TriNessa® Lo

Norgestimate andEthinyl Estradiol Tablets USP,

0.18 mg/0.025 mg, 0.215 mg/0.025 mg, and 0.25 mg/0.025 mg

Rx only

Issued: September 2010

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

DESCRIPTION

TriNessa® Lo tabletsare a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.

Norgestimate and ethinyl estradiol tablets USP

28 Tablets

Each light peach tablet contains 0.18 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 vitamin E, lactose anhydrous, FD&C yellow #6, D&C yellow #10, microcrystalline cellulose, polacrilin potassium, and magnesium stearate.

Each peach 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 vitamin E, lactose anhydrous, FD&C yellow #6, D&C yellow #10, microcrystalline cellulose, polacrilin potassium, and magnesium stearate.

Each orange tablet contains 0.25 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 vitamin E, lactose anhydrous, FD&C yellow #6, microcrystalline cellulose, polacrilin potassium, and magnesium stearate.

Each white tablet contains only inert ingredients, as follows: lactose anhydrous, microcrystalline cellulose, and magnesium stearate.

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 norgestimate and ethinyl estradiol 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 to 14.5 fold) of norgestrel was observed as a result of high affinity binding to SHBG, which limits its biological activity100. The effect of food on the pharmacokinetics of norgestimate and ethinyl estradiol has not been studied.

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

1 NGMN = Norelgestromin, NG = norgestrel, EE = ethinyl estradiol
2 Cmax = peak serum concentration, tmax = time to reach peak serum concentration,

AUC0 to 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 to 24h = h•ng/mL
5 units for EE only – Cmax = pg/mL, AUC0 to 24h = h•pg/mL
NC = not calculated

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 norgestimate and ethinyl estradiol, 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 eva luated 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 Cmax and AUC0 to 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 Cmax by 9% and AUC0 to 24h by 19%, norgestrel Cmax by 12% and AUC0 to 24h by 46%, EE Cmax by 13% and AUC0 to 24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in Cmax and AUC0 to 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 to 40%) of the overall variability in the pharmacokinetics of norelgestromin and ethinyl estradiol following norgestimate and ethinyl estradiol tablets USP 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 norgestimate and ethinyl estradiol 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 (Ki).

Interactions between oral contraceptives and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with norgestimate and ethinyl estradiol (see PRECAUTIONS).

INDICATIONS AND USAGE

TriNessa 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 norgestimate and ethinyl estradiol tablets USP use and a total of 20 pregnancies were reported in norgestimate and ethinyl estradiol tablets USP 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 lists 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.

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10

Source: 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.

1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

5 Foams, creams, gels, vaginal suppositories and vaginal film.

6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

7 With spermicidal cream or jelly.

8 Without spermicides.

9 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 2 light-orange pills), Lo-Ovral®* (1 dose is 4 white pills), Triphasil®* or Tri-Levlen®* (1 dose is 4 yellow pills).

10 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 six months of age.

TriNessa Lo tablets have not been studied for and are 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

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 to 49 years of age 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.

* Deaths are birth-related
** Deaths are method-related
Adapted from H.W. Ory, Family Planning Perspectives, Ref. #35.

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 WARNINGS1a and 1d), changes in serum triglycerides and lipoprotei