ORTHO TRI CYCLEN Lo (norgestimate 0.25 mg ethinyl estradiol 0.025 mg) Dailymed

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

Description

ORTHO TRI-CYCLEN^® Lo Tablets is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.

ORTHO TRI-CYCLEN Lo Tablets

Each white tablet contains 0.180 mg of the progestational compound, norgestimate (+)-13-Ethyl-17-hydroxy-18, 19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester) and 0.025 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, carnauba wax, hypromellose, polyethylene glycol, titanium dioxide, and purified water.

Each light blue tablet contains 0.215 mg of the progestational compound norgestimate (+)-13-Ethyl-17-hydroxy-18, 19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester) and 0.025 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, carnauba wax, hypromellose, polyethylene glycol, titanium dioxide, and purified water.

Each dark blue tablet contains 0.250 mg of the progestational compound norgestimate (+)-13-Ethyl-17-hydroxy-18, 19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester) and 0.025 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, polysorbate 80, carnauba wax, hypromellose, polyethylene glycol, titanium dioxide, and purified water.

Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, pregelatinized starch, ferric oxide, hypromellose, polyethylene glycol, titanium dioxide, talc and purified water.

                                               Norgestimate

                                               Ethinyl Estradiol

Clinical Pharmacology

Oral Contraception

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals and humans, have shown that norgestimate and 17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity.^90–93 Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone.^90,91,94

PHARMACOKINETICS

Absorption

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration. Norgestimate 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. Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of ORTHO TRI-CYCLEN^® Lo are summarized in Table 1. These results indicate that: (1) Peak serum concentrations of NGMN and EE were generally reached by 2 hours after dosing; (2) Accumulation following multiple dosing of the 180 mcg NGM / 25 mcg dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE; (3) The kinetics of NGMN are dose proportional following NGM doses of 180 to 250 mcg; (4) Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study; (5) Non-linear accumulation (4.5–14.5 fold) of norgestrel was observed as a result of high affinity binding to SHBG, which limits its biological activity.¹⁰⁰ The effect of food on the pharmacokinetics of ORTHO TRI-CYCLEN^® Lo has not been studied.

Table 1 provides a summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.

Table 1: Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN^® Lo During a Three Cycle Study

Analyte1	Cycle	Day	Cmax	tmax (h)	AUC0–24h	t1/2 (h)
1 NGMN = Norelgestromin, NG = norgestrel, EE = ethinyl estradiol
2 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.
3 units for all analytes; h = hours
4 units for NGMN and NG – Cmax = ng/mL, AUC0–24h = h.ng/mL
5 units for EE only – Cmax = pg/mL, AUC0–24h = h.pg/mL
NC = not calculated
NGMN (2–4)	1	1	0.91 (0.27)	1.8 (1.0)	5.86 (1.54)	NC
	3	7	1.42 (0.43)	1.8 (0.7)	11.3 (3.2)	NC
		14	1.57 (0.39)	1.8 (0.7)	13.9 (3.7)	NC
		21	1.82 (0.54)	1.5 (0.7)	16.1 (4.8)	28.1(10.6)
NG(2–4)	1	1	0.32 (0.14)	2.0 (1.1)	2.44 (2.04)	NC
	3	7	1.64 (0.89)	1.9 (0.9)	27.9 (18.1)	NC
		14	2.11 (1.13)	4.0 (6.3)	40.7 (24.8)	NC
		21	2.79 (1.42)	1.7 (1.2)	49.9 (27.6)	36.4 (10.2)
EE(2,3,5)	1	1	55.6 (18.1)	1.7 (0.5)	421 (118)	NC
	3	7	91.1 (36.7)	1.3 (0.3)	782 (329)	NC
		14	96.9 (38.5)	1.3 (0.3)	796 (273)	NC
		21	95.9 (38.9)	1.3 (0.6)	771 (303)	17.7(4.4)

Distribution

Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound (>97%) to serum albumin.

Metabolism

Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

Following 3 cycles of administration of ORTHO TRI-CYCLEN^® Lo, the mean (± SD) elimination half-life values, at steady-state, for norelgestromin, norgestrel and ethinyl estradiol were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours, respectively (Table 1). The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways.

Special Populations

Effects of Body Weight, Body Surface Area, and Age

The effects of body weight, body surface area, age and race on the pharmacokinetics of norelgestromin, norgestrel and ethinyl estradiol were evaluated in 79 healthy women using pooled data following single dose administration of NGM 180 or 250 mcg / EE 25 mcg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in C_max and AUC_0–24h values for norelgestromin and ethinyl estradiol and increases in CL/F (oral clearance) for ethinyl estradiol. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN C_max by 9% and AUC_0–24h by 19%, norgestrel C_max by 12% and AUC_0–24h by 46%, EE C_max by 13% and AUC_0–24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in C_max and AUC_0–24h for norelgestromin and were statistically significant, but there was no significant effect for norgestrel or ethinyl estradiol. Only a small to moderate fraction (5–40%) of the overall variability in the pharmacokinetics of norelgestromin and ethinyl estradiol following ORTHO TRI-CYCLEN^® Lo Tablets may be explained by any or all of the above demographic parameters.

In clinical studies involving 1673 subjects with a mean weight of 141 pounds, there was no association between pregnancy and weight.

Renal and Hepatic Impairment

No studies with ORTHO TRI-CYCLEN^® Lo have been conducted in women with renal or hepatic impairment.

Drug-Drug Interactions

Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K_i).

Interactions between oral contraceptives and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with ORTHO TRI-CYCLEN^® Lo (see PRECAUTIONS).

Indications And Usage

ORTHO TRI-CYCLEN^® Lo Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

In an active controlled clinical trial 1,673 subjects completed 11,003 cycles of ORTHO TRI-CYCLEN^® Lo use and a total of 20 pregnancies were reported in ORTHO TRI-CYCLEN^® Lo users.⁹⁹ This represents an overall use-efficacy (typical user efficacy) pregnancy rate of 2.36 per 100 women-years of use.

Oral contraceptives are highly effective for pregnancy prevention. Table 2 uls the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant^® system, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.

	% of Women Experiencing an Unintended Pregnancy Within the First Year of Use		% of Women Continuing Use at One Year
Method	Typical Use	Perfect Use
(1)	(2)	(3)	(4)
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 4 yellow pills).
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.
Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.
Chance	85	85
Spermicides	26	6	40
Periodic abstinence	25		63
  Calendar		9
  Ovulation Method		3
  Sympto-Thermal		2
  Post-Ovulation		1
Withdrawal	19	4
CapWith spermicidal cream or jelly.
  Parous Women	40	26	42
  Nulliparous Women	20	9	56
Sponge
  Parous Women	40	20	42
  Nulliparous Women	20	9	56
Diaphragm	20	6	56
Condom
  Female (Reality®)	21	5	56
  Male	14	3	61
Pill	5		71
  Progestin Only		0.5
  Combined		0.1
IUD
  Progesterone T	2.0	1.5	81
  Copper T380A	0.8	0.6	78
  LNg 20	0.1	0.1	81
Depo-Provera®	0.3	0.3	70
Norplant® and Norplant-2®	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.10	100

ORTHO TRI-CYCLEN^® Lo has not been studied for and is not indicated for use in emergency contraception.

Contraindications

Oral contraceptives should not be used in women who have any of the following conditions:

• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease (current or history)
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast or personal history of breast cancer
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product

Warnings

BOXED WARNING SECTION

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

1.Thromboembolic Disorders and Other Vascular Problems

a.Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.^4–10 The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.¹¹ Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives.

Figure 1: Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use

Figure 1 Adapted from P.M. Layde and V. Beral, Ref. #12.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.¹³ In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.^14–18 Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater.⁹⁷

b.Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.^{2,3,19–24} Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.²⁵ The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.²

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.⁹ The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.²⁶ If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed.

c.Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of hemorrhagic stroke.^27–29

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.³⁰ The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.³⁰ The attributable risk is also greater in older women.³

d.Dose-Related Risk of Vascular Disease from Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.^31–33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.^14–16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for an individual patient.

e.Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.⁸ In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.³⁴ However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2.Estimates of Mortality from Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's.³⁵ Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over.

The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

Table 3: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age

Method of control and outcome	15–19	20–24	25–29	30–34	35–39	40–44
Adapted from H.W. Ory, Family Planning Perspectives, Ref. #35.
No fertility-control methodsDeaths are birth-related	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives, non-smokerDeaths are method-related	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives, smoker	2.2	3.4	6.6	13.5	51.1	117.2
IUD	0.8	0.8	1.0	1.0	1.4	1.4
Condom	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence	2.5	1.6	1.6	1.7	2.9	3.6

3.Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after discontinuation of combination oral contraceptives and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use combination oral contraceptives before age 20. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.^45–48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4.Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.⁴⁹ Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.^50,51

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5.Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6.Oral Contraceptive 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.^56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,^55,56,58,59 when taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

7.Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.^60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.^62–64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8.Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.¹⁷ This effect has been shown to be directly related to estrogen dose.⁶⁵ Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.^17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.⁶⁷ Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9.Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraception.⁹⁸ An increase in blood pressure has been reported in women taking oral contraceptives⁶⁸ and this increase is more likely in older oral contraceptive users⁶⁹ and with extended duration of use.⁶¹ Data from the Royal College of General Practitioners¹² and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease⁷⁰ should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.^68–71

10.Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11.Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

12.Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

1.General

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

2.Physical Examination and Follow-Up

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

3.Lipid Disorders

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

4.Liver Function

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

5.Fluid Retention

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

6.Emotional Disorders

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

7.Contact Lenses

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

8.Drug Interactions

Changes in contraceptive effectiveness associated with co-administration of other products

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results.

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Concurrent use of bosentan and ethinyl estradiol containing products may result in decreased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding.

Increase in plasma ethinyl estradiol levels associated with co-administered drugs

Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Changes in plasma levels of co-administered drugs

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when drugs were administered with oral contraceptives.

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.¹⁰³

Healthcare professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy.

9.Interactions with Laboratory Tests

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

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

10.Carcinogenesis

See WARNINGS.

11.Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS and WARNINGS.

12.Nursing Mothers

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

13.Pediatric Use

Safety and efficacy of ORTHO TRI-CYCLEN^® Lo Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

14.Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

Information For The Patient

See Patient Labeling printed below.

Adverse Reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS).

• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Allergic reaction, including rash, urticaria, and angioedema
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding may occur in females.

Non-contraceptive Health Benefits

The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.^73–78

Effects on menses:

• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies

Other effects:

• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer

Dosage And Administration

Oral Contraception

To achieve maximum contraceptive effectiveness, ORTHO TRI-CYCLEN^® Lo Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. The possibility of ovulation and conception prior to initiation of medication should be considered. ORTHO TRI-CYCLEN^® Lo is available with the DIALPAK^® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided.

Sunday Start

When taking ORTHO TRI-CYCLEN^® Lo the first white "active" tablet should be taken on the first Sunday after menstruation begins. If the menstrual period begins on Sunday, the first white "active" tablet should be taken that day. Take one white, light blue or dark blue "active" tablet daily for 21 days followed by one dark green "reminder" tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

If the patient misses one (1) white, light blue, or dark blue "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) white or light blue "active" tablets in Week 1 or Week 2, the patient should take two (2) "active" tablets the day she remembers and two (2) "active" tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) dark blue "active" tablets in the third week or misses three (3) or more "active" tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling ("How to Take the Pill" section).

Day 1 Start

The dosage of ORTHO TRI-CYCLEN^® Lo for the initial cycle of therapy is one white, light blue or dark blue "active" tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "Day 1" followed by one dark green "reminder" tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course is started the next day.

If the patient misses one (1) white, light blue, or dark blue "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) white or light blue "active" tablets in Week 1 or Week 2, the patient should take two (2) "active" tablets the day she remembers and two (2) "active" tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) dark blue "active" tablets in the third week or misses three (3) or more "active" tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling ("How to Take the Pill" section).

When switching from another oral contraceptive, ORTHO TRI-CYCLEN^® Lo should be started on the same day that a new pack of the previous oral contraceptive would have been started.

The use of ORTHO TRI-CYCLEN^® Lo for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The possibility of ovulation and conception prior to initiation of medication should be considered.

(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.)

Additional Instructions For All Dosing Regimens

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period:

• If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed.
• If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

How Supplied

ORTHO TRI-CYCLEN^® Lo Tablets are available in a buler card (NDC 54868-4730-0) with a DIALPAK^® Tablet Dispenser (unfilled). The buler card contains 28 tablets. Each of the 7 white, round, convex, coated tablets imprinted "O-M" on one side and "180" on the other side contains 0.180 mg of the progestational compound, norgestimate, together with 0.025 mg of the estrogenic compound, ethinyl estradiol. Each of the 7 light blue, round, convex, coated tablets imprinted "O-M" on one side and "215" on the other side contains 0.215 mg of the progestational compound, norgestimate, together with 0.025 mg of the estrogenic compound, ethinyl estradiol. Each of the 7 dark blue, round, convex, coated tablets imprinted "O-M" on one side and "250" on the other side contains 0.250 mg of the progestational compound, norgestimate, together with 0.025 mg of the estrogenic compound, ethinyl estradiol. Each of the 7 dark green, round, convex, coated tablets imprinted "O-M" on one side and "P" on the other side contains inert ingredients.

STORAGE AND HANDLING SECTION

Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F).

Protect from light.

References

• Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.
• Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.1). N Engl J Med 1981; 305:612–618.
• Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.2). N Engl J Med 1981; 305:672–677.
• Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynaecol 1981; 88:838–845.
• Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2(5965):245–248.
• Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975; 2(5956):241–245.
• Royal College of General Practitioners' Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541–546.
• Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981:305:420–424.
• Vessey MP. Female hormones and vascular disease - an epidemiological overview. Br J Fam Plann 1980; 6(Supplement): 1–12.
• Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976–80. Prevent Med 1986; 15:352–362.
• Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339–1342.
• Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of General Practitioners' Oral Contraception Study. (Table 5) Lancet 1981; 1:541–546.
• Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement):913–921.
• Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983; 145:446–452.
• Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983; 308:862–867.
• Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am J Obstet Gynecol 1982;142:766–771.
• Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;31(9)(Supplement):892–897.
• LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986;31(9)(Supplement):906–912.
• Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968;2(5599):193–199.
• Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol 1979;110(2):188–195.
• Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979;242:1150–1154.
• Vessey MP, Doll R, Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968;2(5599):199–205.
• Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 1969; 2(5658):651–657.
• Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease - recent experience. Obstet Gynecol 1982;59(3):299–302.
• Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosocial Sci 1976;8:375–427.
• Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393–399.
• Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973;288:871–878.
• Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978;2:234–236.
• Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979:2(6203):1468–1470.
• Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718–722.
• Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970;2:203–209.
• Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980;280(6224):1157–1161.
• Kay CR. Progestogens and arterial disease - evidence from the Royal College of General Practitioners' Study. Am J Obstet Gynecol 1982;142:762–765.
• Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983;33:75–82.
• Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983;15:50–56.
• The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405–411.
• Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983;2:926–929.
• Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723–725.
• Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986;68:863–868.
• Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748–749.
• McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653–660.
• Huggins GR, Zucker PF. Oral contraceptives and neoplasia; 1987 update. Fertil Steril 1987; 47:733–761.
• McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709–710.
• Shapiro S. Oral contraceptives - time to take stock. N Engl J Med 1987; 315:450–451.
• Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573–577.
• Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930.
• Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339–344.
• WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 290:961–965.
• Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644–648.
• Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433–435.
• Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386–394.
• Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983;48:437–440.
• Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355–1357.
• Forman D, Vincent TJ, Doll R, Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357–1361.
• Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447–452.
• Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981: 140:521–524.
• Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73–79.
• Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225–239.
• Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433–439.
• Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399–1404.
• Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974.
• Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274–278.
• Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796–805.
• Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335–341.
• Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045–1049.
• Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395–410.
• Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985;38:857–864.
• Royal College of General Practitioners' Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.
• Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499–2503.
• Laragh AJ. Oral contraceptive induced hypertension-nine years later. Am J Obstet Gynecol 1976; 126:141–147.
• Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277–288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.)
• Stockley I. Interactions with oral contraceptives. J Pharm 1976;216:140–143.
• The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596–1599.
• The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796–800.
• Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68–69.
• Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419–422.
• Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182–184.
• Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p.1.
• Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828–1833.
• Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39–42.
• LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311–317.
• Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650–654.
• Kay CR, Hannaford PC. Breast cancer and the pill - A further report from the Royal College of General Practitioners' oral contraception study. Br J Cancer 1988;58:675–680.
• Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287–299.
• Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269–280.
• The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973–982.
• Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1–38.
• Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613–617.
• Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618–621.
• Anderson FD, Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992; 156 (Supplement):15–21.
• Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347–352.
• Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL. Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1989; 41(4):399–409.
• Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987; 36(2):181–192.
• Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet Gynecol Scand 1992; 156 (Supplement):34–38.
• Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713–1727.
• Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989;130:878–882.
• Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br Med J, 1996;312:88–90.
• Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996.
• Hampton RM, Short M, Bieber E, et al. Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20. Contraception 2001;63:289–295.
• Sitteri PK, Murai JT, Hammond GL, Nisker JA, Raymoure WJ, Huhn RW. The serum transport of steroid hormones. Rec Prog Horm Res 1982;38:457–510.
• Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294–298.
• Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113–118.
• Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484–489.

Brief Summary Patient Package Insert

Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy. When taken correctly without missing any pills, oral contraceptives are highly effective; however the typical failure rate of large numbers of pill users is 5% per year when women who miss pills are included. Forgetting to take pills considerably increases the chances of pregnancy. For most women oral contraceptives are also free of serious or unpleasant side effects.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• smoke
• have high blood pressure, diabetes, high cholesterol
• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors

Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women.

You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

BOXED WARNING SECTION

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke.

Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use.

The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill:

• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.
• In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.
• High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan, as well as some anti-convulsants and some antibiotics, and herbal preparations containing St. John's Wort (hypericum perforatum) may decrease oral contraceptive effectiveness.

Oral contraceptives may interact with lamotrigine (LAMICTAL^®), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine.

Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.

Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.

Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional.

ORTHO TRI-CYCLEN^® Lo (like all oral contraceptives) is intended to prevent pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

• 1.BE SURE TO READ THESE DIRECTIONS:
  Before you start taking your pills.
  
  Anytime you are not sure what to do.
  
• 2.THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.
  If you miss pills you could get pregnant. This includes starting the pack late.
  
  The more pills you miss, the more likely you are to get pregnant.
  
• 3.MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1–3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your healthcare professional.
• 4.MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.
  On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.
  
• 5.IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.
  Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional.
  
• 6.IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.
• 7.IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.

BEFORE YOU START TAKING YOUR PILLS

• 1.DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
  It is important to take it at about the same time every day.
  
• 2. The 28-pill pack has 21 white, light blue, and dark blue "active" pills (with hormones) to take for 3 weeks. This is followed by 1 week of dark green "reminder" pills (without hormones).
• 3.ALSO FIND:
  • 1)where on the pack to start taking pills,
  • 2)in what order to take the pills.

CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.

• 4.BE SURE YOU HAVE READY AT ALL TIMES:
  ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills.
  
  AN EXTRA, FULL PILL PACK.
  

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your first pack of pills. ORTHO TRI-CYCLEN^® Lo is available with the DIALPAK^® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember.

Sunday Start:

Take the first white "active" pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

Use another method of birth control (such as a condom or spermicide) as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days).

Day 1 Start:

Take the first white "active" pill of the first pack during the first 24 hours of your period.

You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

WHAT TO DO DURING THE MONTH

• 1. Take One Pill At The Same Time Every Day Until The Pack Is Empty
  Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).
  
  Do not skip pills even if you do not have sex very often.
  
• 2. When You Finish A Pack Or Switch Your Brand Of Pills
  Start the next pack on the day after your last dark green "reminder" pill. Do not wait any days between packs.
  

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 white, light blue or dark blue "active" pill:

• 1.Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.
• 2.You do not need to use a back-up birth control method if you have sex.

If you MISS 2 white or light blue "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:

• 1.Take 2 pills on the day you remember and 2 pills the next day.
• 2.Then take 1 pill a day until you finish the pack.
• 3.You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 2 dark blue "active" pills in a row in THE 3RD WEEK:

• 1. If you are a Sunday Starter:
  Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
  
  If you are a Day 1 Starter:
  
  THROW OUT the rest of the pill pack and start a new pack that same day.
  
• 2.You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant.
• 3.You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white, light blue or dark blue "active" pills in a row (during the first 3 weeks):

• 1. If you are a Sunday Starter:
  Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
  
  If you are a Day 1 Starter:
  
  THROW OUT the rest of the pill pack and start a new pack that same day.
  
• 2.You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant.
• 3.You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you forget any of the 7 dark green "reminder" pills in Week 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional.

Â