DailyMed Label: Tilia Fe

DailyMed Label: Tilia Fe

2024

DailyMed Prescription

Tilia Fe

NdAc and EE Tablets and Ferrous Fumarate Tablets

Dr. Reddy’s Laboratories Inc.

NDC: 75907-086

NDC: 75907-086

NDC: 75907-086

NDC: 75907-086

NDC: 75907-086

NDC: 75907-086

Tilia Fe is a graduated estrophasic combined oral contraceptive 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 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 pale yellow 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 light yellow tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; and each light brown tablet contains 1mg norethindrone acetate and 35mcg ethinyl estradiol. Each pale yellow tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.Each pale yellow tablet contains the following inactive ingredients: Ethyl Cellulose, Hypromellose, Lactose Monohydrate, Pregelatinized Starch, Magnesium Stearate, Polyvinyl Alcohol, Titanium Dioxide ,Talc, Macrogol/Polyethylene Glycol, Lecithin (Soya),D&C Yellow #10 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Yellow #6 Aluminum Lake. Each light yellow tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. Each light yellow tablet contains the following inactive ingredients: Ethyl Cellulose, Hypromellose, Lactose Monohydrate, Pregelatinized Starch, Magnesium Stearate, Polyvinyl Alcohol, Titanium Dioxide , Talc , Macrogol/Polyethylene Glycol, Lecithin (Soya), D&C Yellow #10 Aluminum Lake, Iron Oxide Yellow, FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake. Each light brown tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each light brown tablet contains the following inactive ingredients: Ethyl Cellulose, Hypromellose, Lactose Monohydrate, Pregelatinized Starch, Magnesium Stearate, Polyvinyl Alcohol, Titanium Dioxide,Talc , Macrogol/Polyethylene Glycol, Lecithin (Soya), Iron Oxide Yellow, Iron Oxide Red, Iron Oxide Black. The structural formulas are as follows: Each brown tablet contains:  Ferrous Fumarate, Micro-crystalline Cellulose, Hydroxypropyl Cellulose, Crospovidone, Magnesium Stearate, Polyvinyl Alcohol, Iron Oxide Yellow, Talc, Polyethylene Glycol 3350, Iron Oxide Red, Lecithin (Soya), Iron Oxide Black. Each Tilia Fe tablet dispenser contains five pale yellow tablets, seven light yellow tablets, nine light brown tablets, and seven brown tablets. These tablets are to be taken in the following order: one pale yellow tablet each day for five days, then one light yellow tablet each day for seven days, followed by one light brown tablet each day for nine days, and then one brown tablet each day for seven days. structure

Tilia Fe is indicated for the prevention of pregnancy in women who elect to use combined 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 combined 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 a combined oral contraceptive for birth control and plans to stay on it for at least 6 months. Combined 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 Method Typical Use 1 Perfect Use 2 (1) (2) (3) (4) Chance 4 85 85 Spermicides 5 26 6 40 Periodic Abstinence 25 63 Calendar 9 Ovulation Method 3 Symptothermal 6 2 Post-ovulation 1 Cap 7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 7 20 6 56 Withdrawal 19 4 Condom 8 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% 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 combined 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. 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 296 patients received norethindrone acetate and ethinyl estradiol tablets 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 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 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)  *Numbers rounded to nearest integer † Limits for 95% Confidence Interval; not adjusted for baseline differences Norethindrone acetate and ethinyl estradiol tablet 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. fig2

The tablet dispenser has been designed to make Tilia Fe 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 stickers 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 sticker 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 (pale yellow, light yellow and light brown) and seven 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 pale yellow 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 pale yellow is taken on the same day. The patient takes one active tablet daily for 21 days. The last light brown 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 active 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 sticker 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 active tablet in the top row. After the last active 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 sticker over the preprinted days on the tablet dispenser. Following this regimen of 21 active tablets and 7 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 active 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 reexamination of the patient, at which time nonfunctional causes should be considered. Use of Combined Oral Contraceptives in the Event of a Missed Menstrual Period 1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and combined oral contraceptives should be withheld until pregnancy has been ruled out. 2. 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 a combined oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section for Tilia Fe oral contraceptives .

Combined oral contraceptives should not be used in women who currently have the following: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:   • Smoke, if over age 35   • Have cerebrovascular disease   • Have coronary artery disease   • Have current or history of deep vein thrombosis or pulmonary embolism   • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart   • Have inherited or acquired hypercoagulopathies   • Have uncontrolled hypertension or hypertension with vascular disease   • Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches   • Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or end-organ damage, or diabetes mellitus of > 20 years duration • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive • Undiagnosed abnormal genital bleeding • Cholestatic jaundice of pregnancy or jaundice with prior pill use • Hepatic adenomas or carcinomas • Known or suspected pregnancy • Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

It is good medical practice for all women to have annual history and physical examinations, including women using combined oral contraceptives. The physical examination, however, may be deferred until after initiation of combined oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. Combined oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 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 combined 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 a combined 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 combined oral contraceptives. This may also result in breakthrough bleeding. ​Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not coadminister Tilia Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see WARNINGS , RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ). 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 Combined Oral Contraceptives on Other Drugs COCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increase with use of COCs. Certain endocrine and liver function tests and blood components may be affected by combined oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 by column or by radioimmunoassay. Free T 3 resin uptake is decreased, reflecting the elevated TBG; free T 4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by combined oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing combined oral contraceptives. See WARNINGS section. See CONTRAINDICATIONS and WARNINGS sections. 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, combined 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 combined oral contraceptives but to use other forms of contraception until she has completely weaned her child. 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. This product has not been studied in women over 65 years of age and is not indicated in this population.

Tilia Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets) contains five pale yellow tablets, seven light yellow tablets, nine light brown tablets and seven brown tablets in a blister card (NDC 75907-086-28) within a plastic dispenser. Each of the five pale yellow, biconvex, round tablets (debossed with "H2" on one side) contains 1 mg of norethindrone acetate and 20 mcg of ethinyl estradiol. The next seven light yellow, biconvex, round tablets (debossed with "H3" on one side) contain 1 mg of norethindrone acetate and 30 mcg of ethinyl estradiol. The next nine light brown, biconvex, round tablets (debossed with "H4" on one side) contain 1 mg of norethindrone acetate and 35 mcg of ethinyl estradiol. The last seven brown, biconvex, round tablets (debossed with "F" on one side and " N " on the other side) each contain 75 mg ferrous fumarate. Tilia Fe Tablets are available in the following configurations: Carton of 3 compacts   NDC 75907-086-32 Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Protect from light. REFERENCES AVAILABLE UPON REQUEST

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 norethindrone acetate and ethinyl estradiol tablets, serum SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity. 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. 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 norethindrone acetate and ethinyl estradiol tablets 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 ). 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. Norethindrone acetate and ethinyl estradiol tablets increase 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 norethindrone acetate and ethinyl estradiol tablets are approximately 13 hours and 19 hours, respectively. fig1 table1 Race: The effect of race on the disposition of Tilia Fe has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of Tilia Fe has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of a combined 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 Tilia 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 .

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