Tarina Fe 1/20

Name: Tarina Fe 1/20

What do I need to tell my doctor BEFORE I take Tarina Fe 1/20?

For all patients taking Tarina Fe 1/20:

  • If you have an allergy to ethinyl estradiol, norethindrone, or any other part of this medicine.
  • 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, bulging blood vessel (aneurysm), chest pain caused by angina, high blood sugar (diabetes) that affects blood flow, diseased arteries in the brain, disease of a heart valve with problems, heart attack, heart disease, high blood pressure, liver disease, liver tumor, stroke, tumor where estrogen makes it grow, or very bad headache or migraine.
  • 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 surgery and need bedrest.
  • If you are pregnant or may be pregnant. Do not take Tarina Fe 1/20 if you are pregnant.
  • If you are breast-feeding or plan to breast-feed.
  • If you turned yellow during pregnancy or with estrogen-based or hormone contraceptive use.

Children:

  • If your child has not had her first period.

This is not a list of all drugs or health problems that interact with this medicine.

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 Tarina Fe 1/20 with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take Tarina Fe 1/20?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists. This medicine may need to be stopped before certain types of surgery as your doctor has told you. If Tarina Fe 1/20 is stopped, your doctor will tell you when to start taking this medicine again after your surgery or procedure.
  • This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
  • Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
  • Some studies have shown the risk of breast cancer is raised in women taking birth control pills, especially at a younger age. This includes birth control pills that have drugs like this one in them. The risk was also linked to how long the birth control pills were taken. One study showed the risk of breast cancer was also raised in women who took birth control pills within the past 10 years. Talk with the doctor.
  • If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
  • Check your blood sugar as you have been told by your doctor.
  • High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
  • If you are allergic to tartrazine, talk with your doctor. Some products have tartrazine.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Tarina Fe 1/20.
  • Certain drugs, herbal products, or health problems could cause this medicine to not work as well. Be sure your doctor knows about all of your drugs and health problems.
  • This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
  • This medicine may raise the chance of blood clots. The chance is highest during the first year of using Tarina Fe 1/20. The chance is also highest when starting to use hormone-based birth control again after not using it for 4 weeks or more. Talk with the doctor.
  • If you are taking this medicine for pimples (acne), you need to be at least 15 years of age.
  • If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

What are some side effects that I need to call my doctor about right away?

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

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

Tarina Fe 1/20 - 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).

Pharmacokinetics

The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 to 3).

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6).

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 to 3).

Special Population

Race:

The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated.

Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

Precautions

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

2. Physical Examination and Follow-Up

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

4. Liver Function

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Emotional Disorders

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

8. Drug Interactions

Effects of Other Drugs on Oral Contraceptives (78)

Rifampin:

Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.

Anticonvulsants:

Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness.

Troglitazone:

Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a reduction in contraceptive effectiveness.

Antibiotics:

Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Atorvastatin:

Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.

Other:

Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.

Effects of Oral Contraceptives on Other Drugs

Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

9. Interactions with Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

  1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
  2. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
  3. Other binding proteins may be elevated in serum.
  4. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
  5. Triglycerides may be increased.
  6. Glucose tolerance may be decreased.
  7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

10. Carcinogenesis

See WARNINGS section.

11. Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.

12. Nursing Mothers

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

13. Pediatric Use

Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

INFORMATION FOR THE PATIENT

See Patient Labeling.

Tarina Fe 1/20 Dosage and Administration

The tablet blister pack has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in four rows of seven tablets each, with the days of the week appearing on the tablet blister above the first row of tablets.

Note: Each blister card has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.

Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.

The possibility of ovulation and conception prior to initiation of use should be considered.

Dosage and Administration for 28-Day Dosage Regimen

To achieve maximum contraceptive effectiveness, Tarina Fe 1/20 should be taken exactly as directed and at intervals not exceeding 24 hours.

Tarina Fe 1/20 provides a continuous administration regimen consisting of 21 white to off-white tablets of norethindrone acetate and ethinyl estradiol tablets and 7 brown non-hormone containing tablets of ferrous fumarate. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose. There is no need for the patient to count days between cycles because there are no "off-tablet days."

A. Sunday-Start Regimen: The patient begins taking the first white to off-white tablet from the top row of the blister (labeled Sunday) on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first white to off-white tablet is taken on the same day. The patient takes one white to off-white tablet daily for 21 days. The last white to off-white tablet in the blister pack will be taken on a Saturday. Upon completion of all 21 white to off-white tablets, and without interruption, the patient takes one brown tablet daily for 7 days. Upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday white to off-white tablet in the top row. Adhering to this regimen of one white to off-white tablet daily for 21 days, followed without interruption by one brown tablet daily for 7 days, the patient will start all subsequent cycles on a Sunday.

B. Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the blister card. She starts taking one white to off-white tablet daily, beginning with the first white to off-white tablet in the top row. After the last white to off-white tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days). For all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last white to off-white tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet blister. Following this regimen of 21 white to off-white tablets and 7 brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course.

Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

Special Notes on Administration

Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started. In any event, the next course of tablets should be started without interruption. If spotting occurs while the patient is taking white to off-white tablets, continue medication without interruption.

If the patient forgets to take one or more white to off-white tablets, the following is suggested:

One tablet is missed

  • take tablet as soon as remembered
  • take next tablet at the regular time

Two consecutive tablets are missed (week 1 or week 2)

  • take two tablets as soon as remembered
  • take two tablets the next day
  • use another birth control method for seven days following the missed tablets

Two consecutive tablets are missed (week 3)

Sunday-Start Regimen:

  • take one tablet daily until Sunday
  • discard remaining tablets
  • start new pack of tablets immediately (Sunday)
  • use another birth control method for seven days following the missed tablets

Day-1 Start Regimen:

  • discard remaining tablets
  • start new pack of tablets that same day
  • use another birth control method for seven days following the missed tablets

Three (or more) consecutive tablets are missed

Sunday-Start Regimen:

  • take one tablet daily until Sunday
  • discard remaining tablets
  • start new pack of tablets immediately (Sunday)
  • use another birth control method for seven days following the missed tablets

Day-1 Start Regimen:

  • discard remaining tablets
  • start new pack of tablets that same day
  • use another birth control method for seven days following the missed tablets

The possibility of ovulation occurring increases with each successive day that scheduled white to off-white tablets are missed. While there is little likelihood of ovulation occurring if only one white to off-white tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive white to off-white tablets are missed.

If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty. A back-up birth control method is not required during this time. A new pack of tablets should be started no later than the eighth day after the last white to off-white tablet was taken.

In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet blister pack on the next Sunday or the first day (Day-1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered.

Use of Oral Contraceptives in the Event of a Missed Menstrual Period

  1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.
  2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

For the Consumer

Applies to ethinyl estradiol / norethindrone: oral capsule liquid filled, oral tablet, oral tablet chewable

Other dosage forms:

  • oral tablet, oral tablet chewable

Along with its needed effects, ethinyl estradiol / norethindrone 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 / norethindrone:

Incidence not known
  • 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
  • fast heartbeat
  • 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 / norethindrone 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:

Incidence not known
  • 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 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

For Healthcare Professionals

Applies to ethinyl estradiol / norethindrone: oral capsule, oral tablet, oral tablet chewable

General

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]

Women taking oral contraceptive combinations may have experienced 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 has reportedly decreased the frequency of benign breast tumors, decreased the risk of ovarian cysts, decreased the risk of ectopic pregnancy, increased menstrual regularity, decreased the incidence of iron deficiency anemia, decreased the incidence of dysmenorrhea, and decreased the incidence of pelvic inflammatory disease.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, which occurred in approximately 10% of treated women and was 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

Oncologic side effects have included reports of increased risk of invasive breast cancer. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. 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]

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]

Cardiovascular

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]

Cardiovascular side effects have included reports of increased risk of coronary heart disease, stroke, and pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. Earlier studies had suggested that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35% and that combination therapy with a progestin may also decrease coronary risk. Cardiovascular side effects of the estrogen component of this combination have also included reports of hypertension. However, significant blood pressure increases generally occur only in women receiving high-dose estrogen products (50 mcg or more of ethinyl estradiol or equivalent daily). Estrogens have also been associated with edema. In addition, exogenous estrogens may exert cardioprotective effects by causing favorable changes in lipid profiles. These beneficial effects, however, may be partially or completely offset by alterations in lipid profiles induced by exogenous progestins.[Ref]

Endocrine

Endocrine side effects have included reports of 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. (Norethindrone exerts a moderate androgen effect and weak 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 have included 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]

Hematologic side effects have included 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

Genitourinary side effects have commonly included breakthrough bleeding and spotting, especially during the first several cycles of oral contraceptive use. Non-hormonal causes of such bleeding should be excluded. Additional side effects reported with estrogen and/or progestin therapy include changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion, change in cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer and vaginitis.[Ref]

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

Psychiatric

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

Immunologic

Immunologic side effects have included rare cases of oral contraceptive-induced systemic lupus erythematosus.[Ref]

Nervous system

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

Ocular

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

Respiratory

Respiratory side effects have included reports of increased risk of pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism.[Ref]

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

Some side effects of Tarina Fe 1 / 20 may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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