Tri-Previfem

Tri-Previfem is a prescription birth control medication used to prevent pregnancy. Tri-Previfem may also be taken to treat moderate acne in females at least 15 years of age, who have started having menstrual periods, are able to take the pill and want to use the pill for birth control.

Tri-Previfem contains two hormones, norgestimate and ethinyl estradiol, which belong to a group of drugs called hormonal contraceptives. These hormones prevent pregnancy by stopping ovulation and by altering cervical mucus and the lining of the uterus to prevent sperm from entering. 

This medication comes in tablet form and is taken once daily, with or without food.

Common side effects of Tri-Previfem include nausea, breast tenderness, and vaginal bleeding between menstrual periods. 

Tri-Previfem is part of the drug class:

• Combination Progesterone and Estrogen Contraceptives

Some drugs can make birth control pills less effective, which may result in pregnancy. Other drugs may interact with ethinyl estradiol and desogestrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

• If you have an allergy to ethinyl estradiol, norgestimate, or any other part of Tri-Previfem.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have had any of these health problems: Blood clots, blood clotting problem, breast cancer, diseased arteries in the brain, disease of a heart valve with problems, heart disease, chest pain caused by angina, heart attack, stroke, high blood pressure, high cholesterol, a pancreas problem (pancreatitis) due to high blood triglycerides, liver disease, liver tumor, very bad headache or migraine, diabetes that affects blood flow, or tumor where estrogen makes it grow.
• If you have had any of these health problems: Endometrial cancer, cancer of the cervix or vagina, or vaginal bleeding where the cause is not known.
• If you have ever had a cancer where hormones make it grow.
• If you turned yellow during pregnancy or with estrogen-based or hormone contraceptive use.
• If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.
• If you are breast-feeding or plan to breast-feed.
• If you are taking ombitasvir, paritaprevir, and ritonavir (with or without dasabuvir).

This is not a list of all drugs or health problems that interact with Tri-Previfem.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Oral Contraception

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals and humans, have shown that norgestimate and 17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity90-93. Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone90,91,94.

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.

Pharmacokinetics

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration. Norgestimate 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 Tri-Previfem®. Accumulation following multiple dosing of the 250 mcg NGM/35 mcg 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 norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding globulin), which limits its biological activity.

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

The effect of food on the pharmacokinetics of Tri-Previfem® has not been studied.

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

Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

The metabolites of norelgestromin and ethinyl estradiol 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 norgestimate was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate have been identified in human urine following administration of radiolabeled norgestimate. 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.

The effects of body weight, body surface area or age on the pharmacokinetics of Tri-Previfem® have not been studied.

The effects of hepatic impairment on the pharmacokinetics of Tri-Previfem® have not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).

The effects of renal impairment on the pharmacokinetics of Tri-Previfem® have not been studied.

No formal drug-drug interaction studies were conducted with Tri-Previfem®. Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS).

Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki).

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

• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives:

• Mesenteric thrombosis
• Retinal thrombosis

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

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Allergic reaction, including rash, urticaria, angioedema
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

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

• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari syndrome

The following adverse  reactions were also reported in  clinical  trials  or  during  postmarketing  experience: Infections  and Infestations: vaginal infection, urinary  tract infection; Psychiatric Disorders:  mood  altered,  anxiety, insomnia; Gastrointestinal Disorders: flatulence, pancreatitis, diarrhea, constipation; Reproductive System and Breast Disorders: dysmenorrhea; ovarian cyst, vulvovaginal  dryness;  Neoplasms  Benign, Malignant and Unspecified (Including Cysts and Polyps): benign breast neoplasm, fibroadenoma of breast, breast cyst; Nervous System Disorders: syncope, convulsion, paraesthesia; Eye Disorders: visual impairment, dry eye; Ear and Labyrinth  Disorders: vertigo; Cardiac Disorders: tachycardia, palpitations; Vascular Disorders: hot flush; Respiratory, Thoracic and Mediastinal Disorders: dyspnoea; Hepatobiliary  Disorders: hepatitis; Skin and Subcutaneous Tissue Disorders: night  sweats,  hyperhidrosis, photosensitivity reaction, pruritus; Musculoskeletal, Connective Tissue, and Bone Disorders: muscle spasms, pain in  extremity, myalgia, back  pain; General  Disorders and Administration Site Conditions: chest  pain, asthenic conditions.

The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol73-78.

Effects on menses:

• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies

Other effects:

• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer

Rx only

PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully.

This product (like all oral contraceptives) does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Tri-Previfem® Regimen
Each white tablet contains 0.18 mg norgestimate and 0.035 mg ethinyl estradiol. Each light-blue tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol. Each blue tablet contains 0.25 mg norgestimate and 0.035 mg ethinyl estradiol. Each light-green tablet contains inert ingredients.

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

EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR CONTRACEPTION
Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than most other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% per year (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pill correctly, are approximately 5% per year (5 pregnancies per 100 women per year of use). The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

In comparison, typical failure rates for other non-surgical methods of birth control during the first year of use are as follows:
Implant: <1%
Injection: <1%
IUD: 1 to 2%
Diaphragm with spermicides: 20%
Spermicides alone: 26%
Vaginal sponge: 20 to 40%
Female sterilization: <1%
Male sterilization: <1%
Cervical Cap with spermicides: 20 to 40%
Condom alone (male): 14%
Condom alone (female): 21%
Periodic abstinence: 25%
Withdrawal: 19%
No methods: 85%

Tri-Previfem® may also be taken to treat moderate acne if all of the following are true:

• You have started having menstrual cycles
• You are at least 15 years old
• Your healthcare professional says it is safe for you to use the pill
• You want to use the pill for birth control

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions:

• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs

• An inherited problem that makes your blood clot more than normal

• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill
• Liver tumor (benign or cancerous) or active liver disease
• Known or suspected pregnancy
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Hypersensitivity to any component of this product

Tell your healthcare professional if you have had any of these conditions. Your healthcare professional can recommend a safer method of birth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:

• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental depression
• Gallbladder, liver, heart or kidney disease
• History of scanty or irregular menstrual periods

Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives.

Also, be sure to inform your healthcare professional if you smoke or are on any medications.

RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of Developing Blood Clots
Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision.

If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast feeding. If you are breast feeding, you should wait until you have weaned your child before using the pill (see GENERAL PRECAUTIONS, While Breast Feeding).

The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers.

2. Heart Attacks and Strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability.

Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease.

3. Gallbladder Disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens.

4. Liver Tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.

5. Cancer of the Reproductive Organs and Breasts
Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.

Adapted from H.W. Ory, ref. #35. 

In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group less than 40. Over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy in that age group. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group.

The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. Older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with the individual patient needs.

WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain, heaviness in the chest, irregular heart beat or palpitations (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)

SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above, the following may also occur:

1. Irregular Vaginal Bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional.

2. Contact Lenses
If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional.

3. Fluid Retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional.

4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.

5. Other Side Effects
Other side effects may include nausea, vomiting, diarrhea and constipation, change in appetite, headache, nervousness,  depression, dizziness, muscle cramps, loss of scalp hair, rash, skin sensitivity to the sun or ultraviolet light, vaginal infections, urinary tract infections, vertigo, pancreatitis and allergic reactions.

If any of these side effects bother you, call your healthcare professional.

GENERAL PRECAUTIONS

1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy
There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Stop taking your pills if you are pregnant.

There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy.

2. While Breast Feeding
If you are breast feeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combination oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combination oral contraceptives while breast feeding. You should use another method of contraception since breast feeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breast feed for longer periods of time. You should consider starting combination oral contraceptives only after you have weaned your child completely.

3. Laboratory Tests
If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills.

4. Drug Interactions
Tell your healthcare provider about all medicines and herbal products that you take.

Some  medicines  and  herbal  products  may  make  hormonal  birth  control  less  effective, including, but not limited to:

• certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin,  rufinamide, and topiramate
• aprepitant
• barbiturates
• bosentan
• colesevelam
• griseofulvin
• certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors)
• certain non nucleoside reverse transcriptase inhibitors (nevirapine)
• rifampin and rifabutin
• St. John's wort

Use another birth control method (such as a condom and spermicide or diaphragm and spermicide) when you take            medicines that may make Tri-Previfem® (norgestimate and ethinyl estradiol tablets USP) less effective.

Some medicines and grapefruit juice may increase your level of the hormone  ethinyl estradiol if used together, including:

• acetaminophen
• ascorbic acid
• medicines  that  affect  how  your  liver  breaks  down  other medicines (itraconazole, ketoconazole, voriconazole,  and fluconazole)
• certain HIV medicines (atazanavir, indinavir)
• atorvastatin
• rosuvastatin
• etravirine

Hormonal birth control methods may  interact with lamotrigine, a seizure medicine used for epilepsy. This  may increase the risk of seizures, so your  healthcare provider may need  to adjust the dose of lamotrigine.

Women on thyroid replacement therapy may need increased doses of thyroid hormone.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

5. Sexually Transmitted Diseases
Tri-Previfem® (like all oral contraceptives) is intended to prevent pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.

If you miss pills you could get pregnant. This includes starting the pack late.

The more pills you miss, the more likely you are to get pregnant.

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

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.

On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.

Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional.

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

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

It is important to take it at about the same time every day.

2. LOOK AT YOUR PILL PACK

The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is followed by 1 week of “reminder” light-green pills (without hormones).

There are 7 white “active” pills, 7 light-blue “active” pills, 7 blue “active” pills, and 7 light-green “reminder” pills.

3. ALSO FIND:

1. where on the pack to start taking pills,
2. in what order to take the pills.

CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.

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 PACK.

You have a choice of which day to start taking your first pack of pills. Tri-Previfem® is available in the blister pack tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember.

Sunday Start:
Take the first white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

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

Day 1 Start:
Take the first white “active” pill of the first pack during the first 24 hours of your period.

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

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

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

2. When You Finish a Pack or Switch Your Brand of Pills:

Start the next pack on the day after your last “reminder” pill. Do not wait any days between packs.

If you MISS 1 white, light-blue or blue “active” pill:

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

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

If you MISS 2 white or light-blue “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:

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

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

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 2 blue “active” pills in a row in THE 3RD WEEK:

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

If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.

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

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white, light-blue or blue “active” pills in a row (during the first 3 weeks):

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

If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.

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

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

A REMINDER:

PREGNANCY DUE TO PILL FAILURE
The incidence of pill failure resulting in pregnancy is approximately 5%, including women who do not always take the pills exactly as directed. If failure does occur, the risk to the fetus is minimal.

PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.

There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill.

OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional or pharmacist.

OTHER INFORMATION
Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is a time to determine if there are early signs of side effects of oral contraceptive use.

Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills.

HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combination oral contraceptives may provide certain benefits. They are:

• menstrual cycles may become more regular
• blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.
• pain or other symptoms during menstruation may be encountered less frequently
• ectopic (tubal) pregnancy may occur less frequently
• noncancerous cysts or lumps in the breast may occur less frequently
• acute pelvic inflammatory disease may occur less frequently
• oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.

If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read.

Keep out of reach of children.

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

Protect from light.

Ovral®, Alesse®, Nordette®, Lo/Ovral®, and Triphasil® are registered trademarks of Wyeth LLC.

Levlen® and Tri-Levlen® are registered trademarks of Berlex Laboratories, Inc.

LAMICTAL® is a registered trademark of GlaxoSmithKline LLC.

Manufactured In Canada By:
Patheon Inc.
Ontario, Canada L5N 7K9

Manufactured For:
QUALITEST PHARMACEUTICALS USA
Huntsville, AL 35811

Rev. 10/2013

Applies to ethinyl estradiol / norgestimate: oral tablet

Along with its needed effects, ethinyl estradiol / norgestimate may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ethinyl estradiol / norgestimate:

• Abdominal or stomach pain
• absent, missed, or irregular menstrual periods
• anxiety
• change in vision
• changes in skin color
• chest pain or discomfort
• chills
• clay-colored stools
• constipation
• cough
• dark urine
• diarrhea
• dizziness or lightheadedness
• fainting
• fever
• headache
• hives or welts
• itching skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• medium to heavy, irregular vaginal bleeding between regular monthly periods, which may require the use of a pad or a tampon
• nausea and vomiting
• pain or discomfort in the arms, jaw, back, or neck
• pain, tenderness, or swelling of the foot or leg
• pains in the chest, groin, or legs, especially in the calves of the legs
• pounding in the ears
• rash
• redness of the skin
• severe headaches of sudden onset
• slow or fast heartbeat
• sudden loss of coordination or slurred speech
• sudden onset of shortness of breath for no apparent reason
• sudden shortness of breath or troubled breathing
• sweating
• unusual tiredness or weakness
• vomiting of blood

Some side effects of ethinyl estradiol / norgestimate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach cramps
• bloating
• blotchy spots on the exposed skin
• breast enlargement or tenderness
• discouragement
• feeling sad or empty
• irritability
• itching of the vagina or outside the genitals
• loss of interest or pleasure
• pain during sexual intercourse
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• trouble concentrating
• trouble sleeping
• trouble wearing contact lenses

Applies to ethinyl estradiol / norgestimate: oral tablet

Other

Many of the adverse effects experienced by women on oral contraceptive combination products are related to a relative excess or deficiency of the estrogen and progestin components of these formulations. The following categorizes many of the frequent adverse effects by relative excess or deficiency of these components.

Progestin Excess:

Acne, oily skin
Breast tenderness
Depression
Tiredness, fatigue
Hair loss
Hypertension
Increased appetite
Weight gain
Cholestatic jaundice

Progestin Deficiency:

Late breakthrough bleeding
Amenorrhea
Hypermenorrhea

Estrogen Excess:

Nausea
Headache
Melasma
Hypertension
Breast tenderness
Edema

Estrogen Deficiency:

Early/mid-cycle breakthrough bleeding
Increased spotting
Hypomenorrhea[Ref]

General

Women taking oral contraceptive combinations experience several non-contraceptive health benefits. These benefits include protection against two malignant neoplasms (endometrial carcinoma and ovarian cancer). In addition, use of oral contraceptive combinations decreases the frequency of benign breast tumors, decreases the risk of ovarian cysts, decreases the risk of ectopic pregnancy, increases menstrual regularity, decreases the incidence of iron deficiency anemia, decreases the incidence of dysmenorrhea, and decreases the incidence of pelvic inflammatory disease.[Ref]

A number of studies have suggested that use of oral contraceptives decreases the risk of ovarian cancer. Specifically, the risk of epithelial ovarian cancers is decreased by 40%. The protection against ovarian cancer may last for 10 to 15 years after discontinuation of oral contraceptives. After long term use (12 years), the risk of ovarian cancer is decreased by as much as 80%.

The risk of endometrial cancer is decreased by approximately 50%. Protection may last for 15 years after discontinuation and may be greatest for nulliparous women who may be at higher risk for endometrial carcinoma than other women.

The incidence of hospitalization for pelvic inflammatory disease is approximately 50% lower in women taking oral contraceptives. The reason for the decrease in the frequency (or severity) of pelvic inflammatory disease in women taking oral contraceptives has not been fully elucidated.

Some recent studies have suggested that the decrease in frequency of functional ovarian cysts reported with some older formulations may not occur in women taking newer low dose formulations.

One recent study (The Nurses' Health Study) has suggested that long term use of oral contraceptives is safe and does not adversely affect long term risk for mortality.[Ref]

Gastrointestinal

A relatively common gastrointestinal side effect is nausea, which occurs in approximately 10% of treated women and may be more frequent during the first cycles of therapy. Some early reports suggested an association between oral contraceptive use and gallbladder disease.[Ref]

Cases of oral contraceptive-induced esophageal ulceration and geographic tongue have been reported rarely.

More recent studies have suggested that the risk of gallbladder disease is minimal.[Ref]

Oncologic

The World Health Organization committee also noted that some studies "have found a weak association between long-term use of oral contraceptives and breast cancer diagnosed before the age of 36, and perhaps up to the age 45....It is unclear whether this observed association is attributable to bias, the development of new cases of cancer, or accelerated growth of existing cancers."

The World Health Organization committee further concluded that there is no increased risk of breast cancer in women over the age of 45 who have previously taken oral contraceptives. In addition, studies suggest that use of oral contraceptives does not place specific groups of women (like those with a family history of breast cancer) at higher or lower risk, and variations in the hormonal content of oral contraceptives do not influence the risk of breast cancer.

In general, studies evaluating the potential risk of cervical cancer in patients taking oral contraceptives have been complicated by the large number of confounding factors which make investigations into the epidemiology of this neoplasm difficult. Some studies have suggested that women taking oral contraceptives are at increased risk of dysplasia, epidermoid carcinoma, and adenocarcinoma of the cervix. However, other studies have not found such an association.[Ref]

A number of studies have examined a possible relationship between the use of oral contraceptives and the development of breast cancer. Many of the studies have reported conflicting results. A committee of the World Health Organization evaluated these studies and the risks of breast cancer and concluded that: "Numerous studies have found no overall association between oral contraceptive use and risk of breast cancer." In addition, the same committee also examined a possible relationship between oral contraceptive use and neoplasms of the uterine cervix and concluded that: "There are insufficient data to draw any firm conclusions regarding the effects of combined oral contraceptives on the risk of cervical adenocarcinoma."[Ref]

Cardiovascular

Oral contraceptive combinations have been studied extensively for oncologic side effects. A number of studies have examined a possible relationship between the use of oral contraceptives and the development of breast cancer. Many of the studies have reported conflicting results. A committee of the World Health Organization evaluated these studies and the risks of breast cancer and concluded that: "Numerous studies have found no overall association between oral contraceptive use and risk of breast cancer." In addition, the same committee also examined a possible relationship between oral contraceptive use and neoplasms of the uterine cervix and concluded that: "There are insufficient data to draw any firm conclusions regarding the effects of combined oral contraceptives on the risk of cervical adenocarcinoma."[Ref]

Detailed information concerning the effects of oral contraceptive therapy on lipid metabolism is available in the Endocrine paragraph of this side effect monograph.

Some early investigations of women taking high dose estrogen combinations (50 mcg or more of ethinyl estradiol or equivalent daily) suggested that such women may be at increased risk of cardiovascular complications (myocardial infarction, stroke, and vascular thrombosis, including venous thromboembolism). However, more recent large investigations of women taking low dose estrogen combinations have suggested that oral contraceptive use is not associated with an increased risk of serious cardiovascular complications in healthy non smoking women up to the age of 45. (For women aged 35 to 44 who smoke or who have preexisting systemic diseases that may affect the cardiovascular system, use of oral contraceptives is not recommended.)

However, some investigators have suggested that even the new low dose products may result in adverse effects on lipid metabolism and should prompt careful review of a woman's cardiovascular risk factors before a decision to use oral contraceptive combinations is made.

The frequency of both subarachnoid hemorrhage and thrombotic stroke has been reported by some investigators to be higher in women taking oral contraceptive hormones. However, other investigators have suggested that the risk of these effects for women using newer low dose formulations are very small for young women without underlying cardiovascular disease or other risk factors.[Ref]

Endocrine

Endocrine and metabolic effects include complex alterations in plasma lipid profiles and carbohydrate metabolism. In addition, oral contraceptive use has been reported to cause conception delay.[Ref]

All the progestins which occur in commercially available oral contraceptive combinations have adverse effects on lipid profiles. Specifically, these progestins exert antiestrogen and androgen effects and decrease HDL (and HDL2) cholesterol levels and increase LDL cholesterol levels. However, the estrogens in oral contraceptive combinations exert opposing effects. Consequently, alterations in lipid profiles are related to the relative amount and potency of the specific estrogen and progestin in a given product. (Norgestimate exerts strong progestin and antiestrogen effects.)

A number of investigations have suggested that oral contraceptive combinations may decrease glucose tolerance. However, some recent studies with low dose preparations have suggested that decreases in glucose tolerance due to oral contraceptive combinations are generally minimal.

Despite the potentially adverse effects of oral contraceptives on lipid levels and glucose tolerance, some investigators have suggested that young diabetic women without existing vascular disease or severe lipidemias may be candidates for low dose oral contraceptive combinations provided that they receive close monitoring for adverse metabolic effects.[Ref]

Hepatic

Hepatic side effects include focal nodular hyperplasia, intrahepatic cholestasis, liver cell adenomas, hepatic granulomas, hepatic hemangiomas and well-differentiated hepatocellular carcinomas, which have been reported rarely in association with estrogen therapy and therapy with oral contraceptive combinations.[Ref]

The rate of death due to hepatocellular carcinoma in the United States has not changed during the last 25 years (a time during which use of oral contraceptive hormones has increased dramatically).

A committee of the World Health Organization has reported that in developing countries where hepatitis B virus infection and hepatocellular carcinoma are common, "short term use of oral contraceptives does not appear to be associated with an increased risk. Data on the effects of long term use are scarce."

A recent Italian case-control study of women with hepatocellular carcinoma has suggested that the relative risk of hepatocellular carcinoma is 2.2 for oral contraceptive users compared to women who never used oral contraceptives.

A similar American case-control study from 1989 also reported a strong association between oral contraceptive use and hepatocellular carcinoma but concluded that: "If this observed association is causal, the actual number of cases of liver cancer in the United States attributable to oral contraceptive use is small. Therefore, these findings do not have public health importance in the United States and other Western nations."[Ref]

Hematologic

Cases of venous thrombosis, pulmonary embolism (sometimes fatal), and arterial thrombosis have been reported rarely.

Previous thrombotic disease is considered a contraindication to use of oral contraceptive combinations.[Ref]

A hematologic concern is the risk of thromboembolism that is associated with the use of exogenous estrogens. However, because the dose of exogenous estrogens is low in most commercially available preparations, the risk of thromboembolism is minimal for most women (except women who are over age 35 and smoke and women with a history of previous thrombotic diseases).[Ref]

Genitourinary

A common genitourinary side effect is breakthrough bleeding and spotting, especially during the first several cycles of oral contraceptive use. Non-hormonal causes of such bleeding should be excluded.[Ref]

Some women experience oligomenorrhea and amenorrhea following termination or oral contraceptive use.[Ref]

Psychiatric

Psychiatric side effects include depression and precipitation of panic disorder.[Ref]

Immunologic

Immunologic side effects include cases of oral contraceptive-induced systemic lupus erythematosus which have been reported rarely.[Ref]

Other

A case of fatal pulmonary venooclusive disease has been associated with oral contraceptive therapy.[Ref]

Nervous system

Nervous system side effects include chorea, which has been reported once in association with oral contraceptives.[Ref]

Ocular

Ocular side effects include cases of retinal thrombosis, which have been reported rarely. In addition, the manufacturers of oral contraceptive products report that some patients develop changes in contact lens tolerance.[Ref]

Some side effects of Tri-Previfem may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.