Ortho Tri-Cyclen

• Ortho-McNeil Pharmaceutical Corporation

Serious side effects have been reported with Ortho Tri-Cyclen including:

• Blood clots, heart attack and stroke.Tell your healthcare provider right away if you have some or all of the following symptoms:
  • shortness of breath
  • sharp or crushing chest pain
  • weakness or numbness in an arm or leg
  • slurring of speech
  • coughing of blood
  • pain in the calf
  • sudden severe headache or vomiting
  • dizziness or fainting
• Hypertension (high blood pressure). Have your blood pressure monitored by your doctor closely if taking Ortho Tri-Cyclen, especially if you have a history of hypertension or are taking medications to treat hypertension.
• Lipid disorders. Women who are being treated for hyperlipidemia (high blood fat/cholesterol) should be monitored closely, as steroids can elevate lipid levels.
• Breast, ovarian, or uterine cancer. Tell your healthcare provider right away if you detect a lump in the breast or experience new abdominal pain.
• Liver problems. Tell your healthcare provider right away if you have some or all of the following symptoms:
  • severe pain or tenderness in the stomach area
  • yellowing of the skin or eyeballs
• Severe depression. Tell your healthcare provider right away if you have some or all of the following symptoms:
  • difficulty sleeping
  • weakness, lack of energy, fatigue
  • change in mood
• Eye conditions.Tell your healthcare provider right away if you have some or all of the following symptoms:
  • unexplained partial or complete loss of vision
  • double vision
  • bulging of the eyes
• Severe migraine headaches. Tell your healthcare provider right away if you experience recurrent or persistent headaches.

Ortho Tri-Cyclen does not protect against HIV infection or other sexually-transmitted diseases.

Do not take Ortho Tri-Cyclen if you:

• are allergic to Ortho Tri-Cyclen or to any of its ingredients
• have a history of heart attack or stroke
• have blood clots in the legs, lungs, or eyes
• have a history of blood clots in the deep veins of your legs
• have chest pain (angina pectoris)
• have or have had cerebral vascular or coronary artery disease
• have disease of the heart valves with complications
• have severe hypertension (very high blood pressure)
• have diabetes with blood vessel involvement
• have headaches with focal neurological symptoms (movement disorders affecting a specific region of the body, such as the left arm or right leg)
• have had a major surgery requiring a long period of inactivity
• have, may have, or have had cancer of the breast
• have cancer of the lining of the uterus or other estrogen-dependent cancer
• have undiagnosed abnormal genital bleeding
• have jaundice (yellowing of the skin or eyes)
• have liver disease with abnormal liver function
• have tumors of the liver
• are or may be pregnant

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Ortho Tri-Cyclen, there are no specific foods that you must exclude from your diet while taking this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Ortho Tri-Cyclen falls into category X. This medication should not be used during pregnancy as it has the potential to cause miscarriage.

• Store Orthho Tri-Cyclen at room temperature between 59° and 86°F (15° and 30°C).
• Protect this medication from light.
• Keep this and all medicines out of the reach of children.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Thromboembolic Disorders and Other Vascular Problems

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

Liver Disease

Impaired Liver Function

Do not use ORTHO-CYCLEN or Ortho Tri-Cyclen in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4)]. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue ORTHO-CYCLEN or Ortho Tri-Cyclen if jaundice develops.

Liver Tumors

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

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

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

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

High Blood Pressure

ORTHO-CYCLEN and Ortho Tri-Cyclen are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop ORTHO-CYCLEN and Ortho Tri-Cyclen if blood pressure rises significantly.

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

Gallbladder Disease

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

Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who take ORTHO-CYCLEN or Ortho Tri-Cyclen. COCs may decrease glucose tolerance.

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

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

Headache

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

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

Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

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

In clinical trials of ORTHO-CYCLEN and Ortho Tri-Cyclen, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women discontinued ORTHO-CYCLEN and 231 (4.8%) women discontinued Ortho Tri-Cyclen, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14–34% of women using ORTHO-CYCLEN experienced unscheduled bleeding per cycle in the first year; for Ortho Tri-Cyclen, the respective numbers were 13–38%. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

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

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

COC Use Before or During Early Pregnancy

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

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

Depression

Carefully observe women with a history of depression and discontinue ORTHO-CYCLEN or Ortho Tri-Cyclen if depression recurs to a serious degree.

Carcinoma of Breast and Cervix

• ORTHO-CYCLEN and Ortho Tri-Cyclen are contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

  There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

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

Effect on Binding Globulins

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

Monitoring

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

Hereditary Angioedema

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

Chloasma

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

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

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

Stop using Ortho Tri-Cyclen and call your doctor at once if you have:

• signs of a stroke - sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in the lung - chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• signs of a blood clot in your leg - pain, swelling, warmth, or redness in one or both legs;

• heart attack symptoms - chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

• liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• a change in the pattern or severity of migraine headaches;

• swelling in your hands, ankles, or feet;

• a breast lump; or

• symptoms of depression - sleep problems, weakness, tired feeling, mood changes.

Common Ortho Tri-Cyclen side effects may include:

• nausea, vomiting;

• breast tenderness;

• freckles or darkening of facial skin, loss of scalp hair;

• headache, dizziness, nervousness;

• problems with contact lenses;

• changes in weight or appetite;

• irregular menstrual bleeding or spotting;

• vaginal itching or discharge; or

• rash.

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

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

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not use birth control pills if you have: uncontrolled high blood pressure, heart disease, coronary artery disease, circulation problems (especially with diabetes), undiagnosed vaginal bleeding, liver disease or liver cancer, severe migraine headaches, if you also take certain hepatitis C medication, if you have major surgery, if you smoke and are over 35, or if you have ever had a heart attack, a stroke, a blood clot, jaundice caused by pregnancy or birth control pills, or cancer of the breast, uterus/cervix, or vagina.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. You should not take birth control pills if you smoke and are over 35 years old.

Other drugs may interact with birth control pills, including prescription and over-the-counter medicines, vitamins, and herbal products. Some drugs can make birth control pills less effective, which may result in pregnancy. Tell your doctor about all your current medicines and any medicine you start or stop using.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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