Tri-Lo-Marzia

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using birth control pills and call your doctor at once if you have:

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
• signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;
• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs;
• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• a change in the pattern or severity of migraine headaches;
• swelling in your hands, ankles, or feet;
• a breast lump; or
• symptoms of depression--sleep problems, weakness, tired feeling, mood changes.

Common side effects may include:

• nausea, vomiting;
• breast tenderness;
• freckles or darkening of facial skin, loss of scalp hair;
• headache, dizziness, nervousness;
• problems with contact lenses;
• changes in weight or appetite;
• irregular menstrual bleeding or spotting;
• vaginal itching or discharge; or
• rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Do not smoke while taking birth control pills, especially if you are older than 35 years of age.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Coughing up blood.
• Shortness of breath.
• Chest pain or pressure.
• Very bad dizziness or passing out.
• Very upset stomach or throwing up.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Low mood (depression).
• Mood changes.
• Feeling very tired or weak.
• Very bad belly pain.
• Swelling.
• Not able to pass urine or change in how much urine is passed.
• A lump in the breast, breast soreness, or nipple discharge.
• Vaginal itching or discharge.
• Spotting or vaginal bleeding that is very bad or does not go away.
• Bulging eyes.
• Change in eyesight.
• Change in how contact lenses feel in the eyes.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Oral Contraception

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

Do not prescribe Tri-Lo-Marzia 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:

   o  Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]

   o  Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS (5.1)]

   o  Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1)]

   o  Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS (5.1)]

   o  Have coronary artery disease [see WARNINGS AND PRECAUTIONS (5.1)]

   o  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)]

   o  Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.3)]

   o  Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS (5.5)]

   o  Have headaches with focal neurological symptoms or migraine headaches with aura [see WARNINGS AND PRECAUTIONS (5.6)]

         o 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)]

The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:

• Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]
• Vascular events [see WARNINGS AND PRECAUTIONS (5.1)]
• Liver disease [see WARNINGS AND PRECAUTIONS (5.2)]

Adverse reactions commonly reported by COC users are:

• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

Clinical Trial Experience

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).

Postmarketing Experience

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.

There have been no reports of serious ill effects from overdosage of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

Mechanism of Action

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.

Pharmacodynamics

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

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 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 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

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 Cmax and AUC0 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 Cmax by 9% and AUC0 to 24h by 19%, NG Cmax by 12% and AUC0 to 24h by 46%, EE Cmax by 13% and AUC0 to 24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in Cmax and AUC0 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.