
Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older.
Use of this product before menarche is not indicated.
PREGNANCY
11.
Pregnancy Pregnancy Category X.
See CONTRAINDICATIONS and WARNINGS sections.
NUSRING MOTHERS
12.
Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement.
In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk.
If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.
DOSAGE AND ADMINISTRATION
The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible.
The tablets are arranged in four rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.
Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen.
Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen.
If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.
Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.
The possibility of ovulation and conception prior to initiation of use should be considered.
Dosage and Administration for 28-Day Dosage Regimen To achieve maximum contraceptive effectiveness, Tilia™ Fe should be taken exactly as directed and at intervals not exceeding 24 hours.
Tilia™ Fe provides a continuous administration regimen consisting of 21 active tablets of norethindrone acetate and ethinyl estradiol and 7 brown, non-hormone containing tablets of ferrous fumarate.
The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose.
There is no need for the patient to count days between cycles because there are no “off-tablet days.” A.
Sunday-Start Regimen: The patient begins taking the first white tablet from the top row of the dispenser (labeled Sunday) on the first Sunday after menstrual flow begins.
When menstrual flow begins on Sunday, the first white tablet is taken on the same day.
The patient takes one active tablet daily for 21 days.
The last active (green) tablet in the dispenser will be taken on a Saturday.
Upon completion of all 21 active tablets, and without interruption, the patient takes one brown tablet daily for 7 days.
Upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday white tablet in the top row.
Adhering to this regimen of one active tablet daily for 21 days, followed without interruption by one brown tablet daily for 7 days, the patient will start all subsequent cycles on a Sunday.
B.
Day-1 Start Regimen: The first day of menstrual flow is Day 1.
The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser.
She starts taking one active tablet daily, beginning with the first white tablet in the top row.
After the last active, green tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days).
For all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last active tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser.
Following this regimen of 21 active tablets and 7 inactive, brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course.
Tablets should be taken regularly at the same time each day and can be taken without regard to meals.
It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.
Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started.
In any event, the next course of tablets should be started without interruption.
If spotting occurs while the patient is taking white tablets, continue medication without interruption.
If the patient forgets to take one or more active tablets, the following is suggested: One tablet is missed take tablet as soon as remembered take next tablet at the regular time Two consecutive tablets are missed (Week 1 or Week 2) take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (Week 3) Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled active tablets are missed.
While there is little likelihood of ovulation occurring if only one active tablet is missed, the possibility of spotting or bleeding is increased.
This is particularly likely to occur if two or more consecutive active tablets are missed.
If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty.
A back-up birth control method is not required during this time.
A new pack of tablets should be started no later than the eighth day after the last active tablet was taken.
In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day-1) depending on her regimen.
Persistent bleeding which is not controlled by this method indicates the need for re-examination of the patient, at which time nonfunctional causes should be considered.
Use of Oral Contraceptives in the Event of a Missed Menstrual Period If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.
If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.
After several months on treatment, bleeding may be reduced to a point of virtual absence.
This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.
Acne The timing of initiation of dosing with Tilia™ Fe for acne should follow the guidelines for use of Tilia™ Fe as an oral contraceptive.
Consult the section for oral contraceptives.