Ortho Tri-Cyclen / Ortho-Cyclen

Oral Contraceptive

ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for use by females of reproductive potential to prevent pregnancy .

Acne

ORTHO TRI-CYCLEN is indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. ORTHO TRI-CYCLEN should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control .

How To Start Ortho-Cyclen Or Ortho Tri-Cyclen

ORTHO-CYCLEN and ORTHO TRI-CYCLEN are dispensed in either a DIALPAK Tablet dispenser or a VERIDATE Tablet Dispenser . ORTHO-CYCLEN and ORTHO TRI-CYCLEN may be started using either a Day 1 start or a Sunday start . For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.

How To Take Ortho-Cyclen Or Ortho Tri-Cyclen

Table 1: Instructions for Administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN

Starting ORTHO-CYCLEN or ORTHO TRI-CYCLEN after Abortion or Miscarriage

First-trimester

• After a first-trimester abortion or miscarriage, ORTHO-CYCLEN or ORTHO TRICYCLEN may be started immediately. An additional method of contraception is not needed if ORTHO-CYCLEN or ORTHO TRI-CYCLEN is started immediately.
• If ORTHO-CYCLEN or ORTHO TRI-CYCLEN is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

Second-trimester

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start ORTHO-CYCLEN or ORTHO TRICYCLEN, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient"s first cycle pack of ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

Starting ORTHO-CYCLEN or ORTHO TRI-CYCLEN after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with ORTHO-CYCLEN or ORTHO TRI-CYCLEN following the instructions in Table 1 for women not currently using hormonal contraception.
• ORTHO-CYCLEN or ORTHO TRI-CYCLEN are not recommended for use in lactating women .
• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of ORTHO-CYCLEN or ORTHO TRI-CYCLEN. .

DIALPAK® Tablet Dispenser: SET THE DAY:

Day 1 Start: turn the dial on the empty DIALPAK until the arrow points to the first day of the patient"s period.

Sunday Start: the arrow on the empty DIALPAK should point to SU (Sunday).

Insert the new refill by lining up the “V” shape on the refill with the “V” shape at the top of the DIALPAK. Snap the refill in place. Pill “1” is ready to be taken. Always begin the pill cycle with pill “1,” as shown on the inner part of the refill ring.

Remove pill “1” by pushing down on the pill. The pill will come out through a hole in the back of the DIALPAK.

The patient should wait 24 hours to take the next pill. To take pill “2,” turn the dial on the DIALPAK in a clockwise direction to the next day. Continue to take one pill each day until all the pills have been taken.

Turn the dial to the pill “1” position to remove the empty refill and insert a new refill. The first pill in every refill will always be taken on the same day of the week, no matter when the patient"s next period starts.

VERIDATE® Tablet Dispenser

• Place the refill in the VERIDATE Tablet Dispenser so that the V notch in the refill is at the top of the dispenser. Press the refill down so that it fits firmly under all the nibs .
• If the patient starts pill-taking on Sunday, the first active pill should be taken on the first Sunday after the patient"s menstrual period begins. Remove the first active pill at the top of the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser.

ORTHO-CYCLEN:

• If the patient will start pill-taking on “Day 1,” choose a blue pill that corresponds with the day of the week the patient will take the first pill. Remove that blue pill by pressing the pill through the hole in the bottom of the dispenser.

ORTHO TRI-CYCLEN:

• If the patient will start pill-taking on a day other than Sunday, a calendar label has been provided and should be placed over the calendar in the center of the VERIDATE. To place the label correctly, identify the correct starting day, locate that day printed in blue on the label, and line that day up with the first white pill directly under the V notch at the top of the dispenser. Remove the label from the backing. Press the center of the label down onto the center of the printed calendar. Remove that white pill by pressing the pill through the hole in the bottom of the dispenser.
• After all the dark green pills have been taken, insert a new refill into the VERIDATE. The patient should take the first pill on the next day, even if the patient"s period is not over yet.

To Insert New Refill (ORTHO-CYCLEN or ORTHO TRI-CYCLEN):

• Lift the empty refill out of the VERIDATE Tablet Dispenser.
• Insert the new refill so that the V notch in the refill is at the top of the dispenser. Press the refill down so that it fits firmly under the nibs.

Missed Tablets

Table 2: Instructions for Missed ORTHO-CYCLEN or ORTHO TRI-CYCLEN Tablets

Advice In Case Of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet .

ORTHO-TRICYCLEN Use For Acne

The timing of initiation of dosing with ORTHO TRI-CYCLEN for acne should follow the guidelines for use of ORTHO TRI-CYCLEN as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section (2.1) for instructions.

Do not prescribe ORTHO-CYCLEN or ORTHO TRI-CYCLEN to women who are known to have the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
  • Smoke, if over age 35
  • Have deep vein thrombosis or pulmonary embolism, now or in the past
  • Have inherited or acquired hypercoagulopathies
  • Have cerebrovascular disease
  • Have coronary artery disease
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
  • Have uncontrolled hypertension
  • Have diabetes mellitus with vascular disease
  • Have headaches with focal neurological symptoms or migraine headaches with aura
    • Women over age 35 with any migraine headaches
• Liver tumors, benign or malignant, or liver disease
• Undiagnosed abnormal uterine bleeding
• Pregnancy, because there is no reason to use COCs during pregnancy
• Breast cancer or other estrogen-or progestin-sensitive cancer, now or in the past

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 .
• 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 . 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 . 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.

High Blood Pressure

ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease . 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 TRICYCLEN. 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 .

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 . 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.

Patient Counseling Information

Counsel patients about the following information:

• Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs .
• Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC .
• ORTHO-CYCLEN and ORTHO TRI-CYCLEN do not protect against HIV infection (AIDS) and other sexually transmitted infections.
• ORTHO-CYCLEN and ORTHO TRI-CYCLEN are not to be used during pregnancy; if pregnancy occurs during use of ORTHO-CYCLEN or ORTHO TRI-CYCLEN instruct the patient to stop further use .
• Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed .
• Use a back-up or alternative method of contraception when enzyme inducers are used with ORTHO-CYCLEN or ORTHO TRI-CYCLEN .
• COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established ).
• Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken an active tablet for 7 consecutive days .
• Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Use In Specific Populations

Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

Nursing Mothers

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

Pediatric Use

Safety and efficacy of ORTHO-CYCLEN Tablets and ORTHO TRI-CYCLEN Tablets have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

There was no significant difference between ORTHO TRI-CYCLEN Tablets and placebo in mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population.

Geriatric Use

ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in postmenopausal women and are not indicated in this population.

Hepatic Impairment

The pharmacokinetics of ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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.

Renal Impairment

The pharmacokinetics of ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in women with renal impairment.

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

No drug-drug interaction studies were conducted with ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

Effects Of Other Drugs On Combined Oral Contraceptives

Substances Decreasing The Plasma Concentrations Of COCs

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John"s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.

Substances Increasing The Plasma Concentrations Of COCs

Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors And Non-Nucleoside Reverse Transcriptase Inhibitors

Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir) or increase (e.g., indinavir and atazanavir/ritonavir))/HCV protease inhibitors (decrease (e.g., boceprevir and telaprevir)) or with non-nucleoside reverse transcriptase inhibitors (decrease (e.g., nevirapine) or increase (e.g., etravirine)).

Effects Of Combined Oral Contraceptives On Other Drugs

• COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations.
• COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs.

Interference With Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

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

• Serious cardiovascular events and stroke
• Vascular events
• Liver disease

Adverse reactions commonly reported by COC users are:

• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

ORTHO-CYCLEN

The safety of ORTHO-CYCLEN was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of ORTHO-CYCLEN for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.

Common Adverse Reactions ( ≥ 2% of subjects)

The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

Adverse Reactions Leading to Study Discontinuation

Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions ( ≥ 1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).

Serious Adverse Reactions

breast cancer (1 subject), mood disorders including depression, irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis (DVT) (1 subject).

ORTHO TRI-CYCLEN

The safety of ORTHO TRI-CYCLEN was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of ORTHO TRI-CYCLEN for contraception. Two trials were randomized active-controlled trials and 4 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles; in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial, subjects were followed for up to 6 cycles.

Common Adverse Reactions ( ≥ 2% of subjects)

The most common adverse reactions reported by at least 2% of the 4,826 women were the following in order of decreasing incidence: headache/migraine (33.6%), breast issues (including breast pain, enlargement, and discharge) (8.0%), vaginal infection (7.1%), abdominal/gastrointestinal pain (5.6%), mood disorders (including mood alteration and depression) (3.8%), genital discharge (3.2%), and changes in weight (including weight fluctuation, increased or decreased) (2.5%).

Adverse Reactions Leading to Study Discontinuation

Over the trials, between 9 to 27% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions ( ≥ 1%) leading to discontinuation were: metrorrhagia (4.3%), nausea/vomiting (2.8%), headache/migraine (2.4%), mood disorders (including depression and mood altered) (1.1%), and weight increased (1.1%).

Serious Adverse Reactions

breast cancer (1 subject), carcinoma of the cervix in situ (1 subject), hypertension (1 subject), and migraine (2 subjects).

Postmarketing Experience

The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations: Urinary tract infection;

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst;

Immune System Disorders: Hypersensitivity;

Metabolism and Nutrition Disorders: Dyslipidemia;

Psychiatric Disorders: Anxiety, insomnia;

Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness;

Eye Disorders: Visual impairment, dry eye, contact lens intolerance;

Ear and Labyrinth Disorders: Vertigo;

Cardiac Disorders: Tachycardia, palpitations;

Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush;

Arterial Events: Arterial thromboembolism, myocardial infarction, cerebrovascular accident;

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea;

Gastrointestinal Disorders: Pancreatitis, abdominal distension, diarrhea, constipation;

Hepatobiliary Disorders: Hepatitis;

Skin and Subcutaneous Tissue Disorders: Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne;

Musculoskeletal, Connective Tissue, and Bone Disorders: Muscle spasms, pain in extremity, myalgia, back pain;

Reproductive System and Breast Disorders: Ovarian cyst, suppressed lactation, vulvovaginal dryness;

General Disorders and Administration Site Conditions: Chest pain, asthenic conditions.

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

Mechanism Of Action

• Oral Contraception
  COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.
• Acne
  Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone-binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with ORTHO-CYCLEN or ORTHO TRICYCLEN.

Pharmacokinetics

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).

Table 3: Summary of NGMN, NG and EE pharmacokinetic parameters.

Food Effect

The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has not been studied.

Distribution

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

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM"s primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of ¹⁴C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.

Clinical Studies

Contraception

In three US clinical trials with ORTHO-CYCLEN, 1,651 women aged 18 to 38 years were studied for up to 24 cycles, proving a total of 24,272 cycles of exposure. The racial demographic was about 73-86% Caucasian, 8-13% African-American, 6-14% Hispanic with the remainder Asian or Other ( ≤ 1%). There were no exclusions on the basis of weight; the weight range for women treated was 82-303 lbs, with a mean weight of about 135 lbs. The pregnancy rate was approximately 1 pregnancy per 100 women-years.

In four clinical trials with ORTHO TRI-CYCLEN, 4,756 women aged 15 to 41 years were studied for 24 cycles, providing a total of 45,244 cycles of exposure. The racial demographic was about 87-90% Caucasian, 6-10% African-American, with the remainder Asian ( ≤ 1%) or Other (2-5%). There were no exclusions on the basis of weight; the weight range for women treated was 80-310 lbs, with a mean weight of about 132 lbs. The pregnancy rate was approximately 1 pregnancy per 100 women-years.

Acne

ORTHO TRI-CYCLEN was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, six-(28 day) cycle studies. Two hundred twenty-one patients received ORTHO TRI-CYCLEN and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changed from 55 to 31 (42% reduction) in patients treated with ORTHO TRI-CYCLEN and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table 4 summarizes the changes in lesion count for each type of lesion. Based on the investigator"s global assessment conducted at the final visit, patients treated with ORTHO TRI-CYCLEN showed a statistically significant improvement in total lesions compared to those treated with placebo.

Table 4: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials. Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat Population.

Dosage Forms And Strengths

ORTHO-CYCLEN

ORTHO-CYCLEN Tablets are available in blister cards. Each blister card contains 28 tablets in the following order:

• 21 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one side and “P” on the other side contains inert ingredients

ORTHO TRI-CYCLEN

ORTHO TRI-CYCLEN Tablets are available in blister cards. Each blister card contains 28 tablets in the following order:

• 7 white, round, biconvex, coated tablet imprinted “O 180” on one side and “35” on the other side of the tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 light blue, round, biconvex, coated tablet imprinted “O 215” on one side and “35” on the other side of the tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one side and “P” on the other side contains inert ingredients

Storage And Handling

ORTHO-CYCLEN

ORTHO-CYCLEN Tablets are available in a blister card with a DIALPAK Tablet Dispenser (unfilled): (NDC 50458-197-00)

Each blister card (28 tablets) contains in the following order:

• 21 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one side and “P” on the other side contains inert ingredients

ORTHO-CYCLEN Tablets are packaged in a carton (NDC 50458-197-15) containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers.

ORTHO-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 50458-197-20).

ORTHO TRI-CYCLEN

ORTHO TRI-CYCLEN Tablets are available in a blister card with a DIALPAK Tablet Dispenser (unfilled): (NDC 50458-191-00)

Each blister card (28 tablets) contains in the following order:

• 7 white, round, biconvex, coated tablet imprinted “O 180” on one side and “35” on the other side of the tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 light blue, round, biconvex, coated tablet imprinted “O 215” on one side and “35” on the other side of the tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one side and “P” on the other side contains inert ingredients

ORTHO TRI-CYCLEN Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK Tablet dispensers: (NDC 50458-191-15)

ORTHO TRI-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 50458-191-20).

Keep out of reach of children.

Storage Conditions

• Store at 20-25°C (68-77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Protect from light.

Mfd. by: Janssen Ortho, LLC, Manati, Puerto Rico 00674, Mfd. for: Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560. Revised April 2015