These Highlights Do Not Include All The Information Needed To Use Tri-lo-marzia Safely And Effectively. See Full Prescribing Information For Tri-lo-marzia. Tri-lo-marzia™ (norgestimate And Ethinyl Estradiol Tablets Usp), For Oral Use Initial U.s. Approval: 1989

Warnings and Precautions ( 5.11)                                          12/2021

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS ( 4)].

If a woman taking Tri-Lo-Marzia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-Lo-Marzia if indicated.

Consider discontinuation of Tri-Lo-Marzia in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking Tri-Lo-Marzia.

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.

Carefully observe women with a history of depression and discontinue Tri-Lo-Marzia if depression recurs to a serious degree.

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

Tri-Lo-Marzia are available in a blister containing 28 tablets packed in a pouch (NDC 72789-435-79).

Each blister (28 tablets) contains in the following order:

• 7 white to off white, round, film-coated tablets debossed with 'LU' on one side and "E21" on the other side contains 0.18 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 light blue, round, film-coated tablets debossed with 'LU' on one side and "E22" on the other side contains 0.215 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 blue, round, film-coated tablets debossed with 'LU' on one side and "E23" on the other side contains 0.25 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 green, round, biconvex, film-coated tablets (non-hormonal placebo) debossed with 'LU' on one side and "E24" on the other side contains inert ingredients

Impaired Liver Function

Do not use Tri-Lo-Marzia in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS ( 4)]. 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. Discontinue Tri-Lo-Marzia if jaundice develops.

Liver Tumors

Tri-Lo-Marzia is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS ( 4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

Safety and efficacy of Tri-Lo-Marzia Tablets 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.

Tri-Lo-Marzia has not been studied in postmenopausal women and is not indicated in this population.

• A high risk of arterial or venous thrombotic diseases ( 4)
• Liver tumors or liver disease ( 4)
• Undiagnosed abnormal uterine bleeding ( 4)
• Pregnancy ( 4)
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive ( 4)
• Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4)

The most common adverse reactions reported during clinical trials (≥2%) were: headache/migraine, nausea/vomiting, breast issues, abdominal pain, menstrual disorders, mood disorders, acne, vulvovaginal infection, abdominal distension, weight increased, fatigue. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1)

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.

The pharmacokinetics of Tri-Lo-Marzia has not been studied in women with renal impairment.

No specific pharmacodynamic studies were conducted with Tri-Lo-Marzia.

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 NGM.

Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of Tri-Lo-Marzia are summarized in Table 3.

Peak serum concentrations of NGMN and EE were generally reached by 2 hours after administration of Tri-Lo-Marzia. Accumulation following multiple dosing of the 0.18 mg NGM / 0.025 mg EE dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE. The pharmacokinetics of NGMN is dose proportional following NGM doses of 0.18 to 0.25 mg. Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study. Non-linear accumulation (4.5 to 14.5 fold) of NG was observed as a result of high affinity binding to SHBG, which limits its biological activity.

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

Food Effect:

The effect of food on the pharmacokinetics of Tri-Lo-Marzia 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 vivoconcentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K _i). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

Following 3 cycles of administration of Tri-Lo-Marzia, the mean (± SD) elimination half-life values, at steady-state, for NGMN, NG and EE were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (Table 2). The metabolites of NGMN and EE are eliminated by renal and fecal pathways.

Use in Specific Populations

Effects of Body Weight, Body Surface Area, and Age:

The effects of body weight, body surface area, age and race on the pharmacokinetics of NGMN, NG and EE were evaluated in 79 healthy women using pooled data following single dose administration of NGM 0.18 or 0.25 mg / EE 0.025 mg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in C _maxand AUC _{0 to 24h}values for NGMN and EE and increases in CL/F (oral clearance) for EE. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN C _maxby 9% and AUC _{0 to 24h}by 19%, NG C _maxby 12% and AUC _{0 to 24h}by 46%, EE C _maxby 13% and AUC _{0 to 24h}by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in C _maxand AUC _{0 to 24h}for NGMN and were statistically significant, but there was no significant effect for NG or EE. Only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of NGMN and EE following Tri-Lo-Marzia Tablets may be explained by any or all of the above demographic parameters.

Tri-Lo-Marzia™ Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see CLINICAL STUDIES ( 14)].

The pharmacokinetics of Tri-Lo-Marzia 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).]

Tri-Lo-Marzia is an estrogen/progestin COC, indicated for use by women to prevent pregnancy. ( 1.1)

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].
• Protect from light.
• Keep this and all medication out of reach of children.

Tri-Lo-Marzia is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS ( 4)]. For women with well-controlled hypertension, monitor blood pressure and stop Tri-Lo-Marzia if blood pressure rises significantly.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis.

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.

Breast Cancer

Tri-Lo-Marzia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [ see  CONTRAINDICATIONS ( 4) ].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [ see  POSTMARKETING EXPERIENCE ( 6.2) ].

Cervical Cancer

Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

• Thromboembolic Disorders and Other Vascular Problems:Stop Tri-Lo-Marzia if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1)
• Liver Disease:Discontinue Tri-Lo-Marzia if jaundice occurs. ( 5.2)
• High Blood Pressure:If used in women with well-controlled hypertension, monitor blood pressure and stop Tri-Lo-Marzia if blood pressure rises significantly. ( 5.4)
• Carbohydrate and Lipid Metabolic Effects:Monitor prediabetic and diabetic women taking Tri-Lo-Marzia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.6)
• Headache:Evaluate significant change in headaches and discontinue Tri-Lo-Marzia if indicated. ( 5.7)
• Bleeding Irregularities and Amenorrhea:Evaluate irregular bleeding or amenorrhea. ( 5.8)

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

• Take one tablet daily by mouth at the same time every day. ( 2.2)
• Take tablets in the order directed on the blister. ( 2.2)
• Do not skip or delay tablet intake. ( 2.2)

Tri-Lo-Marzia consists of 28 round, film-coated tablets in the following order ( 3):

• 7 white to off white tablets each containing 0.18 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 light blue tablets each containing 0.215 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 blue tablets each containing 0.25 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 green tablets (inert)

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

Figure 1: Risk of Breast Cancer with Combined Oral Contraceptive Use

RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.

The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations

Urinary tract infection

Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps)

Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Dyslipidemia

Psychiatric Disorders

Anxiety, insomnia

Nervous System Disorders

Syncope, convulsion, paresthesia, dizziness

Eye Disorders

Visual impairment, dry eye, contact lens intolerance

Ear and Labyrinth Disorders

Vertigo

Cardiac Disorders

Tachycardia, palpitations

Vascular Events

Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush

Arterial Events

Arterial thromboembolism, myocardial infarction, cerebrovascular accident

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

Gastrointestinal Disorders

Pancreatitis, abdominal distension, diarrhea, constipation

Hepatobiliary Disorders

Hepatitis

Skin and Subcutaneous Tissue Disorders

Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne

Musculoskeletal, Connective Tissue, and Bone Disorders

Muscle spasms, pain in extremity, myalgia, back pain

Reproductive System and Breast Disorders

Ovarian cyst, suppressed lactation, vulvovaginal dryness

General Disorders and Administration Site Conditions

Chest pain, asthenic conditions.

Starting Tri-Lo-Marzia after Abortion or Miscarriage

First-trimester:

• After a first-trimester abortion or miscarriage, Tri-Lo-Marzia may be started immediately. An additional method of contraception is not needed if Tri-Lo-Marzia is started immediately.
• If Tri-Lo-Marzia 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 pack of Tri-Lo-Marzia.

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-Lo-Marzia, 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-Lo-Marzia. [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), and FDA-APPROVED PATIENT LABELING.]

Starting Tri-Lo-Marzia after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Tri-Lo-Marzia following the instructions in Table 1 for women not currently using hormonal contraception.
• Tri-Lo-Marzia 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-Lo-Marzia. [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), USE IN SPECIFIC POPULATIONS AND ( 8.1AND 8.3), and FDA-APPROVED PATIENT LABELING].

Blister Pack:

SET THE DAY

• Sunday Start:Each blister has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen.
• Day 1 Start:
  • Six different day label strips of the week have been provided with this pack in order to accommodate a Day-1 Start regimen.
  • Pick the day label strip that starts with the first day of your period. Place this day label strip over the area that has the days of the week (starting with Sunday) pre-printed on the blister (Refer figure below).

• Remove pill "1" by pushing down on the pill. The pill will come out through a hole in the back of the strip.
• The patient should wait 24 hours to take the next pill. Continue to take one pill each day until all the pills have been taken.
• When your blister is empty, you will start a new blister on the day after pill "28." The first pill in every refill will always be taken on the same day of the week, no matter when the patient's next period starts.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of Tri-Lo-Marzia was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of Tri-Lo-Marzia for contraception. This trial examined healthy, nonpregnant, volunteers aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active with regular coitus. Subjects were followed for up to 13 28-day cycles.

Common Adverse Reactions (≥ 2% of subjects)

The most common adverse reactions reported by at least 2% of the 1,723 women using the 28-day regimen were the following in order of decreasing incidence: headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues (including tenderness, pain, enlargement, swelling, discharge, discomfort, cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders (including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%), mood disorders (including depression, mood altered, mood swings and depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%), abdominal distension (2.8%), weight increased (2.4%), fatigue (2.1%).

Adverse Reactions Leading to Study Discontinuation

In the clinical trial of Tri-Lo-Marzia 4% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were headache/migraine (1.2%), nausea/vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%).

Serious Adverse Reactions

Carcinoma of the cervix in situ(1 subject) and cervical dysplasia (1 subject).

Nursing mothers: Not recommended; can decrease milk production. ( 8.3)

Tri-Lo-Marzia is dispensed in a blister [see HOW SUPPLIED/STORAGE AND HANDLING ( 16)]. Tri-Lo-Marzia 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.

The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

Blister Pack:

NDC: 68180-837-71

28 Tablets

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

Pouch:

NDC: 68180-837-71

28 Tablets

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

NDC: 72789-435-79

1 Blisters of 28 Tablets Each

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Unscheduled Bleeding and Spotting

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product.

In the clinical trial of Tri-Lo-Marzia, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 1,673 women (11,015 evaluable cycles). A total of 3 (0.2%) women discontinued Tri-Lo-Marzia, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 7 to 17% of women using Tri-Lo-Marzia experienced unscheduled bleeding per cycle in the first year. The percent of women who experienced unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use Tri-Lo-Marzia may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

Carefully monitor prediabetic and diabetic women who take Tri-Lo-Marzia. COCs may decrease glucose tolerance.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Tri-Lo-Marzia use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see USE IN SPECIFIC POPULATIONS ( 8.1)].

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].

• Stop Tri-Lo-Marzia if an arterial thrombotic event or venous thrombotic (VTE) event occurs.
• Stop Tri-Lo-Marzia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see ADVERSE REACTIONS ( 6.2)].
• If feasible, stop Tri-Lo-Marzia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
• Start Tri-Lo-Marzia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
• Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.

[see WARNINGS AND PRECAUTIONS ( 5.2, 5.11) and USE IN SPECIFIC POPULATIONS ( 8.1).

Substances Decreasing the Plasma Concentrations of COCs

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of COCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing St. John's wort. Interactions between COCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam

Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of ethinyl estradiol (EE). The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances Increasing the Plasma Concentrations of COCs

Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

• COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.
• COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs.

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

See full prescribing information for complete boxed warning.

• Tri-Lo-Marzia is contraindicated in women over 35 years old who smoke. ( 4)
• Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. ( 4)

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Tri-Lo-Marzia prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS ( 4)] . Tri-Lo-Marzia can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Do not co-administer Tri-Lo-Marzia Tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS ( 5.3)] .

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS ( 4)].

If a woman taking Tri-Lo-Marzia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-Lo-Marzia if indicated.

Consider discontinuation of Tri-Lo-Marzia in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking Tri-Lo-Marzia.

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.

Carefully observe women with a history of depression and discontinue Tri-Lo-Marzia if depression recurs to a serious degree.

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

Tri-Lo-Marzia are available in a blister containing 28 tablets packed in a pouch (NDC 72789-435-79).

Each blister (28 tablets) contains in the following order:

• 7 white to off white, round, film-coated tablets debossed with 'LU' on one side and "E21" on the other side contains 0.18 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 light blue, round, film-coated tablets debossed with 'LU' on one side and "E22" on the other side contains 0.215 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 blue, round, film-coated tablets debossed with 'LU' on one side and "E23" on the other side contains 0.25 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 green, round, biconvex, film-coated tablets (non-hormonal placebo) debossed with 'LU' on one side and "E24" on the other side contains inert ingredients

Impaired Liver Function

Do not use Tri-Lo-Marzia in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS ( 4)]. 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. Discontinue Tri-Lo-Marzia if jaundice develops.

Liver Tumors

Tri-Lo-Marzia is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS ( 4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

Safety and efficacy of Tri-Lo-Marzia Tablets 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.

Tri-Lo-Marzia has not been studied in postmenopausal women and is not indicated in this population.

• A high risk of arterial or venous thrombotic diseases ( 4)
• Liver tumors or liver disease ( 4)
• Undiagnosed abnormal uterine bleeding ( 4)
• Pregnancy ( 4)
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive ( 4)
• Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4)

The most common adverse reactions reported during clinical trials (≥2%) were: headache/migraine, nausea/vomiting, breast issues, abdominal pain, menstrual disorders, mood disorders, acne, vulvovaginal infection, abdominal distension, weight increased, fatigue. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1)

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.

The pharmacokinetics of Tri-Lo-Marzia has not been studied in women with renal impairment.

Warnings and Precautions ( 5.11)                                          12/2021

No specific pharmacodynamic studies were conducted with Tri-Lo-Marzia.

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 NGM.

Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of Tri-Lo-Marzia are summarized in Table 3.

Peak serum concentrations of NGMN and EE were generally reached by 2 hours after administration of Tri-Lo-Marzia. Accumulation following multiple dosing of the 0.18 mg NGM / 0.025 mg EE dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE. The pharmacokinetics of NGMN is dose proportional following NGM doses of 0.18 to 0.25 mg. Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study. Non-linear accumulation (4.5 to 14.5 fold) of NG was observed as a result of high affinity binding to SHBG, which limits its biological activity.

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

Food Effect:

The effect of food on the pharmacokinetics of Tri-Lo-Marzia 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 vivoconcentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K _i). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

Following 3 cycles of administration of Tri-Lo-Marzia, the mean (± SD) elimination half-life values, at steady-state, for NGMN, NG and EE were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (Table 2). The metabolites of NGMN and EE are eliminated by renal and fecal pathways.

Use in Specific Populations

Effects of Body Weight, Body Surface Area, and Age:

The effects of body weight, body surface area, age and race on the pharmacokinetics of NGMN, NG and EE were evaluated in 79 healthy women using pooled data following single dose administration of NGM 0.18 or 0.25 mg / EE 0.025 mg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in C _maxand AUC _{0 to 24h}values for NGMN and EE and increases in CL/F (oral clearance) for EE. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN C _maxby 9% and AUC _{0 to 24h}by 19%, NG C _maxby 12% and AUC _{0 to 24h}by 46%, EE C _maxby 13% and AUC _{0 to 24h}by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in C _maxand AUC _{0 to 24h}for NGMN and were statistically significant, but there was no significant effect for NG or EE. Only a small to moderate fraction (5 to 40%) of the overall variability in the pharmacokinetics of NGMN and EE following Tri-Lo-Marzia Tablets may be explained by any or all of the above demographic parameters.

Tri-Lo-Marzia™ Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see CLINICAL STUDIES ( 14)].

The pharmacokinetics of Tri-Lo-Marzia 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).]

Tri-Lo-Marzia is an estrogen/progestin COC, indicated for use by women to prevent pregnancy. ( 1.1)

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].
• Protect from light.
• Keep this and all medication out of reach of children.

Tri-Lo-Marzia is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS ( 4)]. For women with well-controlled hypertension, monitor blood pressure and stop Tri-Lo-Marzia if blood pressure rises significantly.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC related cholestasis.

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.

Breast Cancer

Tri-Lo-Marzia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [ see  CONTRAINDICATIONS ( 4) ].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [ see  POSTMARKETING EXPERIENCE ( 6.2) ].

Cervical Cancer

Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

• Thromboembolic Disorders and Other Vascular Problems:Stop Tri-Lo-Marzia if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1)
• Liver Disease:Discontinue Tri-Lo-Marzia if jaundice occurs. ( 5.2)
• High Blood Pressure:If used in women with well-controlled hypertension, monitor blood pressure and stop Tri-Lo-Marzia if blood pressure rises significantly. ( 5.4)
• Carbohydrate and Lipid Metabolic Effects:Monitor prediabetic and diabetic women taking Tri-Lo-Marzia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.6)
• Headache:Evaluate significant change in headaches and discontinue Tri-Lo-Marzia if indicated. ( 5.7)
• Bleeding Irregularities and Amenorrhea:Evaluate irregular bleeding or amenorrhea. ( 5.8)

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

• Take one tablet daily by mouth at the same time every day. ( 2.2)
• Take tablets in the order directed on the blister. ( 2.2)
• Do not skip or delay tablet intake. ( 2.2)

Tri-Lo-Marzia consists of 28 round, film-coated tablets in the following order ( 3):

• 7 white to off white tablets each containing 0.18 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 light blue tablets each containing 0.215 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 blue tablets each containing 0.25 mg norgestimate and 0.025 mg ethinyl estradiol
• 7 green tablets (inert)

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

Figure 1: Risk of Breast Cancer with Combined Oral Contraceptive Use

RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.

The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations

Urinary tract infection

Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps)

Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Dyslipidemia

Psychiatric Disorders

Anxiety, insomnia

Nervous System Disorders

Syncope, convulsion, paresthesia, dizziness

Eye Disorders

Visual impairment, dry eye, contact lens intolerance

Ear and Labyrinth Disorders

Vertigo

Cardiac Disorders

Tachycardia, palpitations

Vascular Events

Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush

Arterial Events

Arterial thromboembolism, myocardial infarction, cerebrovascular accident

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

Gastrointestinal Disorders

Pancreatitis, abdominal distension, diarrhea, constipation

Hepatobiliary Disorders

Hepatitis

Skin and Subcutaneous Tissue Disorders

Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne

Musculoskeletal, Connective Tissue, and Bone Disorders

Muscle spasms, pain in extremity, myalgia, back pain

Reproductive System and Breast Disorders

Ovarian cyst, suppressed lactation, vulvovaginal dryness

General Disorders and Administration Site Conditions

Chest pain, asthenic conditions.

Starting Tri-Lo-Marzia after Abortion or Miscarriage

First-trimester:

• After a first-trimester abortion or miscarriage, Tri-Lo-Marzia may be started immediately. An additional method of contraception is not needed if Tri-Lo-Marzia is started immediately.
• If Tri-Lo-Marzia 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 pack of Tri-Lo-Marzia.

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-Lo-Marzia, 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-Lo-Marzia. [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), and FDA-APPROVED PATIENT LABELING.]

Starting Tri-Lo-Marzia after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Tri-Lo-Marzia following the instructions in Table 1 for women not currently using hormonal contraception.
• Tri-Lo-Marzia 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-Lo-Marzia. [see CONTRAINDICATIONS ( 4), WARNINGS AND PRECAUTIONS ( 5.1), USE IN SPECIFIC POPULATIONS AND ( 8.1AND 8.3), and FDA-APPROVED PATIENT LABELING].

Blister Pack:

SET THE DAY

• Sunday Start:Each blister has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen.
• Day 1 Start:
  • Six different day label strips of the week have been provided with this pack in order to accommodate a Day-1 Start regimen.
  • Pick the day label strip that starts with the first day of your period. Place this day label strip over the area that has the days of the week (starting with Sunday) pre-printed on the blister (Refer figure below).

• Remove pill "1" by pushing down on the pill. The pill will come out through a hole in the back of the strip.
• The patient should wait 24 hours to take the next pill. Continue to take one pill each day until all the pills have been taken.
• When your blister is empty, you will start a new blister on the day after pill "28." The first pill in every refill will always be taken on the same day of the week, no matter when the patient's next period starts.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of Tri-Lo-Marzia was evaluated in 1,723 subjects who participated in a randomized, partially blinded, multicenter, active-controlled clinical trial of Tri-Lo-Marzia for contraception. This trial examined healthy, nonpregnant, volunteers aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active with regular coitus. Subjects were followed for up to 13 28-day cycles.

Common Adverse Reactions (≥ 2% of subjects)

The most common adverse reactions reported by at least 2% of the 1,723 women using the 28-day regimen were the following in order of decreasing incidence: headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues (including tenderness, pain, enlargement, swelling, discharge, discomfort, cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders (including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%), mood disorders (including depression, mood altered, mood swings and depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%), abdominal distension (2.8%), weight increased (2.4%), fatigue (2.1%).

Adverse Reactions Leading to Study Discontinuation

In the clinical trial of Tri-Lo-Marzia 4% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were headache/migraine (1.2%), nausea/vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%).

Serious Adverse Reactions

Carcinoma of the cervix in situ(1 subject) and cervical dysplasia (1 subject).

Nursing mothers: Not recommended; can decrease milk production. ( 8.3)

Tri-Lo-Marzia is dispensed in a blister [see HOW SUPPLIED/STORAGE AND HANDLING ( 16)]. Tri-Lo-Marzia 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.

The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

Blister Pack:

NDC: 68180-837-71

28 Tablets

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

Pouch:

NDC: 68180-837-71

28 Tablets

TRI-LO-MARZIA™ (norgestimate and ethinyl estradiol tablets USP)

0.18 mg 0.025 mg, 0.215 mg 0.025 mg, 7 0.25 mg 0.025 mg

28 Day Regimen

NDC: 72789-435-79

1 Blisters of 28 Tablets Each

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Unscheduled Bleeding and Spotting

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different contraceptive product.

In the clinical trial of Tri-Lo-Marzia, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 1,673 women (11,015 evaluable cycles). A total of 3 (0.2%) women discontinued Tri-Lo-Marzia, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 7 to 17% of women using Tri-Lo-Marzia experienced unscheduled bleeding per cycle in the first year. The percent of women who experienced unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use Tri-Lo-Marzia may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

Carefully monitor prediabetic and diabetic women who take Tri-Lo-Marzia. COCs may decrease glucose tolerance.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue Tri-Lo-Marzia use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see USE IN SPECIFIC POPULATIONS ( 8.1)].

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].

• Stop Tri-Lo-Marzia if an arterial thrombotic event or venous thrombotic (VTE) event occurs.
• Stop Tri-Lo-Marzia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see ADVERSE REACTIONS ( 6.2)].
• If feasible, stop Tri-Lo-Marzia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
• Start Tri-Lo-Marzia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
• Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.

[see WARNINGS AND PRECAUTIONS ( 5.2, 5.11) and USE IN SPECIFIC POPULATIONS ( 8.1).

Substances Decreasing the Plasma Concentrations of COCs

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of COCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant and products containing St. John's wort. Interactions between COCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam

Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of ethinyl estradiol (EE). The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances Increasing the Plasma Concentrations of COCs

Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

• COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.
• COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs.

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

See full prescribing information for complete boxed warning.

• Tri-Lo-Marzia is contraindicated in women over 35 years old who smoke. ( 4)
• Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. ( 4)

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Tri-Lo-Marzia prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS ( 4)] . Tri-Lo-Marzia can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Do not co-administer Tri-Lo-Marzia Tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS ( 5.3)] .