TRINESSA- norgestimate and ethinyl estradiol
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.
The following product is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.
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.
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 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.
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.
|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.
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.
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.
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.
The effects of body weight, body surface area or age on the pharmacokinetics of TriNessa ® have not been studied.
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).
The effects of renal impairment on the pharmacokinetics of TriNessa ® have not been studied.
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.
|% of Women Experiencing an Unintended Pregnancy within the First Year of Use||% of Women Continuing Use at One Year *|
|Method||Typical Use †||Perfect Use ‡|
|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.|
|Norplant® and Norplant-2®||0.05||0.05||88|
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.
|TriNessa® (N=221)||Placebo (N=234)||Difference in Counts between TriNessa® and Placebo at 6 Months|
|# of Lesions||Counts||% Reduction||Counts||% Reduction|
|Sixth Month Mean||10||48%||13||30%||3 (95%CI: -1.2, 5.1)|
|Sixth Month Mean||22||34%||25||21%||3 (95% CI: -0.2, 7.8)|
|Sixth Month Mean||31||42%||38||27%||7 (95% CI: 2.0, 11.9)|
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