Tilia® Fe(norethindrone Acetate And Ethinyl Estradiol Tablets, Usp And Ferrous Fumarate Tablets*)

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.

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.

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 lightorange

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

*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.

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 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.

Oral contraceptives should not be used in women who currently have the following:

• 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

• 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 ).

• An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis

• Arterial thromboembolism

• Pulmonary embolism

• Myocardial infarction

• Cerebral hemorrhage

• Cerebral thrombosis

• Hypertension

• Gallbladder disease

• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis

• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea

• Vomiting

• Gastrointestinal symptoms (such as abdominal cramps and bloating)

• Breakthrough bleeding

• Spotting

• Change in menstrual flow

• Amenorrhea

• Temporary infertility after discontinuation of treatment

• Edema

• Melasma which may persist

• Breast changes: tenderness, enlargement, secretion

• Change in weight (increase or decrease)

• Change in cervical erosion and secretion

• Diminution in lactation when given immediately postpartum

• Cholestatic jaundice

• Migraine

• Rash (allergic)

• Mental depression

• Reduced tolerance to carbohydrates

• Vaginal candidiasis

• Change in corneal curvature (steepening)

• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome

• Cataracts

• Changes in appetite

• Cystitis-like syndrome

• Headache

• Nervousness

• Dizziness

• Hirsutism

• Loss of scalp hair

• Erythema multiforme

• Erythema nodosum

• Hemorrhagic eruption

• Vaginitis

• Porphyria

• Impaired renal function

• Hemolytic uremic syndrome

• Budd-Chiari syndrome

• Acne

• Changes in libido

• Colitis

Tilia Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets) contain five pale yellow tablets, seven light yellow tablets, nine light brown tablets and seven brown tablets in a blister card (NDC 51862-896-01) within a plastic dispenser.

Each of the five pale yellow, biconvex, round tablets (debossed with "H2" on one side) contain 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 contains 75 mg ferrous fumarate.

Tilia Fe Tablets are available in the following configurations:

Carton of 1 compact    NDC 51862-896-02

Carton of 3 compacts   NDC 51862-896-03

Carton of 6 compacts   NDC 51862-896-06

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Protect from light.

Keep this drug and all drugs out of the reach of children.

Rx Only.

REFERENCES AVAILABLE UPON REQUEST

Tilia Fe is a graduated estrophasic 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.

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.

Tilia Fe

(Each pale yellow tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each light yellow tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each light brown 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.

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.

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.

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).

No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets 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. 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.

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.

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.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

See WARNINGS section.

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.

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.

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.

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 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 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.

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.

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.

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 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.

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

TABLET DISPENSER

The Tilia Fe 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 above the first row of tablets.

Each pale yellow, biconvex, round tablet debossed with "H2" on one side contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.

Each light yellow, biconvex, round tablet debossed with "H3" on one side contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol.

Each light brown, biconvex, round tablet debossed with "H4" on one side contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.

Each brown, biconvex, round tablet debossed with "F" on one side and "N" on the other side contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit.

DIRECTIONS

To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.

2. LOOK AT YOUR PILL PACK.

The pill pack has 21 "active" pills (with hormones) to take for 3 weeks, followed by 1 week of "reminder" brown pills (without hormones).

3. ALSO FIND:

1) where on the pack to start taking pills,

2) in what order to take the pills (follow the arrows), and

3) the week numbers as shown in the following pictures:

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.

Tilia Fe will contain: 21 ACTIVE PILLS for Weeks 1, 2, and 3. Week 4 will contain BROWN PILLS ONLY .

4. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills.

An EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember.

DAY-1 START:

1. Pick the day label sticker that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.)

2. Place this day label sticker on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic.

3. Take the first pale yellow pill of the first pack during the first 24 hours of your period.

4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START:

1. Take the first pale yellow pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.

Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs.

28 pills: Start the next pack on the day after your last "reminder" pill. Do not wait any days between packs.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 "active" pill:

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 "active" pills in a row in Week 1 OR Week 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills the next day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

If you MISS 2 "active" pills in a row in THE 3rd WEEK:

1. If you are a Day-1 Starter:

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

If you MISS 3 OR MORE "active" pills in a row (during the first 3 weeks):

1. If you are a Day-1 Starter:

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

REMINDER:

IF YOU FORGET ANY OF THE 7 BROWN "REMINDER" PILLS IN WEEK 4:

THROW AWAY THE PILLS YOU MISSED.

KEEP TAKING 1 PILL EACH DAY UNTIL THE PACK IS EMPTY.

YOU DO NOT NEED A BACK-UP METHOD.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic.

See patient labeling printed below.

Tilia Fe (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

What You Should Know About Oral Contraceptives

Any woman who considers using oral contraceptives (the "birth control pill'' or "the pill'') should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or "birth control pills'' or "the pill'' are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:

Implant: <1%

Injection: <1%

IUD: <1 to 2%

Diaphragm with spermicides: 20%

Spermicides alone: 26%

Vaginal Sponge: 20 to 40%

Female sterilization: <1%

Male sterilization: <1%

Cervical Cap: 20 to 40%

Condom alone (male): 14%

Condom alone (female): 21%

Periodic abstinence: 25%

Withdrawal: 19%

No method: 85%

Tilia Fe may also be taken to treat moderate acne if all of the following are true:

• Your doctor says it is safe for you to use the pill

• You are at least 15 years old

• You have started having menstrual periods

• You want to use the pill for birth control

• You plan to stay on the pill for at least 6 months

• Your acne has not improved with acne medicines that you put on your skin

Norethindrone acetate and ethinyl estradiol tablet users who started with about 74 acne pimples had about 42 pimples after 6 months of treatment. Placebo users who started with about 72 acne pimples had about 49 pimples after six months of treatment. Use Tilia Fe to treat acne only if you want the pill for birth control and plan to stay on it for at least 6 months.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

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

Tilia Fe (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

Tilia Fe may also be taken to treat moderate acne in females who are at least 15 years of age, have started having menstrual periods, are able to use the pill and want the pill for birth control, plan to stay on the pill for at least 6 months, and have not improved with acne medicines that are put on the skin.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke

• Have high blood pressure, diabetes, high cholesterol

• Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of 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.

Certain endocrine and liver function tests and blood components may be affected by 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), T₄ by column or by radioimmunoassay. Free T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ 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 oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

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.

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.

Tilia Fe

(Each pale yellow tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each light yellow tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each light brown 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.

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.

Tilia Fe is a graduated estrophasic 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.

Tilia Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets) contain five pale yellow tablets, seven light yellow tablets, nine light brown tablets and seven brown tablets in a blister card (NDC 51862-896-01) within a plastic dispenser.

Each of the five pale yellow, biconvex, round tablets (debossed with "H2" on one side) contain 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 contains 75 mg ferrous fumarate.

Tilia Fe Tablets are available in the following configurations:

Carton of 1 compact    NDC 51862-896-02

Carton of 3 compacts   NDC 51862-896-03

Carton of 6 compacts   NDC 51862-896-06

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Protect from light.

Keep this drug and all drugs out of the reach of children.

Rx Only.

REFERENCES AVAILABLE UPON REQUEST

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.

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).

No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets 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. 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.

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.

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.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

• An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis

• Arterial thromboembolism

• Pulmonary embolism

• Myocardial infarction

• Cerebral hemorrhage

• Cerebral thrombosis

• Hypertension

• Gallbladder disease

• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis

• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea

• Vomiting

• Gastrointestinal symptoms (such as abdominal cramps and bloating)

• Breakthrough bleeding

• Spotting

• Change in menstrual flow

• Amenorrhea

• Temporary infertility after discontinuation of treatment

• Edema

• Melasma which may persist

• Breast changes: tenderness, enlargement, secretion

• Change in weight (increase or decrease)

• Change in cervical erosion and secretion

• Diminution in lactation when given immediately postpartum

• Cholestatic jaundice

• Migraine

• Rash (allergic)

• Mental depression

• Reduced tolerance to carbohydrates

• Vaginal candidiasis

• Change in corneal curvature (steepening)

• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome

• Cataracts

• Changes in appetite

• Cystitis-like syndrome

• Headache

• Nervousness

• Dizziness

• Hirsutism

• Loss of scalp hair

• Erythema multiforme

• Erythema nodosum

• Hemorrhagic eruption

• Vaginitis

• Porphyria

• Impaired renal function

• Hemolytic uremic syndrome

• Budd-Chiari syndrome

• Acne

• Changes in libido

• Colitis

Oral contraceptives should not be used in women who currently have the following:

• 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

• 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 ).

See WARNINGS section.

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.

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.

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.

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 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 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.

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.

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.

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 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.

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.

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 lightorange

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

*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.

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

TABLET DISPENSER

The Tilia Fe 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 above the first row of tablets.

Each pale yellow, biconvex, round tablet debossed with "H2" on one side contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.

Each light yellow, biconvex, round tablet debossed with "H3" on one side contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol.

Each light brown, biconvex, round tablet debossed with "H4" on one side contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.

Each brown, biconvex, round tablet debossed with "F" on one side and "N" on the other side contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit.

DIRECTIONS

To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.

2. LOOK AT YOUR PILL PACK.

The pill pack has 21 "active" pills (with hormones) to take for 3 weeks, followed by 1 week of "reminder" brown pills (without hormones).

3. ALSO FIND:

1) where on the pack to start taking pills,

2) in what order to take the pills (follow the arrows), and

3) the week numbers as shown in the following pictures:

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.

Tilia Fe will contain: 21 ACTIVE PILLS for Weeks 1, 2, and 3. Week 4 will contain BROWN PILLS ONLY .

4. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills.

An EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember.

DAY-1 START:

1. Pick the day label sticker that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.)

2. Place this day label sticker on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic.

3. Take the first pale yellow pill of the first pack during the first 24 hours of your period.

4. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START:

1. Take the first pale yellow pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.

Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs.

28 pills: Start the next pack on the day after your last "reminder" pill. Do not wait any days between packs.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 "active" pill:

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 "active" pills in a row in Week 1 OR Week 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills the next day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

If you MISS 2 "active" pills in a row in THE 3rd WEEK:

1. If you are a Day-1 Starter:

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

If you MISS 3 OR MORE "active" pills in a row (during the first 3 weeks):

1. If you are a Day-1 Starter:

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant.

3. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken an "active" pill every day for 7 days.

REMINDER:

IF YOU FORGET ANY OF THE 7 BROWN "REMINDER" PILLS IN WEEK 4:

THROW AWAY THE PILLS YOU MISSED.

KEEP TAKING 1 PILL EACH DAY UNTIL THE PACK IS EMPTY.

YOU DO NOT NEED A BACK-UP METHOD.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic.

See patient labeling printed below.

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 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.

Tilia Fe (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

What You Should Know About Oral Contraceptives

Any woman who considers using oral contraceptives (the "birth control pill'' or "the pill'') should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or "birth control pills'' or "the pill'' are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:

Implant: <1%

Injection: <1%

IUD: <1 to 2%

Diaphragm with spermicides: 20%

Spermicides alone: 26%

Vaginal Sponge: 20 to 40%

Female sterilization: <1%

Male sterilization: <1%

Cervical Cap: 20 to 40%

Condom alone (male): 14%

Condom alone (female): 21%

Periodic abstinence: 25%

Withdrawal: 19%

No method: 85%

Tilia Fe may also be taken to treat moderate acne if all of the following are true:

• Your doctor says it is safe for you to use the pill

• You are at least 15 years old

• You have started having menstrual periods

• You want to use the pill for birth control

• You plan to stay on the pill for at least 6 months

• Your acne has not improved with acne medicines that you put on your skin

Norethindrone acetate and ethinyl estradiol tablet users who started with about 74 acne pimples had about 42 pimples after 6 months of treatment. Placebo users who started with about 72 acne pimples had about 49 pimples after six months of treatment. Use Tilia Fe to treat acne only if you want the pill for birth control and plan to stay on it for at least 6 months.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

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

Tilia Fe (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

Tilia Fe may also be taken to treat moderate acne in females who are at least 15 years of age, have started having menstrual periods, are able to use the pill and want the pill for birth control, plan to stay on the pill for at least 6 months, and have not improved with acne medicines that are put on the skin.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke

• Have high blood pressure, diabetes, high cholesterol

• Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of 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.

Certain endocrine and liver function tests and blood components may be affected by 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), T₄ by column or by radioimmunoassay. Free T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ 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 oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.