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ORTHO-CYCLEN® and
ORTHO TRI-CYCLEN®
(norgestimate/ethinyl estradiol)
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].
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).
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ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies].
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].
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]. 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.
Table 1: Instructions for Administration of
ORTHO-CYCLEN or ORTHO TRI-CYCLEN
| 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:
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Day 1 Start:
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Sunday Start:
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| 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: |
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| Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. | |
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.
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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.
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VERIDATE® Tablet Dispenser
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ORTHO-CYCLEN:
ORTHO TRI-CYCLEN:
To Insert New Refill (ORTHO-CYCLEN or ORTHO TRI-CYCLEN):
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. |
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].
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.
ORTHO-CYCLEN Tablets are available in blister cards. Each blister card contains 28 tablets in the following order:
ORTHO TRI-CYCLEN Tablets are available in blister cards. Each blister card contains 28 tablets in the following order:
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:
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 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:
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.
Mfd. by: Janssen Ortho, LLC, Manati, Puerto Rico 00674, Mfd. for: Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560. Revised April 2015
The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:
Adverse reactions commonly reported by COC users are:
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.
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.
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%).
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%).
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).
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.
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%).
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%).
breast cancer (1 subject), carcinoma of the cervix in situ (1 subject), hypertension (1 subject), and migraine (2 subjects).
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.
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.
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.
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.
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]).
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.
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Included as part of the PRECAUTIONS section.
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]. 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.
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. 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.
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. 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.
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.
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.
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).
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.
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.
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].
Carefully observe women with a history of depression and discontinue ORTHO-CYCLEN or ORTHO TRI-CYCLEN if depression recurs to a serious degree.
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.
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.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
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.
See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Counsel patients about the following information:
[See WARNINGS AND PRECAUTIONS and Use in Specific Populations]
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.
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.
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.
ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in postmenopausal women and are not indicated in this population.
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 and WARNINGS AND PRECAUTIONS]
The pharmacokinetics of ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in women with renal impairment.
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.
Do not prescribe ORTHO-CYCLEN or ORTHO TRI-CYCLEN to women who are known to have the following conditions:
No specific pharmacodynamic studies were conducted with ORTHO-CYCLEN or ORTHO TRICYCLEN.
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.
| Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle Study | ||||||
| Analyte | Cycle | Day | Cmax | tmax (h) | AU C0-24h | t½ (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 | t½ (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) | |
| 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, t½ = 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 |
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The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has not been studied.
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.
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.
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.
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.
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.
| # of Lesions | ORTHO TRI-CYCLEN (N=221) |
Placebo (N=234) |
Difference in Counts between ORTHO TRI-CYCLEN and Placebo at 6 Months | |
| Counts | % Reduction | Counts % Reduction | ||
| 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% | |
| *LOCF: Last Observation Carried Forward | ||||
ORTHO-CYCLEN
[OR-tho si-klin]
ORTHO TRI-CYCLEN
[OR-tho tri-si-klin]
(norgestimate and ethinyl estradiol) Tablets
What is the most important information I should know about ORTHOCYCLEN 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 TRICYCLEN 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.
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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 TRICYCLEN.
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:
Other serious side effects include:
What are the most common side effects of ORTHO-CYCLEN or ORTHO TRICYCLEN?
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 ORTHOCYCLEN 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 si-klin]
ORTHO TRI-CYCLEN
[OR-tho tri-si-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-CYCLEN
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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 A
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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 B
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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.
Figure C
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Step 4. Swallow the pill. You will take 1 pill every day, at the same time each day.
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.
Figure D
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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.
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 E
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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.
Figure F
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Instructions for using your VERIDATE pill dispenser:
ORTHO-CYCLEN
ORTHO TRI-CYCLEN
Figure A
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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 B
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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.
Figure C
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Day 1 Start:
If you take ORTHO-CYCLEN:
Figure D
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If you take ORTHO TRI-CYCLEN:
Figure E
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Figure F
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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 G
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Step 4. The next day take a dark green pill from the inner ring. See Figure H.
Figure H
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Step 5. Insert a new refill:
Figure I
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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:
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.
