Tri-Nymyo (Page 4 of 7)

7.3 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Tri-Nymyo with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

Safety and efficacy of norgestimate and ethinyl estradiol tablets have been established in women of reproductive age. Efficacy is expected to be the same for post- pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

There was no significant difference between tri-cycle norgestimate and ethinyl estradiol tablets and placebo in mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population.

8.5 Geriatric Use

Tri-Nymyo has not been studied in postmenopausal women and are not indicated in this population.

8.6 Hepatic Impairment

The pharmacokinetics of Tri-Nymyo has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. [See Contraindications ( 4) and Warnings and Precautions ( 5.2).]

8.7 Renal Impairment

The pharmacokinetics of Tri-Nymyo has not been studied in women with renal impairment.

10 OVERDOSAGE

There have been no reports of serious ill effects from overdosage of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

11 DESCRIPTION

Tri-Nymyo is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17 )-(+)-) and ethinyl estradiol is designated as (19-nor-17 -pregna,1,3,5(10)-trien-20-yne-3,17-diol).

  • Each active green tablet contains 0.18 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include: FD&C Blue No.2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, titanium dioxide, iron oxide black,iron oxide yellow, macrogol/ polyethylene glycol 3350 NF, lecithin, talc, polyvinyl alcohol,lactose monohydrate, magnesium stearate and pregelatinized corn starch.
  • Each active light blue tablet contains 0.215 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include: FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, titanium dioxide, iron oxide black, polyvinyl alcohol, talc, macrogol/polyethylene glycol 3350 NF, lecithin, lactose monohydrate, magnesium stearate and pregelatinized corn starch.
  • Each active blue tablet contains 0.25 mg of norgestimate and 0.035 mg of ethinyl estradiol. Inactive ingredients include: FD&C Blue No. 2 Aluminium Lake, FD&C Blue No. 1 Aluminum lake, FD&C Red No. 40 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake,titanium dioxide, polyvinyl alcohol, talc, macrogol/PEG 3350 NF, lecithin, lactose monohydrate, magnesium stearate and pregelatinized corn starch.
  • Each white placebo tablet containing only inert ingredients, as follows: titanium dioxide, polydextrose, hypromellose, triacetin, macrogol/polyethylene glycol, lactose monohydrate, magnesium stearate and pregelatinized corn starch.
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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

  • Oral Contraception

    COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

  • 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.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Tri-Nymyo.

12.3 Pharmacokinetics

Absorption

Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM 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 Tri-Nymyo. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE 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 NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3).

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Food Effect

The effect of food on the pharmacokinetics of Tri-Nymyo has not been studied.

Distribution

NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Metabolism

NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM’s primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of NGMN and EE 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 NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. 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.

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