TriNessa: Package Insert and Label Information

TRINESSA- norgestimate and ethinyl estradiol
Watson Pharmaceuticals

WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including TriNessa® , should not be used by women who are over 35 years of age and smoke.

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

DESCRIPTION

The following product is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.

TriNessa® Tablets

Each white tablet contains 0.180 mg of the progestational compound, norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide.

Each light blue tablet contains 0.215 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 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, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide.

Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 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, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide.

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

Chemical Structure

Nogestimate

Chemical Structure

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

Acne

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

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.

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

Table 1: Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of TriNessa® During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0–24h t1/2 (h)
Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0–24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated.
NGMN and NG: Cmax = ng/mL, AUC0–24h =h∙ng/mL
EE: Cmax =pg/mL, AUC0–24h =h∙pg/mL
NGMN 3 7 1.80 (0.46) 1.42 (0.73) 15.0 (3.88) NC
14 2.12 (0.56) 1.21 (0.26) 16.1 (4.97) NC
21 2.66 (0.47) 1.29 (0.26) 21.4 (3.46) 22.3 (6.54)
NG 3 7 1.94 (0.82) 3.15 (4.05) 34.8 (16.5) NC
14 3.00 (1.04) 2.21 (2.03) 55.2 (23.5) NC
21 3.66 (1.15) 2.58 (2.97) 69.3 (23.8) 40.2 (15.4)
EE 3 7 124 (39.5) 1.27 (0.26) 1130 (420) NC
14 128 (38.4) 1.32 (0.25) 1130 (324) NC
21 126 (34.7) 1.31 (0.56) 1090 (359) 15.9 (4.39)

The effect of food on the pharmacokinetics of TriNessa® has not been studied.

Distribution

Norelgestromin and norgestrel 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 and induces an increase in the serum concentrations of SHBG.

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

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

Special Populations

The effects of body weight, body surface area or age on the pharmacokinetics of TriNessa ® have not been studied.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of TriNessa ® have not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).

Renal Impairment

The effects of renal impairment on the pharmacokinetics of TriNessa ® have not been studied.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with TriNessa ® . Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS).

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 ).

TriNessa Indications and Usage

TriNessa ® is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

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

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.

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)
Hatcher et al, 1998, Ref. #1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.
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.
*
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
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.
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.
§
The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration 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).
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.
#
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 percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
Þ
Foams, creams, gels, vaginal suppositories, and vaginal film.
ß
Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
à
With spermicidal cream or jelly.
è
Without spermicides.
Chance # 85 85
Spermicides Þ 26 6 40
Periodic abstinence 25 63
Calendar 9
Ovulation Method 3
Sympto-Thermal ß 2
Post-Ovulation 1
Cap à
Parous Women 40 26 42
Nulliparous Women 20 9 56
Sponge
Parous Women 40 20 42
Nulliparous Women 20 9 56
Diaphragm à 20 6 56
Withdrawal 19 4
Condom è
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

TriNessa® has not been studied for and is not indicated for use in emergency contraception.

In four clinical trials with TriNessa® , a total of 4,756 subjects completed 45,244 cycles, and the use-efficacy pregnancy rate was approximately 1 pregnancy per 100 women-years.

TriNessa® was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. 221 patients received TriNessa® and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changes from 55 to 31 (42% reduction) in patients treated with TriNessa® and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table 3 summarizes the changes in lesion count for each type of lesion in the ITT population. Based on the investigator’s global assessment conducted at the final visit, patients treated with TriNessa® showed a statistically significant improvement in total lesions compared to those treated with placebo.

Table 3: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials. Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat Population.
TriNessa® (N=221) Placebo (N=234) Difference in Counts between TriNessa® and Placebo at 6 Months
# of Lesions Counts % Reduction Counts % Reduction
*
LOCF: Last Observation Carried Forward
INFLAMMATORY LESIONS
Baseline Mean 19 19
Sixth Month Mean 10 48% 13 30% 3 (95%CI: -1.2, 5.1)
NON-INFLAMMATORY LESIONS
Baseline Mean 36 35
Sixth Month Mean 22 34% 25 21% 3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
Baseline Mean 55 54
Sixth Month Mean 31 42% 38 27% 7 (95% CI: 2.0, 11.9)

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