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

DESCRIPTION

Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.

ORTHO TRI-CYCLEN® 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, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium dioxide.

ORTHO-CYCLEN® Tablets

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, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium dioxide.

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 androgenicity90–93 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 firstpass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg 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.

The effect of food on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® 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 14C-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 ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® 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 ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. 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).

INDICATIONS AND USAGE

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

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

Oral contraceptives are highly effective for pregnancy prevention. Table II 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.

ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® have not been studied for and are not indicated for use in emergency contraception.

In clinical trials with ORTHO-CYCLEN®, 1,651 subjects completed 24,272 cycles and the overall use-efficacy (typical user efficacy) pregnancy rate was approximately 1 pregnancy per 100 women-years. This rate includes patients who did not take the drug correctly.

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

ORTHO TRI-CYCLEN® was eva luated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. 221 patients received ORTHO TRI-CYCLEN® and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changes from 55 to 31 (42% reduction) in patients treated with ORTHO TRI-CYCLEN® and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table III 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 ORTHO TRI-CYCLEN® showed a statistically significant improvement in total lesions compared to those treated with placebo.