At least two functional auxiliaries are produced from norgestimate: norgestimate 3-oxime (reduced norgestimate; norelgestromin) and norelgestromin [1].

Absorption, Distribution and Excretion
Oral norgestimate has a Tmax of 0.5-2h. On day 21 of cycle 3, 17-desacetylnorgestimate reaches a Cmax of 1.82ng/mL, with a Tmax of 1.5h, and an AUC of 16.1h\*ng/mL. At the same time, norgestrel reaches a Cmax of 2.79ng/mL, with a Tmax of 1.7h, and an AUC of 49.9h\*ng/mL.
Norgestimate is 45-49% eliminated in urine and 16-49% eliminated in feces. Unchanged norgestimate is not detected in urine.
Data regarding the volume of distribution of norgestimate are not readily available.
Data regarding the clearance of norgestimate is not readily available.
Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration.
Peak serum concentrations of norelgestromin (NGMN) and ethinyl estradiol (EE) are generally reached by 2 hours after administration of MonoNessa. Accumulation following multiple dosing of the 250 ug Norgestimate (NGM)/ 35 ug 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 ug to 250 ug. ... 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.
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.
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.

---

Metabolism / Metabolites
Norgestimate is rapidly deacetylated to the active 17-desacetylnorgestimate, which is deoximated to the active norgestrel. 17-desacetylnorgestimate is metabolized to a number of undefined hydroxylated metabolites, mainly by CYP3A4 and to a lesser extend by CYP2B6 and CYP2C9. Norgestrel is O-glucuronidated by UGT1A1 or oxidized to a number of undefined hydroxylated metabolites by CYP3A4.
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.
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.
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,(17alpha)-(-); 18,19-Dinor-5beta-17-pregnan-20-yn,3alpha,17beta-dihydroxy-13-ethyl,(17alpha), various hydroxylated metabolites and conjugates of these metabolites.
There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. ...

---

Biological Half-Life
Norgestimate is rapidly deacetylated. The active metabolites of norgestimate, 17-desacetyl norgestimate, has a half life of 12-30h, while norgestrel has a half life of 36.4±10.2h.

Protein Binding
17-desacetylnorgestimate is 97.2% bound to albumin and Norgestrel is >97% protein bound, including 92.5% bound to sex hormone binding globulin.

---

Interactions
Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

[1]. All progestins are not created equal. Steroids. 2003 Nov;68(10-13):879-90.

[2]. Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am J Obstet Gynecol. 1992 Oct;167(4 Pt 2):1191-6.

Norgestimate is a steroid ester, a ketoxime and a terminal acetylenic compound. It has a role as a contraceptive drug, a progestin and a synthetic oral contraceptive.
Norgestimate was first described in the literature in 1977. It was developed by Ortho Pharmaceutical Corporation as part of an effort to develop new hormonal contraceptives with reduced adverse effects. It is commonly formulated with [ethinylestradiol] as a combined oral contraceptive that can also be used to treat moderate acne vulgaris. Norgestimate was granted FDA approval on 29 December 1989.

---

Drug Indication
Norgestimate is formulated with [ethinylestradiol] as a combined oral contraceptive. It can also be given with low dose ethinylestradiol for contraception as well as the treatment of moderate acne vulgaris in women ≥15 years old.

---

Mechanism of Action
Progesterone analogs like norgestimate decrease the frequency of gonadotropin releasing hormone pulses from the hypothalamus, decreasing follicle stimulating hormone and luteinizing hormone. These actions prevent ovulation. Norgestimate suppresses the hypothalamo-pituitary-axis, reducing androgen synthesis. It also induces production of sex hormone binding globulin, which decreases free testosterone. These actions together result in less testosterone being available to stimulate sebaceous glands, resulting in effective treatment of some forms of acne.
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. Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone.
Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis. /Progestins/
Progestins are capable of affecting serum concentrations of other hormones, particularly estrogen. Estrogenic effects are modified by the progestins, either by reducing the availability or stability of the hormone receptor complex or by turning off specific hormone-responsive genes by direct interaction with the progestin receptor in the nucleus. In addition, estrogen priming is necessary to increase progestin effects by upregulating the number of progestin receptors and/or increasing progesterone production, causing a negative feedback mechanism that inhibits estrogen receptors. /Progestins/

---

Therapeutic Uses
Contraceptives, Oral, Synthetic; Norgestrel/analogs & derivatives
Norgestimate/ethinyl estradiol is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. /Included in US product label/

---

Drug Warnings
/BOXED WARNING/ 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 MonoNessa, should not be used by women who are over 35 years of age and smoke.
Oral contraceptives should not be used in women who currently have 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 past 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; acute or chronic hepatocellular disease with abnormal liver function; hepatic adenomas or carcinomas; known or suspected pregnancy; hypersensitivity to any component of this product.
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.
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 stroke. 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. 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. The attributable risk is also greater in older women.
For more Drug Warnings (Complete) data for Norgestimate (44 total), please visit the HSDB record page.

---

Pharmacodynamics
Norgestimate is a progestin that suppresses ovulation for contraception and reduces free testosterone to treat moderate acne vulgaris. The therapeutic index is wide as overdoses are rare. Patients should be counselled regarding the risk of vascular problems, liver disease, hypertension, metabolic effects, headaches, and bleeding irregularities.

C23H31NO3

369.4971

369.23

C, 74.76; H, 8.46; N, 3.79; O, 12.99

35189-28-7

Norgestimate-d6;1263194-12-2

6540478

White to off-white solid powder

1.2±0.1 g/cm3

497.9±45.0 °C at 760 mmHg

216ºC

254.9±28.7 °C

0.0±2.9 mmHg at 25°C

1.611

5

1

4

4

27

744

6

O(C(C([H])([H])[H])=O)[C@@]1(C#C[H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])/C(/C([H])([H])C([H])([H])[C@]4([H])[C@@]3([H])C([H])([H])C([H])([H])[C@@]21C([H])([H])C([H])([H])[H])=N/O[H]

KIQQMECNKUGGKA-NMYWJIRASA-N

InChI=1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1

[(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate

Norgestimate; ORF-10131; D 138; AC-655; RWJ-10131; Dexnorgestrel acetime; Norgestrel oxime acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 74~125 mg/mL (200.3~338.3 mM)
Ethanol: ~4 mg/mL (~10.8 mM)

Solubility in Formulation 1: 2.08 mg/mL (5.63 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (5.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (5.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)