ORTHO TRI CYCLEN- norgestimate and ethinyl estradiol 
ORTHO CYCLEN- norgestimate and ethinyl estradiol 
Janssen Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ORTHO-CYCLEN or ORTHO TRI-CYCLEN safely and effectively. See full prescribing information for ORTHO-CYCLEN and ORTHO TRI-CYCLEN.

ORTHO-CYCLEN ® and ORTHO TRI-CYCLEN ® (norgestimate/ethinyl estradiol) tablets, for oral use
Initial U.S. Approval: 1989

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

See full prescribing information for complete boxed warning.

  • ORTHO-CYCLEN or ORTHO TRI-CYCLEN is contraindicated in women over 35 years old who smoke. (4)
  • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. (4)

RECENT MAJOR CHANGES

Contraindications (4) 08/2017
Warnings and Precautions (5.3) 08/2017

INDICATIONS AND USAGE

ORTHO-CYCLEN and ORTHO TRI-CYCLEN are estrogen/progestin COCs, indicated for use by women to prevent pregnancy. (1.1)

ORTHO TRI-CYCLEN is also 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. (1.2)

DOSAGE AND ADMINISTRATION

  • Take one tablet daily by mouth at the same time every day. (2.2)
  • Take tablets in the order directed on the blister pack. (2.2)
  • Do not skip or delay tablet intake. (2.2)

DOSAGE FORMS AND STRENGTHS

ORTHO-CYCLEN consists of 28 round, biconvex, coated tablets in the following order (3):

  • 21 blue tablets each containing 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
  • 7 dark green tablets (inert)

ORTHO TRI-CYCLEN consists of 28 round, biconvex, coated tablets in the following order (3):

  • 7 white tablets each containing 0.180 mg norgestimate and 0.035 mg ethinyl estradiol
  • 7 light blue tablets each containing 0.215 mg norgestimate and 0.035 mg ethinyl estradiol
  • 7 blue tablets each containing 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
  • 7 dark green tablets (inert)

CONTRAINDICATIONS

  • A high risk of arterial or venous thrombotic diseases (4)
  • Liver tumors or liver disease (4)
  • Undiagnosed abnormal uterine bleeding (4)
  • Pregnancy (4)
  • Breast cancer or other estrogen- or progestin-sensitive cancer (4)
  • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)

WARNINGS AND PRECAUTIONS

  • Thromboembolic Disorders and Other Vascular Problems: Stop ORTHO-CYCLEN or ORTHO TRI-CYCLEN if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1)
  • Liver disease: Discontinue ORTHO-CYCLEN or ORTHO TRI-CYCLEN if jaundice occurs. (5.2)
  • High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop ORTHO-CYCLEN or ORTHO TRI-CYCLEN if blood pressure rises significantly. (5.4)
  • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.6)
  • Headache: Evaluate significant change in headaches and discontinue ORTHO-CYCLEN or ORTHO TRI-CYCLEN if indicated. (5.7)
  • Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. (5.8)

ADVERSE REACTIONS

The most common adverse reactions reported during clinical trials (≥2%) were:

ORTHO-CYCLEN: headache/migraine, abdominal/gastrointestinal pain, vaginal infection, genital discharge, breast issues (including breast pain, discharge, and enlargement), mood disorders (including depression and mood altered), flatulence, nervousness, rash. (6.1)

ORTHO TRI-CYCLEN: headache/migraine, breast issues (including breast pain, enlargement, and discharge), vaginal infection, abdominal/gastrointestinal pain, mood disorders (including mood alteration and depression), genital discharge, changes in weight (including weight increased or decreased). (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceutical, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Drugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. (7.1)

USE IN SPECIFIC POPULATIONS

Nursing mothers: Not recommended; can decrease milk production. (8.3)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

1 INDICATIONS AND USAGE

1.1 Oral Contraceptive

1.2 Acne

2 DOSAGE AND ADMINISTRATION

2.1 How to Start ORTHO-CYCLEN or ORTHO TRI-CYCLEN

2.2 How to Take ORTHO-CYCLEN or ORTHO TRI-CYCLEN

2.3 Missed Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

2.5 ORTHO-TRICYCLEN Use for Acne

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Problems

5.2 Liver Disease

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

5.4 High Blood Pressure

5.5 Gallbladder Disease

5.6 Carbohydrate and Lipid Metabolic Effects

5.7 Headache

5.8 Bleeding Irregularities and Amenorrhea

5.9 COC Use Before or During Early Pregnancy

5.10 Depression

5.11 Carcinoma of Breast and Cervix

5.12 Effect on Binding Globulins

5.13 Monitoring

5.14 Hereditary Angioedema

5.15 Chloasma

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Combined Oral Contraceptives

7.2 Effects of Combined Oral Contraceptives on Other Drugs

7.3 Interference with Laboratory Tests

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Contraception

14.2 Acne

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage Conditions

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4)].

1 INDICATIONS AND USAGE

1.1 Oral Contraceptive

ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14)].

1.2 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 [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 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 [see How Supplied/Storage and Handling (16)]. ORTHO-CYCLEN and ORTHO TRI-CYCLEN may be started using either a Day 1 start or a Sunday start (see Table 1). 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.

2.2 How to Take ORTHO-CYCLEN or ORTHO TRI-CYCLEN

Table 1: Instructions for Administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN
Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling.

Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start)


Important:
Consider the possibility of ovulation and conception prior to initiation of this product.


Tablet Color:
  • ORTHO-CYCLEN active tablets are blue (Day 1 to Day 21).
  • ORTHO TRI-CYCLEN active tablets are white (Day 1 to Day 7), light blue (Day 8 to Day 14) and blue (Day 15 to Day 21).
  • ORTHO-CYCLEN and ORTHO TRI-CYCLEN both have dark green inactive tablets (Day 22 to Day 28).
Day 1 Start:
  • Take first active tablet without regard to meals on the first day of menses.
  • Take subsequent active tablets once daily at the same time each day for a total of 21 days.
  • Take one dark green inactive tablet daily for 7 days and at the same time of day that active tablets were taken.
  • Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet)
Sunday Start:
  • Take first active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, 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.
  • Take subsequent active tablets once daily at the same time each day for a total of 21 days.
  • Take one dark green inactive tablet daily for the following 7 days and at the same time of day that active tablets were taken.
  • Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed.
Switching to ORTHO-CYCLEN or ORTHO TRI-CYCLEN from another oral contraceptive Start on the same day that a new pack of the previous oral contraceptive would have started.
Switching from another contraceptive method to ORTHO-CYCLEN or ORTHO TRI-CYCLEN Start ORTHO-CYCLEN or ORTHO TRI-CYCLEN:
  • Transdermal patch
  • On the day when next application would have been scheduled
  • Vaginal ring
  • On the day when next insertion would have been scheduled
  • Injection
  • On the day when next injection would have been scheduled
  • Intrauterine contraceptive
  • On the day of removal
  • If the IUD is not removed on first day of the patient's menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack.
  • Implant
  • On the day of removal

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

First-trimester

  • After a first-trimester abortion or miscarriage, ORTHO-CYCLEN or ORTHO TRI-CYCLEN 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 TRI-CYCLEN, 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. [see Contraindications (4), Warnings and Precautions (5.1), and FDA-Approved Patient Labeling.]

Starting ORTHO-CYCLEN or ORTHO TRI-CYCLEN after Childbirth

DIALPAK® Tablet Dispenser:

Figure 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).
Figure 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.
Figure Remove pill "1" by pushing down on the pill. The pill will come out through a hole in the back of the DIALPAK.
Figure 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.
Figure 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 (see illustration below).
  • 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.
Figure

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.

2.3 Missed Tablets

Table 2: Instructions for Missed ORTHO-CYCLEN or ORTHO TRI-CYCLEN Tablets
  • If one active tablet is missed in Weeks 1, 2, or 3
Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished.
  • If two active tablets are missed in Week 1 or Week 2
Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.
  • If two active tablets are missed in the third week or three or more active tablets are missed in a row in Weeks 1, 2, or 3
Day 1 start: Throw out the rest of the pack and start a new pack that same day.
Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.

2.4 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 [see FDA-Approved Patient Labeling].

2.5 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.

3 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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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.

5.3 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.

5.4 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.

5.5 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.

5.6 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.

5.7 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).

5.8 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.

5.9 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)].

5.10 Depression

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

5.11 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.

5.12 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.

5.13 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.

5.14 Hereditary Angioedema

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

5.15 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.

6 ADVERSE REACTIONS

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

Adverse reactions commonly reported by COC users are:

6.1 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).

6.2 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, venous thrombosis (including Budd Chiari Syndrome and hepatic vein thrombosis);

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.

7 DRUG INTERACTIONS

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.

7.1 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]).

7.2 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.

7.3 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.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer ORTHO-CYCLEN or ORTHO TRI-CYCLEN with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 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.

8.4 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 post-pubertal 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.

8.5 Geriatric Use

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

8.6 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. [See Contraindications (4) and Warnings and Precautions (5.2).]

8.7 Renal Impairment

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

10 OVERDOSAGE

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.

11 DESCRIPTION

Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)-(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol).

ORTHO-CYCLEN

  • Each active blue tablet contains 0.250 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.
  • Each dark green placebo tablet containing only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.

ORTHO TRI-CYCLEN

  • Each active white tablet contains 0.180 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water, and titanium dioxide.
  • Each active light blue tablet contains 0.215 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water, and titanium dioxide.
  • Each active blue tablet contains 0.250 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.
  • Each dark green placebo tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.

Chemical Structure 1

Chemical Structure 2

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

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

12.3 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.
Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0–24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated.
NGMN and NG: Cmax = ng/mL, AUC0–24h = h∙ng/mL
EE: Cmax = pg/mL, AUC0–24h = h∙pg/mL
Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0–24h t1/2 (h)
NGMN 3 7 1.80 (0.46) 1.42 (0.73) 15.0 (3.88) NC
14 2.12 (0.56) 1.21 (0.26) 16.1 (4.97) NC
21 2.66 (0.47) 1.29 (0.26) 21.4 (3.46) 22.3 (6.54)
NG 3 7 1.94 (0.82) 3.15 (4.05) 34.8 (16.5) NC
14 3.00 (1.04) 2.21 (2.03) 55.2 (23.5) NC
21 3.66 (1.15) 2.58 (2.97) 69.3 (23.8) 40.2 (15.4)
EE 3 7 124 (39.5) 1.27 (0.26) 1130 (420) NC
14 128 (38.4) 1.32 (0.25) 1130 (324) NC
21 126 (34.7) 1.31 (0.56) 1090 (359) 15.9 (4.39)
Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0–24h t1/2 (h)
NGMN 1 1 1.78 (0.397) 1.19 (0.250) 9.90 (3.25) 18.4 (5.91)
3 21 2.19 (0.655) 1.43 (0.680) 18.1 (5.53) 24.9 (9.04)
NG 1 1 0.649 (0.49) 1.42 (0.69) 6.22 (2.46) 37.8 (14.0)
3 21 2.65 (1.11) 1.67 (1.32) 48.2 (20.5) 45.0 (20.4)
EE 1 1 92.2 (24.5) 1.2 (0.26) 629 (138) 10.1 (1.90)
3 21 147 (41.5) 1.13 (0.23) 1210 (294) 15.0 (2.36)

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-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1).]

14 CLINICAL STUDIES

14.1 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.

14.2 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.
ORTHO TRI-CYCLEN
(N=221)
Placebo
(N=234)
Difference in Counts between ORTHO TRI-CYCLEN and Placebo at 6 Months
# of Lesions Counts % Reduction Counts % Reduction
*
LOCF: Last Observation Carried Forward
INFLAMMATORY LESIONS
  Baseline Mean 19 19
  Sixth Month Mean 10 48% 13 30% 3 (95% CI: -1.2, 5.1)
NON-INFLAMMATORY LESIONS
  Baseline Mean 36 35
  Sixth Month Mean 22 34% 25 21% 3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
  Baseline Mean 55 54 7 (95% CI: 2.0, 11.9)
  Sixth Month Mean 31 42% 38 27%

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

ORTHO-CYCLEN

ORTHO-CYCLEN Tablets are available in a single pouch containing a VERIDATE blister card (refill) of 28 tablets (NDC 50458-197-28). ORTHO-CYCLEN Tablets are packaged in a carton containing 6 pouches and 6 unfilled VERIDATE Tablet Dispensers (NDC 50458-197-06).

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 also available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 50458-197-20 and NDC 50458-197-12).

ORTHO-CYCLEN Tablets are available in a DIALPAK Tablet Dispenser (unfilled) and DIALPAK refills (NDC 50458-197-00 and NDC 50458-197-15).

ORTHO TRI-CYCLEN

ORTHO TRI-CYCLEN Tablets are available in a single pouch containing a VERIDATE blister card (refill) of 28 tablets (NDC 50458-191-28.) ORTHO TRI-CYCLEN Tablets are packaged in a carton containing 6 pouches and 6 unfilled VERIDATE Tablet dispensers (NDC 50458-191-06).

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 also available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 50458-191-20 and NDC 50458-191-12).

ORTHO TRI-CYCLEN Tablets are available in a DIALPAK Tablet Dispenser (unfilled) and DIALPAK refills (NDC 50458-191-00 and NDC 50458-191-15).

16.2 Storage Conditions

  • Store at 20–25°C (68–77°F); excursions permitted to 15° to 30°C (59° to 86°F).
  • Protect from light.
  • Keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

Counsel patients about the following information:

Mfd. by:
Janssen Ortho LLC
Manati, Puerto Rico 00674

Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560

© 1998 Janssen Pharmaceutical Companies

Patient Information
ORTHO-CYCLEN [OR-tho sī-klin]
ORTHO TRI-CYCLEN [OR-tho trī-sī-klin]
(norgestimate and ethinyl estradiol)
Tablets

What is the most important information I should know about ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Do not use ORTHO-CYCLEN or ORTHO TRI-CYCLEN if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

What is ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

ORTHO-CYCLEN or ORTHO TRI-CYCLEN is a birth control pill (oral contraceptive) used by women to prevent pregnancy.

ORTHO TRI-CYCLEN is also used to treat moderate acne vulgaris in females 15 years of age and older, who have no known history of allergies or problems taking birth control pills, and have started their menstrual cycle ("period"). ORTHO TRI-CYCLEN should only be used to treat acne in women who want to take birth control pills to prevent pregnancy.

How does ORTHO-CYCLEN or ORTHO TRI-CYCLEN work for contraception?

Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.

Based on the results of clinical studies, about 1 out of 100 women may get pregnant during the first year they use ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.

Figure

Who should not take ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Do not take ORTHO-CYCLEN or ORTHO TRI-CYCLEN if you:

If any of these conditions happen while you are taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN, stop taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

What should I tell my healthcare provider before taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Tell your healthcare provider if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

ORTHO-CYCLEN or ORTHO TRI-CYCLEN may affect the way other medicines work, and other medicines may affect how well ORTHO-CYCLEN or ORTHO TRI-CYCLEN works.

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

How should I take ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Read the Instructions for Use at the end of this Patient Information.

What are the possible serious side effects of ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:

Call your healthcare provider or go to a hospital emergency room right away if you have:

  • leg pain that will not go away
  • sudden severe shortness of breath
  • sudden change in vision or blindness
  • chest pain
  • a sudden, severe headache unlike your usual headaches
  • weakness or numbness in your arm or leg
  • trouble speaking

Other serious side effects include:

What are the most common side effects of ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

These are not all the possible side effects of ORTHO-CYCLEN or ORTHO TRI-CYCLEN. For more information, ask your healthcare provider or pharmacist.

You may report side effects to the FDA at 1-800-FDA-1088.

What else should I know about taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

How should I store ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

General information about the safe and effective use of ORTHO-CYCLEN or ORTHO TRI-CYCLEN.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORTHO-CYCLEN or ORTHO TRI-CYCLEN for a condition for which it was not prescribed. Do not give ORTHO-CYCLEN or ORTHO TRI-CYCLEN to other people, even if they have the same symptoms that you have.

This Patient Information summarizes the most important information about ORTHO-CYCLEN or ORTHO TRI-CYCLEN. You can ask your pharmacist or healthcare provider for information about ORTHO-CYCLEN or ORTHO TRI-CYCLEN that is written for health professionals.

For more information, call 1-800-JANSSEN (1-800-526-7736).

Do birth control pills cause cancer?

Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones.

Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.

What if I want to become pregnant?

You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.

What should I know about my period when taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

Your periods may be lighter and shorter than usual. Some women may miss a period. Irregular vaginal bleeding or spotting may happen while you are taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN, especially during the first few months of use. This usually is not a serious problem. It is important to continue taking your pills on a regular schedule to prevent a pregnancy.

What are the ingredients in ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

ORTHO-CYCLEN:

Active ingredients: Each blue pill contains norgestimate and ethinyl estradiol.

Inactive ingredients:

Blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.

Dark-green pills: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.

ORTHO TRI-CYCLEN:

Active ingredients: Each white, light-blue, and blue pill contains norgestimate and ethinyl estradiol.

Inactive ingredients:

White pills: carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water, and titanium dioxide.

Light-blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water, and titanium dioxide.

Blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.

Dark-green pills: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.

Instructions For Use
ORTHO-CYCLEN [OR-tho sī-klin]
ORTHO TRI-CYCLEN [OR-tho trī-sī-klin]
(norgestimate and ethinyl estradiol)
Tablets

Important Information about taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN

Before you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN:

When should I start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?

If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you have not used a hormonal birth control method before:

If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you are switching from another birth control pill:

If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and previously used a vaginal ring or transdermal patch:

If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you are switching from a progestin-only method such as an implant or injection:

If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you are switching from an intrauterine device or system (IUD or IUS):

Keep a calendar to track your period:
If this is the first time
you are taking birth control pills, read, "When should I start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?" above. Follow these instructions for either a Sunday Start or a Day 1 Start.

Sunday Start:
You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday.

Day 1 Start:
You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period.

ORTHO-CYCLEN or ORTHO TRI-CYCLEN comes in either a DIALPAK pill dispenser or a VERIDATE pill dispenser. Read the instructions below for using your DIALPAK pill dispenser or your VERIDATE pill dispenser.

Instructions for using your DIALPAK pill dispenser:

ORTHO-CYCLENFigure
  • Each DIALPAK pill dispenser has 28 pills.
    • ORTHO-CYCLEN
      • 21 blue pills with hormones, for Days 1 to 21.
      • 7 dark green pills (without hormones), for Days 22 to 28.
ORTHO TRI-CYCLENFigure
 
  • ORTHO TRI-CYCLEN
    • 7 white pills with hormone, for Days 1 to 7
    • 7 light-blue pills with hormone, for Days 8 to 14
    • 7 blue pills with hormones, for Days 15 to 21
    • 7 dark green pills (without hormones), for Days 22 to 28.
Figure AFigure A Step 1. SET THE DAY on your DIALPAK
Sunday Start:
The arrow on your empty DIALPAK should point to SU (Sunday).
Day 1 Start: Turn the dial on your empty DIALPAK in a clockwise direction until the arrow points to the first day of your period (if your period starts on Tuesday, the arrow will point to TU). See Figure A.
Figure BFigure B Step 2. Insert the new refill by lining up the "V" shape on the refill with the "V" shape at the top of your DIALPAK.
Press the refill down so that it fits firmly. See Figure B. Snap the refill in place. You are ready to take pill "1". You should always begin your pill cycle with pill "1", as shown on the inner part of the refill ring.
Figure CFigure C Step 3. Remove pill "1" by pushing down on the pill. The pill will come out through a hole in the back of the DIALPAK. See Figure C.
Step 4. Swallow the pill. You will take 1 pill every day, at the same time each day.
Figure DFigure D Step 5. Wait 24 hours to take your next pill.
To take pill "2," turn the dial on your DIALPAK in a clockwise direction to the next day. See Figure D. Continue to take 1 pill each day until all the pills have been taken.
Step 6. Take your pill at the same time every day. It is important to take the correct pill each day and not miss any pills.

To help you remember, take your pill at the same time as another daily activity, like turning off your alarm clock or brushing your teeth.

Figure EFigure E Step 7. Remove your empty pack. See Figure E. You will start a new refill on the first day after pill "28". Turn the dial to the pill "1" position to remove the empty refill pack. When your refill is empty, keep your DIALPAK case.
Figure FFigure F Step 8. Insert a new refill pack. See Figure F. Insert a new refill pack. Remember to take your first pill in every refill on the same day of the week, no matter when your next period starts.

Instructions for using your VERIDATE pill dispenser:

 
ORTHO-CYCLEN
  • 21 blue pills with hormones, for Days 1 to 21
  • 7 dark green pills (without hormones), for Days 22 to 28
 
ORTHO TRI-CYCLEN
  • 7 white pills with hormone, for Days 1 to 7
  • 7 light-blue pills with hormone, for Days 8 to 14
  • 7 blue pills with hormones, for Days 15 to 21
  • 7 dark green pills (without hormones), for Days 22 to 28
Figure A

Figure A

Figure BFigure B Step 1. Place the refill in the VERIDATE Pill 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. See Figure B.
Figure CFigure C Step 2. Starting your pills.
Sunday Start:
Remove the first pill at the top of the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser. See Figure C.
  • If your healthcare provider tells you to start taking your pill on Sunday, take your first pill on the first Sunday after your period begins.
  • If your period begins on Sunday, take your first pill that day.
Figure DFigure D Day 1 Start:
If you take ORTHO-CYCLEN:
  • If your healthcare provider tells you to start taking your pill on "Day 1," choose a blue pill that corresponds with the day of the week on which you are taking the first pill.
  • Remove that blue pill by pressing the pill through the hole in the bottom of the dispenser. See Figure D.
Figure EFigure E
Figure FFigure F
If you take ORTHO TRI-CYCLEN:
  • If your healthcare provider tells you to start taking your pill on a day other than Sunday, you will need the calendar label found in your pill package and place it over the calendar in the center of the VERIDATE. See Figure E.
  • To correctly place the calendar label on the VERIDATE:
    • find your correct starting day
    • find that day printed in blue on the label
    • line your blue starting day up with the first white pill which is 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. See Figure F.
Figure GFigure G Step 3. Continue taking 1 pill every day from the VERIDATE in a clockwise direction until no pills remain in the outer ring. See Figure G.
Figure HFigure H Step 4. The next day take a dark green pill from the inner ring. See Figure H.
  • Continue to take a dark green pill each day until all 7 pills are taken.
  • During this time your period should begin.
Figure IFigure I Step 5. Insert a new refill:
  • After you have taken all the dark green pills, insert a new refill into the VERIDATE and take the first pill on the next day, even if your period is not yet over.
  • Lift the empty refill out of the VERIDATE Pill Dispenser. See Figure I.
  • Follow the instructions in Step 1 to replace the new refill.

What should I do if I miss any ORTHO-CYCLEN or ORTHO TRI-CYCLEN pills?

If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:

If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:

 
  • Take the 2 missed pills as soon as possible and the next 2 pills the next day.
  • Then continue to take 1 pill every day until you finish the pack.
  • Use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after missing your pills.

If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row during Weeks 1, 2, or 3 of the pack, follow these steps:

If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

Mfd. by:

Janssen Ortho LLC

Manati, Puerto Rico 00674

Mfd. for:

Janssen Pharmaceuticals, Inc.

Titusville, New Jersey 08560

© 1998 Janssen Pharmaceutical Companies

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised August 2017

PRINCIPAL DISPLAY PANEL - ORTHO TRI-CYCLEN Kit Carton

28
day

NDC 50458-191-15

ORTHO
TRI~CYCLEN
®
(norgestimate/ethinyl estradiol)

Each white tablet contains 0.180 mg
norgestimate and 0.035 mg ethinyl
estradiol. Each light blue tablet contains
0.215 mg norgestimate and 0.035 mg
ethinyl estradiol. Each blue tablet
contains 0.250 mg norgestimate and
0.035 mg ethinyl estradiol. Each green
tablet contains inert ingredients.

Rx only.

Store at 25°C (77°F); excursions permitted to
15°-30°C (59°-86°F).
Keep out of reach of children. Protect from light.

Contains: 6 Dialpak®
Tablet Dispensers
and 6 Refills

janssen

Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674

Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560

© Janssen 1998

PRINCIPAL DISPLAY PANEL - ORTHO TRI-CYCLEN Kit Carton

PRINCIPAL DISPLAY PANEL - ORTHO-CYCLEN Kit Carton

28
day

NDC 50458-197-15

ORTHO~
CYCLEN
®
(norgestimate/ethinyl estradiol)

Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl
estradiol. Each green tablet contains inert ingredients.

Rx only.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
Keep out of the reach of children. Protect from light.

janssen

Contains: 6 Dialpak®
Tablet Dispensers
and 6 Refills

Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674

Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560

© Janssen 1998

PRINCIPAL DISPLAY PANEL - ORTHO-CYCLEN Kit Carton
ORTHO TRI CYCLEN 
norgestimate and ethinyl estradiol kit
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50458-191
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:50458-191-15 6 in 1 CARTON 12/29/1989 02/28/2019
1 NDC:50458-191-00 1 in 1 BLISTER PACK; Type 0: Not a Combination Product
2 NDC:50458-191-20 48 in 1 CARTON 12/29/1989 03/31/2018
2 1 in 1 DIALPACK; Type 0: Not a Combination Product
3 NDC:50458-191-12 12 in 1 CARTON 12/29/1989 01/31/2019
3 1 in 1 DIALPACK; Type 0: Not a Combination Product
4 NDC:50458-191-06 6 in 1 CARTON 12/29/1989 02/28/2020
4 NDC:50458-191-28 28 in 1 BLISTER PACK
4 1 in 1 DIALPACK; Type 0: Not a Combination Product
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1
Part 2
Part 3
Part 4
Part 1 of 4
ORTHO TRI CYCLEN 
norgestimate and ethinyl estradiol tablet, coated
Product Information
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
norgestimate (UNII: C291HFX4DY) (norgestimate - UNII:C291HFX4DY) norgestimate 0.180 mg
ethinyl estradiol (UNII: 423D2T571U) (ethinyl estradiol - UNII:423D2T571U) ethinyl estradiol 0.035 mg
Inactive Ingredients
Ingredient Name Strength
Carnauba Wax (UNII: R12CBM0EIZ)  
Croscarmellose Sodium (UNII: M28OL1HH48)  
Hypromellose, Unspecified (UNII: 3NXW29V3WO)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Microcrystalline Cellulose (UNII: OP1R32D61U)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color WHITE Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;180;35
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019697 12/29/1989
Part 2 of 4
ORTHO TRI CYCLEN 
norgestimate and ethinyl estradiol tablet, coated
Product Information
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
norgestimate (UNII: C291HFX4DY) (norgestimate - UNII:C291HFX4DY) norgestimate 0.215 mg
ethinyl estradiol (UNII: 423D2T571U) (ethinyl estradiol - UNII:423D2T571U) ethinyl estradiol 0.035 mg
Inactive Ingredients
Ingredient Name Strength
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Aluminum Oxide (UNII: LMI26O6933)  
Carnauba Wax (UNII: R12CBM0EIZ)  
Croscarmellose Sodium (UNII: M28OL1HH48)  
Hypromellose, Unspecified (UNII: 3NXW29V3WO)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Microcrystalline Cellulose (UNII: OP1R32D61U)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color BLUE (light blue) Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;215;35
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019697 12/29/1989
Part 3 of 4
ORTHO TRI CYCLEN 
norgestimate and ethinyl estradiol tablet, coated
Product Information
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
norgestimate (UNII: C291HFX4DY) (norgestimate - UNII:C291HFX4DY) norgestimate 0.25 mg
ethinyl estradiol (UNII: 423D2T571U) (ethinyl estradiol - UNII:423D2T571U) ethinyl estradiol 0.035 mg
Inactive Ingredients
Ingredient Name Strength
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Aluminum Oxide (UNII: LMI26O6933)  
Carnauba Wax (UNII: R12CBM0EIZ)  
Croscarmellose Sodium (UNII: M28OL1HH48)  
Hypromellose, Unspecified (UNII: 3NXW29V3WO)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Microcrystalline Cellulose (UNII: OP1R32D61U)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Polysorbate 80 (UNII: 6OZP39ZG8H)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color BLUE Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;250;35
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019697 12/29/1989
Part 4 of 4
INERT 
inert tablet, coated
Product Information
Route of Administration ORAL
Inactive Ingredients
Ingredient Name Strength
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Aluminum Oxide (UNII: LMI26O6933)  
Ferric Oxide Red (UNII: 1K09F3G675)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Starch, Corn (UNII: O8232NY3SJ)  
Polyvinyl Alcohol, Unspecified (UNII: 532B59J990)  
Talc (UNII: 7SEV7J4R1U)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color GREEN (DARK GREEN) Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;M;P
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019697 12/29/1989
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019697 12/29/1989
ORTHO CYCLEN 
norgestimate and ethinyl estradiol kit
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50458-197
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:50458-197-15 6 in 1 CARTON 12/29/1989 03/31/2019
1 NDC:50458-197-00 1 in 1 BLISTER PACK; Type 0: Not a Combination Product
2 NDC:50458-197-20 48 in 1 CARTON 12/29/1989 02/28/2018
2 1 in 1 DIALPACK; Type 0: Not a Combination Product
3 NDC:50458-197-12 12 in 1 CARTON 12/29/1989 05/31/2019
3 1 in 1 DIALPACK; Type 0: Not a Combination Product
4 NDC:50458-197-06 6 in 1 CARTON 12/29/1989 07/30/2019
4 NDC:50458-197-28 28 in 1 BLISTER PACK
4 1 in 1 DIALPACK; Type 0: Not a Combination Product
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 21 
Part 2
Part 1 of 2
ORTHO CYCLEN 
norgestimate and ethinyl estradiol tablet, coated
Product Information
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
norgestimate (UNII: C291HFX4DY) (norgestimate - UNII:C291HFX4DY) norgestimate 0.25 mg
ethinyl estradiol (UNII: 423D2T571U) (ethinyl estradiol - UNII:423D2T571U) ethinyl estradiol 0.035 mg
Inactive Ingredients
Ingredient Name Strength
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Aluminum Oxide (UNII: LMI26O6933)  
Carnauba Wax (UNII: R12CBM0EIZ)  
Croscarmellose Sodium (UNII: M28OL1HH48)  
Hypromellose, Unspecified (UNII: 3NXW29V3WO)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Microcrystalline Cellulose (UNII: OP1R32D61U)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Polysorbate 80 (UNII: 6OZP39ZG8H)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color BLUE Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;250;35
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019653 12/29/1989
Part 2 of 2
INERT 
inert tablet, coated
Product Information
Route of Administration ORAL
Inactive Ingredients
Ingredient Name Strength
FD&C Blue No. 2 (UNII: L06K8R7DQK)  
Aluminum Oxide (UNII: LMI26O6933)  
Ferric Oxide Red (UNII: 1K09F3G675)  
Lactose, Unspecified Form (UNII: J2B2A4N98G)  
Magnesium Stearate (UNII: 70097M6I30)  
Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A)  
Starch, Corn (UNII: O8232NY3SJ)  
Polyvinyl Alcohol, Unspecified (UNII: 532B59J990)  
Talc (UNII: 7SEV7J4R1U)  
Titanium Dioxide (UNII: 15FIX9V2JP)  
Water (UNII: 059QF0KO0R)  
Product Characteristics
Color GREEN (DARK GREEN) Score no score
Shape ROUND (BICONVEX) Size 6mm
Flavor Imprint Code O;M;P
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019653 12/29/1989
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA019653 12/29/1989
Labeler - Janssen Pharmaceuticals, Inc. (063137772)
Establishment
Name Address ID/FEI Business Operations
Janssen Ortho, LLC 084894661 MANUFACTURE(50458-191, 50458-197) , ANALYSIS(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Gedeon Richter Plc 644781932 API MANUFACTURE(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Gedeon Richter Plc. 401140279 API MANUFACTURE(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Janssen Pharmaceuticals, Inc. 868441320 ANALYSIS(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Janssen Pharmaceuticals, Inc. 063137772 ANALYSIS(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Aspen Oss B.V. 491013870 API MANUFACTURE(50458-191, 50458-197)
Establishment
Name Address ID/FEI Business Operations
Aspen Oss B.V. 491017488 API MANUFACTURE(50458-191, 50458-197)

Revised: 5/2019
Document Id: a5100f0c-d6a0-4340-91ab-04bb630476cb
Set id: 384e7a40-dcbd-4908-bf5e-65abc9932973
Version: 17
Effective Time: 20190516
 
Janssen Pharmaceuticals, Inc.