Tri-Estarylla

Ethinyl estradiol and norgestimate is a combination drug that contains female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and norgestimate is used as contraception to prevent pregnancy.

Ethinyl estradiol and norgestimate may also be used for purposes not listed in this medication guide.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Take Tri-Estarylla at the same time of day.
• Take with or without food. Take with food if it causes an upset stomach.
• If you also take colesevelam, take it at least 4 hours after you take this medicine.
• Do not skip doses, even if you do not have sex very often.
• If you throw up or have diarrhea, Tri-Estarylla may not work as well to prevent pregnancy. If this happens within 3 to 4 hours after you take an active tablet, take another tablet. If it goes on for more than 1 day, use an extra form of birth control and call your doctor. Call your doctor if you throw up or have diarrhea and are not sure what to do.
• If you miss 2 periods in a row, take a pregnancy test before starting a new cycle.

What do I do if I miss a dose?

• If a dose is missed, check the package insert or call the doctor to find out what to do. If using this medicine to prevent pregnancy, another form of birth control may need to be used for some time to prevent pregnancy.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Weight gain.
• Headache.
• Upset stomach or throwing up.
• Gas.
• Feeling nervous and excitable.
• Belly pain.
• Enlarged breasts.
• Tender breasts.
• Period (menstrual) changes. These include spotting or bleeding between cycles.
• This medicine may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

How to Start Tri-Estarylla™

Tri-Estarylla™ (norgestimate and ethinyl estradiol tablets, USP), is dispensed in a blister pack [see HOW SUPPLIED/STORAGE AND HANDLING (16)]. Tri-Estarylla™ may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.

How to Take Tri-Estarylla™

Table 1: Instructions for Administration of Tri-Estarylla™

Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling.
Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: • Tri-Estarylla™ active tablets are white (Day 1 to Day 7), light blue (Day 8 to Day 14) and blue (Day15 to Day 21). • Tri-Estarylla™ has green inactive tablets (Day 22 to Day 28).	Day 1 Start: • Take first active tablet without regard to meals on the first day of menses. • Take subsequent active tablets once daily at the same time each day for a total of 21 days. • Take one green inactive tablet daily for 7 days and at the same time of day that active tablets were taken. • Begin each subsequent blister pack on the same day of Tri-Estarylla™ the week as the first cycle blister pack (i.e., on the day after taking the last inactive tablet)
	Sunday Start: • Take first active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of Tri-Estarylla™. • Take subsequent active tablets once daily at the same time each day for a total of 21 days. • Take one green inactive tablet daily for the following 7 days and at the same time of day that active tablets were taken. • Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed.
• Switching to Tri-Estarylla™ from another oral contraceptive	Start on the same day that a new pack of the previous oral contraceptive would have started.
• Switching from another contraceptive method to Tri-Estarylla™	Start Tri-Estarylla™:
• Transdermal patch	• On the day when next application would have been scheduled
• Vaginal ring	• On the day when next insertion would have been scheduled
• Injection	• On the day when next injection would have been scheduled
• Intrauterine contraceptive	• On the day of removal • If the IUD is not removed on first day of the patient's menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack.
• Implant	• On the day of removal

Starting Tri-Estarylla™ after Abortion or Miscarriage

First-trimester

• After a first-trimester abortion or miscarriage, Tri-Estarylla™ may be started immediately. An additional method of contraception is not needed if Tri-Estarylla™ is started immediately. • If Tri-Estarylla™ is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle blister pack of Tri-Estarylla™.

Second-trimester

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Tri-Estarylla™, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of Tri-Estarylla™. [See CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), and FDA-Approved Patient Labeling.]

Starting Tri-Estarylla™ after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Tri-Estarylla™ following the instructions in Table 1 (above) for women not currently using hormonal contraception. • Tri-Estarylla™ is not recommended for use in lactating women [see USE IN SPECIFIC POPULATIONS (8.3)]. • If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Tri-Estarylla™. [See CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), USE IN SPECIFIC POPULATIONS (8.1 and 8.3), and FDA-Approved Patient Labeling].

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 BLISTER PACK

The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed by 1 week of "reminder" green 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) 3) The week numbers as shown in the diagram below

4.BE SURE YOU HAVE READY AT ALL TIMES:

  Another kind of birth control (such as a condom or spermicide) to use as a back-up method in case you miss pills.   An extra, full pill blister pack.

Missed Tablets

Table 2: Instructions for Missed Tri-Estarylla™ Tablets

If one active tablet is missed in Weeks 1, 2, or 3	Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished.
If two active tablets are missed in Week 1 or Week 2	Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.
If two active tablets are missed in the third week or three or more active tablets are missed in a row in Weeks 1, 2, or 3	Day 1 start: Throw out the rest of the pack and start a new pack that same day. Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.

Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].

Tri-Estarylla™ Use for Acne

The timing of initiation of dosing with Tri-Estarylla™ for acne should follow the guidelines for use of Tri-Estarylla™ as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section (2.1) for instructions

Tri-Estarylla™ Tablets are available in blister cards. Each blister pack contains

28 tablets in the following order:

• 7 white (active) tablets are round, debossed with SZ on one side and T2 on the other side and contains 0.18 mg of norgestimate and 0.035 mg of ethinyl estradiol. • 7 light blue (active) tablets are round, debossed with SZ on one side and T3 on the other side and contains 0.215 mg of norgestimate and 0.035 mg of ethinyl estradiol. • 7 blue (active) tablets are round, debossed with SZ on one side and T4 on the other side and contains 0.25 mg of norgestimate and 0.035 mg of ethinyl estradiol. • 7 green (inert) tablets are round, debossed with SZ on one side and J1 on the other side.

Do not prescribe Tri-Estarylla™ to women who are known to have the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: • Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)] • Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS (5.1)] • Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1)] • Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS (5.1)] • Have coronary artery disease [see WARNINGS AND PRECAUTIONS (5.1)] • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS AND PRECAUTIONS (5.1)] • Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.3)] • Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS (5.5)] • Have headaches with focal neurological symptoms or migraine headaches with aura [see WARNINGS AND PRECAUTIONS (5.6)] 1. Women over age 35 with any migraine headaches [see WARNINGS AND PRECAUTIONS (5.6)] • Liver tumors, benign or malignant, or liver disease [see WARNINGS AND PRECAUTIONS (5.2)] • Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS (5.7)] • Pregnancy, because there is no reason to use COCs during pregnancy [see WARNINGS AND PRECAUTIONS (5.8) and USE IN SPECIFIC POPULATIONS (8.1)] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see WARNINGS AND PRECAUTIONS (5.10)]

Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

Nursing Mothers

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

Pediatric Use

Safety and efficacy of Tri-Estarylla™ have been established in women of reproductive age. Efficacy is expected to be the same for post-pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

There was no significant difference between Tri-Estarylla™ tablets and placebo in mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population.

Geriatric Use

Tri-Estarylla™ has not been studied in postmenopausal women and are not indicated in this population.

Hepatic Impairment

The pharmacokinetics of Tri-Estarylla™ has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. [See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.2).]

Renal Impairment

The pharmacokinetics of Tri-Estarylla™ has not been studied in women with renal impairment.

Mechanism of Action

• Oral Contraception

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

• Acne

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone-binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with norgestimate and ethinyl estradiol.

Pharmacokinetics

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of norgestimate/ ethinyl estradiol. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).

Table 3: Summary of NGMN, NG and EE pharmacokinetic parameters.

Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0–24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated.
NGMN and NG: Cmax = ng/mL, AUC0–24h = h∙ng/mL
EE: Cmax= pg/mL, AUC0–24h = h∙pg/mL
Mean (SD) Pharmacokinetic Parameters of Norgestimate and Ethinyl Estradiol During a Three Cycle Study
Analyte	Cycle	Day	Cmax	tmax (h)	AUC0-24h	t1/2(h)
NGMN	3	7	1.80 (0.46)	1.42 (0.73)	15 (3.88)	NC
		14	2.12 (0.56)	1.21 (0.26)	16.1 (4.97)	NC
		21	2.66 (0.47)	1.29 (0.26)	21.4 (3.46)	22.3 (6.54)
NG	3	7	1.94 (0.82)	3.15 (4.05)	34.8 (16.5)	NC
		14	3 (1.04)	2.21 (2.03)	55.2 (23.5)	NC
		21	3.66 (1.15)	2.58 (2.97)	69.3 (23.8)	40.2 (15.4)
EE	3	7	124 (39.5)	1.27 (0.26)	1130 (420)	NC
		14	128 (38.4)	1.32 (0.25)	1130 (324)	NC
		21	126 (34.7)	1.31 (0.56)	1090 (359)	15.9 (4.39)

Food Effect

The effect of food on the pharmacokinetics of norgestimate and ethinyl estradiol has not been studied.

Distribution

NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM's primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45 to 49%) and 37% (16 to 49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.

Carcinogenesis, Mutagenesis, Impairment of Fertility

[See WARNINGS AND PRECAUTIONS (5.2, 5.10) and USE IN SPECIFIC POPULATIONS (8.1).]

How Supplied

Tri-EstaryllaTM (norgestimate and ethinyl estradiol tablets, USP) is available in blisters containing 28 tablets as follows:

Each blister card contains 21 active tablets and 7 inactive tablets.

7 white (active) tablets are round, debossed with SZ on one side and T2 on the other side and contains 0.18 mg of norgestimate and 0.035 mg of ethinyl estradiol .

7 light blue (active) tablets are round, debossed with SZ on one side and T3 on the other side and contains 0.215 mg of norgestimate and 0.035 mg of ethinyl estradiol .

7 blue (active) tablets are round, debossed with SZ on one side and T4 on the other side and contains 0.25 mg of norgestimate and 0.035 mg of ethinyl estradiol .

7 green (inert) tablets are round, debossed with SZ on one side and J1 on the other side.

  NDC 0781-4060-15, one box containing 3 individual unit cartons

Storage Conditions

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

Keep out of reach of children