Portia

Drug Description

Portia®
(levonorgestrel and ethinyl estradiol tablets USP)

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Portia® (levonorgestrel and ethinyl estradiol tablets USP) consists of 21 pink active tablets, each containing 0.15 mg of levonorgestrel, USP, (18, 19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-(-)-), a totally synthetic progestogen, and 0.03 mg of ethinyl estradiol, USP, (19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and 7 white inert tablets. The inactive ingredients in the pink active tablets include anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose. The ingredients in the film-coating include FD&C blue no. 1 aluminum lake, FD&C red no. 40 aluminum lake, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide. Each white inert tablet contains anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose.

The structural formulas are as follows:

Levonorgestrel, USP

Levonorgestrel Structural Formula - Illustration

C₂₁H₂₈O₂ M.W. 312.45

Ethinyl Estradiol, USP

Ethinyl Estradiol Structural Formula - Illustration

C₂₀H₂₄O₂ M.W. 296.40

Indications

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization and the IUD, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD

Method	Perfect Use	Typical Use
Levonorgestrel implants	0.05	0.05
Male sterilization	0.1	0.15
Female sterilization	0.5	0.5
Depo-Provera® (injectable progestogen)	0.3	0.3
Oral contraceptives		5
Combined	0.1	NA
Progestin only	0.5	NA
IUD
Progesterone	1.5	2
Copper T 380A	0.6	0.8
Condom (male) without spermicide	3	14
(Female) without spermicide	5	21
Cervical cap
Nulliparous women	9	20
Parous women	26	40
Vaginal sponge
Nulliparous women	9	20
Parous women	20	40
Diaphragm with spermicidal cream or jelly	6	20
Spermicides alone (foam, creams, jellies, and vaginal suppositories)	6	26
Periodic abstinence (all methods)	1 to 9*	25
Withdrawal	4	19
No contraception (planned pregnancy)	85	85
*Depending on method (calendar, ovulation, symptothermal, post-ovulation). Adapted from Hatcher RA et al, Contraceptive Technology: 17^th Revised Edition. NY, NY: Ardent Media, Inc., 1998.

Dosage

DOSAGE AND ADMINISTRATION

To achieve maximum contraceptive effectiveness, Portia (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours.

The dosage of Portia is one pink tablet daily for 21 consecutive days, followed by one white inert tablet daily for 7 consecutive days, according to prescribed schedule.

It is recommended that tablets be taken at the same time each day, preferably after the evening meal or at bedtime.

During the first cycle of medication, the patient is instructed to begin taking Portia on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (pink) is taken that day. One pink tablet should be taken daily for 21 consecutive days, followed by one white inert tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within three days following discontinuation of pink tablets and may not have finished before the next pack is started. During the first cycle, contraceptive reliance should not be placed on Portia until a pink tablet has been taken daily for 7 consecutive days and a nonhormonal back-up method of birth control should be used during those 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient begins her next and all subsequent 28 day courses of tablets on the same day of the week (Sunday) on which she began her first course, following the same schedule: 21 days on pink tablets - 7 days on white inert tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself by using another method of birth control until she has taken a pink tablet daily for 7 consecutive days.

When the patient is switching from a 21 day regimen of tablets, she should wait 7 days after her last tablet before she starts Portia. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21 day regimen. When the patient is switching from a 28 day regimen of tablets, she should start her first pack of Portia on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin Portia the next day. If switching from an implant or injection, the patient should start Portia on the day of implant removal or, if using an injection, the day the next injection would be due. In switching from a progestin-only pill, injection or implant, the patient should be advised to use a nonhormonal back-up method of birth control for the first 7 days of tablet-taking.

If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. Although the occurrence of pregnancy is highly unlikely if Portia tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

For additional patient instructions regarding missed pills, see the “WHAT TO DO IF YOU MISS PILLS” section in the DETAILED PATIENT LABELING below.

Anytime the patient misses two or more pink tablets, she should also use another method of contraception until she has taken a pink tablet daily for seven consecutive days. If the patient misses one or more white tablets, she is still protected against pregnancy provided she begins taking pink tablets again on the proper day.

If breakthrough bleeding occurs following missed pink tablets, it will usually be transient and of no consequence. While there is little likelihood of ovulation occurring if only one or two pink tablets are missed, the possibility of ovulation increases with each successive day that scheduled pink tablets are missed.

Portia may be initiated no earlier than day 28 postpartum in the non-lactating mother or after a second trimester abortion due to the increased risk for thromboembolism (see CONTRAINDICATONS, WARNINGS AND PRECAUTIONS concerning thromboembolic disease). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet taking. However, if intercourse has already occurred, pregnancy should be excluded before the start of combined oral contraceptive use or the patient must wait for her first menstrual period.

In the case of first trimester abortion, if the patient starts Portia immediately, additional contraceptive measures are not needed. It is to be noted that early resumption of ovulation may occur if Parlodel (bromocriptine mesylate) has been used for the prevention of lactation.

HOW SUPPLIED

Portia® (levonorgestrel and ethinyl estradiol tablets USP, 0.15 mg/ 0.03 mg) 28 tablets are packaged in cartons of six blister cards (NDC 0555-9020-58). Each card contains 21 pink, round, film-coated, biconvex, unscored active tablets, debossed with stylized b on one side and 992 on the other side, and 7 white, round, biconvex, unscored inert tablets, debossed with stylized b on one side and 208 on the other side.

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

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

REFERENCES AVAILABLE UPON REQUEST

TEVA PHARMACEUTICALS USA, INC., North Wales, PA 19454. Revised: Apr 2017

Side Effects

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

Thromboembolic disorders and other vascular problems (including thrombophlebitis, arterial thromboembolism, pulmonary embolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis), carcinoma of the reproductive organs, hepatic neoplasia (including hepatic adenomas or benign liver tumors), ocular lesions (including retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid effects, elevated blood pressure, and headache.

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 pain, cramps and bloating)
Breakthrough bleeding
Spotting
Change in menstrual flow
Amenorrhea
Temporary infertility after discontinuation of treatment
Edema/fluid retention
Melasma/chloasma which may persist
Breast changes: tenderness, pain, enlargement, secretion
Change in weight or appetite (increase or decrease)
Change in cervical erosion and secretion
Diminution in lactation when given immediately postpartum
Cholestatic jaundice
Rash (allergic)
Mood changes, including depression
Vaginitis, including candidiasis
Change in corneal curvature (steepening)
Intolerance to contact lenses
Mesenteric thrombosis
Decrease in serum folate levels
Exacerbation of systemic lupus erythematosus
Exacerbation of porphyria
Exacerbation of chorea
Aggravation of varicose veins
Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

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

Congenital anomalies
Premenstrual syndrome
Cataracts
Optic neuritis, which may lead to partial or complete loss of vision
Cystitis-like syndrome
Nervousness
Dizziness
Hirsutism
Loss of scalp hair
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Impaired renal function
Hemolytic uremic syndrome
Budd-Chiari syndrome
Acne
Changes in libido
Colitis
Sickle-cell disease
Cerebral-vascular disease with mitral valve prolapse
Lupus-like syndromes
Pancreatitis
Dysmenorrhea

Drug Interactions

Interactions between ethinyl estradiol and other substances may lead to decreased or increased serum ethinyl estradiol concentrations. Decreased ethinyl estradiol plasma concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the combination oral contraceptive.

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when coadministered, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Reduced ethinyl estradiol concentrations have been associated with concomitant use of substances that induce hepatic microsomal enzymes, such as rifampin, rifabutin, barbiturates, phenylbutazone, phenytoin sodium, griseofulvin, topiramate, some protease inhibitors, modafinil, and possibly St. John's wort.

Substances that may decrease plasma ethinyl estradiol concentrations by other mechanisms include any substance that reduces gut transit time and certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines) by a decrease of enterohepatic circulation of estrogens.

During concomitant use of ethinyl estradiol containing products and substances that may lead to decreased plasma steroid hormone concentrations, it is recommended that a nonhormonal back-up method of birth control be used in addition to the regular intake of Portia (levonorgestrel and ethinyl estradiol tablets). If the use of a substance which leads to decreased ethinyl estradiol plasma concentrations is required for a prolonged period of time, combination oral contraceptives should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased ethinyl estradiol plasma concentrations, use of a nonhormonal backup method of birth control is recommended for 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinyl estradiol concentrations. It may take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use, and rate of elimination of the inducing substance.

Some substances may increase plasma ethinyl estradiol concentrations. These include:

Competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen.
Substances that inhibit cytochrome P450 3A4 isoenzymes such as indinavir, fluconazole, and troleandomycin. Troleandomycin may increase the risk of intrahepatic cholestasis during co-administration with combination oral contraceptives.
Atorvastatin (unknown mechanism)

Ethinyl estradiol may interfere with the mechanism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, tissue concentrations may be either increased (e.g. cyclosporine, theophylline, corticosteroids) or decreased.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

Concomitant Use With HCV Combination Therapy - Liver Enzyme Elevation

Do not co-administer Portia with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment).

Clinical Pharmacology

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).

Medication Guide

PATIENT INFORMATION

BRIEF SUMMARY PATIENT PACKAGE INSERT

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as “birth-control pills” or “the pill,” are taken to prevent pregnancy, and when taken correctly, have a failure rate of less than 1% per year when used without missing any pills. The average failure rate of large numbers of pill users is 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

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

smoke
have high blood pressure, diabetes, high cholesterol, or a tendency to form blood clots, or are obese
have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors

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

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.

Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use.

The serious side effects of the pill occur very infrequently, especially if you are in good health and do not smoke. However, you should know that the following medical conditions have been associated with or made worse by the pill:

Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. Women with migraine also may be at increased risk of stroke.
Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.
High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, and possibly St. Johnâ€™s wort, may decrease oral contraceptive effectiveness.

Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill were examined more often, so that breast cancer was more likely to be detected.

Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use the pill. However, this finding may be related to factors other than the use of the pill.

Taking the pill provides some important noncontraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.

Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider 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 provider believes that it is appropriate to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider.

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DETAILED PATIENT LABELING

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

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 leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare providerâ€™s advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or “birth-control pills” or “the pill” are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% when used perfectly, without missing any pills. Average failure rates are 5% per year. The chance of becoming pregnant increases with each missed pill during the menstrual cycle.

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

TABLE: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD

Method	Perfect Use	Average Use
Levonorgestrel implants	0.05	0.05
Male sterilization	0.1	0.15
Female sterilization	0.5	0.5
Depo-Provera® (injectable progestogen)	0.3	0.3
Oral contraceptives		5
Combined	0.1	NA
Progestin only	0.5	NA
IUD
Progesterone	1.5	2
Copper T 380A	0.6	0.8
Condom (male) without spermicide	3	14
(Female) without spermicide	5	21
Cervical cap
Never given birth	9	20
Given birth	26	40
Vaginal sponge
Never given birth	9	20
Given birth	20	40
Diaphragm with spermicidal cream or jelly	6	20
Spermicides alone (foam, creams, jellies, and vaginal suppositories)	6	26
Periodic abstinence (all methods)	1 to 9*	25
Withdrawal	4	19
No contraception (planned pregnancy)	85	85
*Depending on method (calendar, ovulation, symptothermal, post-ovulation). Adapted from Hatcher RA et al, Contraceptive Technology: 17^th Revised Edition. NY, NY: Ardent Media, Inc., 1998.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have had any of the following conditions:

Heart attack or stroke
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
Blood clots in the deep veins of your legs
Known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina, or certain hormonally-sensitive cancers
Liver tumor (benign or cancerous)
Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

Or, if you have any of the following:

Chest pain (angina pectoris)
Unexplained vaginal bleeding (until a diagnosis is reached by your doctor)
Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill
Known or suspected pregnancy
Heart valve or heart rhythm disorders that may be associated with formation of blood clots
Diabetes affecting your circulation
Uncontrolled high blood pressure
Active liver disease with abnormal liver function tests
Allergy or hypersensitivity to any of the components of Portia (levonorgestrel and ethinyl estradiol tablets)

Tell your healthcare provider if you have ever had any of these conditions. Your healthcare provider can recommend another method of birth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES

Tell your healthcare provider if you or any family member has ever had:

Breast nodules, fibrocystic disease of the breast, an abnormal breast X-ray or mammogram
Diabetes
Elevated cholesterol or triglycerides
High blood pressure
A tendency to form blood clots
Migraine or other headaches or epilepsy
Mental depression
Gallbladder, heart, or kidney disease
History of scanty or irregular menstrual periods

Women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives. Also, be sure to inform your doctor or healthcare provider 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 the most serious side effects of taking oral contraceptives and can be fatal. 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 have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor about stopping oral contraceptives three to 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 or a midtrimester pregnancy termination. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on breastfeeding in GENERAL PRECAUTIONS.)

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.

Women with migraine (especially migraine with aura) who take oral contraceptives also may be at higher risk of stroke.

3. Gallbladder Disease

Oral contraceptive users probably have a greater risk than non-users 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, a possible but not definite association has been found with the pill and liver cancers in two studies in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.

5. Cancer of the Reproductive Organs

Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives.

6. Lipid Metabolism and Inflammation of the Pancreas

In patients with inherited defects of lipid metabolism, there have been reports of significant elevations of plasma triglycerides during estrogen therapy. This has led to pancreatitis in some cases.

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.

ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE

Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility-control methods*	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives nonsmoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1	1	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/ spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6
*Deaths are birth related †Deaths are method related

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, except for those women over the age of 40, when the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. 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 donâ€™t smoke should not take oral contraceptives is based on information from older highdose pills and on less-selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest-dose pill that is effective.

WARNING SIGNALS

If any of these adverse effects occur while you are taking oral contraceptives, call your doctor 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 or heaviness in the chest (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 doctor or healthcare provider 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

1. 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 doctor or healthcare provider.

2. Contact Lenses

If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or healthcare provider.

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 doctor or healthcare provider.

4. Melasma

A spotty darkening of the skin is possible, particularly of the face.

5. Other Side Effects

Other side effects may include nausea, breast tenderness, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, inflammation of the pancreas, and allergic reactions.

If any of these side effects bother you, call your doctor or healthcare provider.

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 provider before doing so. 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 provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception.

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 studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn child of any medication taken during pregnancy.

2. While Breastfeeding

If you are breastfeeding, consult your doctor 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, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely.

3. Laboratory Tests

If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain blood tests may be affected by birth control pills.

4. Drug Interactions

Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital) and phenytoin (Dilantin® is one brand of this drug), primidone (Mysoline®), topiramate (Topamax®), phenylbutazone (Butazolidin is one brand), some drugs used for HIV such as ritonavir (Norvir®), modafinil (Provigil®) and possibly certain antibiotics (such as ampicillin and other penicillins, and tetracyclines) and St. Johnâ€™s wort. You may need to use an additional method of contraception during any cycle in which you take drugs that can make oral contraceptives less effective.

Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, so your physician may need to adjust the dose of lamotrigine.

Some medicines may make birth control pill less effective, including:

Barbiturates
Bosentan
Carbamazepine
Felbamate
Griseofulvin
Oxcarbazepine
Phenytoin
Rifampin
St. Johnâ€™s wort
Topiramate

As with all prescription products, you should notify your healthcare provider of any other medicines and herbal products you are taking. You may need to use a barrier contraceptive when you take drugs or products that can make birth control pills less effective.

You should inform your healthcare provider about all medicines you are taking, including nonprescription products.

5. Sexually Transmitted Diseases

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

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

If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 TO 3 PACKS OF PILLS.

If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnâ€™t go away, check with your doctor or clinic.

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

5. IF YOU HAVE VOMITING (within 3 to 4 hours after you take your pill), you should follow the instructions for WHAT TO DO IF YOU MISS PILLS.

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

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

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

BEFORE YOU START TAKING YOUR PILLS

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

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

2. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 28 PILLS:

The 28 pill pack has 21 “active” pink pills (with hormones) to take for 3 weeks, followed by 1 week of reminder white pills (without hormones).

3. ALSO FIND:

1) where on the pack to start taking pills, and

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

Pack to start taking pills - Illustration

4. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as condoms, spermicide, or sponge) to use as a back-up in case you miss pills. AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

The 28 day pill pack accommodates a SUNDAY START only. Pick a time of day which will be easy to remember.

SUNDAY START:

These instructions are for the 28 day pill pack.

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

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

WHAT TO DO DURING THE MONTH

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

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

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

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

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

WHAT TO DO IF YOU MISS PILLS

The pill may not be as effective if you miss pink “active” pills, and particularly if you miss the first few or the last few pink “active” pills in a pack.

If you MISS 1 pink “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 pink “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 MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms, spermicide, or sponge) as a back-up for those 7 days.

If you MISS 2 pink “active” pills in a row in THE 3rd WEEK:

The Sunday Starter instructions are for the 28 day pill pack.

1. Sunday Starter:

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

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

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

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

The Sunday Starter instructions are for the 28 day pill pack.

1. Sunday Starter:

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

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

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

A REMINDER FOR THOSE ON 28 DAY PACKS

If you forget any of the 7 white “reminder” pills in Week 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method if you start your next pack on time.

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

Use a BACK-UP METHOD anytime you have sex.

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

PREGNANCY DUE TO PILL FAILURE

The incidence of pill failure resulting in pregnancy is approximately less than 1% if taken every day as directed, but average failure rates are 5%. If you do become pregnant, the risk to the fetus is minimal, but you should stop taking your pills and discuss the pregnancy with your doctor.

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 provider or pharmacist.

OTHER INFORMATION

Your healthcare provider 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 provider believes that it is appropriate to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare provider 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 provider, 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 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.
Ovarian cysts may occur 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 doctor or pharmacist. They have a more technical leaflet called the Professional Labeling which you may wish to read.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

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