# Norelgestromin

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.
Side effects of the combination of an estrogen and norelgestromin include menstrual irregularities, headaches, nausea, abdominal pain, breast tenderness, mood changes, and others. Norelgestromin is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has very weak androgenic activity and no other important hormonal activity.
Norelgestromin was introduced for medical use in 2002. It is sometimes referred to as a "third-generation" progestin. Norelgestromin is marketed widely throughout the world. It is available as a generic medication.

## Medical uses

Norelgestromin is used in combination with ethinyl estradiol in contraceptive patches. These patches mediate their contraceptive effects by suppressing gonadotropin levels as well as by causing changes in the cervical mucus and endometrium that diminish the likelihood of pregnancy.

### Available forms

Norelgestromin is available only as a transdermal contraceptive patch in combination with ethinyl estradiol. The Ortho Evra patch is a 20 cm$^2$, once-weekly adhesive that contains 6.0 mg norelgestromin and 0.6 mg ethinyl estradiol and delivers 200 μg/day norelgestromin and 35 μg/day ethinyl estradiol.

## Side effects

Norelgestromin has mostly been studied in combination with an estrogen, so the side effects of norelgestromin specifically or on its own have not been well-defined. Side effects associated with the combination of ethinylestradiol and norelgestromin as a transdermal patch in premenopausal women, with greater than or equal to 2.5% incidence over 6 to 13 menstrual cycles, include breast symptoms (including discomfort, engorgement, and/or pain; 22.4%), headaches (21.0%), application site reactions (17.1%), nausea (16.6%), abdominal pain (8.1%), dysmenorrhea (7.8%), vaginal bleeding and menstrual disorders (6.4%), mood, affect, and anxiety disorders (6.3%), vomiting (5.1%), diarrhea (4.2%), vaginal yeast infections (3.9%), dizziness (3.3%), acne (2.9%), migraine (2.7%), weight gain (2.7%), fatigue (2.6%), and pruritus (2.5%).

## Pharmacology
### Pharmacodynamics

Norelgestromin is a progestogen. It is one of the active metabolites of norgestimate. Unlike many related progestins, norelgestromin reportedly has negligible androgenic activity. However, it produces levonorgestrel as an active metabolite to some extent, which does have some androgenic activity. Nonetheless, transdermally-administered norelgestromin does not counteract the increase in sex hormone-binding globulin levels produced by ethinyl estradiol.
Relative affinities (%) of norelgestromin and metabolites :
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
| Norelgestromin | 10 | 0 | ? | ? | ? | 0 | ? |
| Levonorgestrel (3-keto-NGMN) | 150–162 | 45 | 0 | 1–8 | 17–75 | 50 | 0 |
| Notes: Values are percentages (%). Reference ligands (100%) were prome- gestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, E2 for the ERTooltip estrogen receptor, DEXATooltip dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, DHTTooltip dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: ||||||||

### Pharmacokinetics

Upon application of a transdermal patch containing norelgestromin and ethinyl estradiol, plateau levels of both are reached by approximately 48 hours, and steady-state levels are reached within 2 weeks of application. Absorption following application to the buttock, upper outer arm, abdomen, and upper torso was assessed and, while absorption from the abdomen was slightly lower, it was considered to be therapeutically equivalent for the various areas. Mean levels of norelgestromin at steady-state ranged from 0.305 ng/mL to 1.53 ng/mL, with an average of about 0.725 ng/mL. The plasma protein binding of norelgestromin is 99%, and it is bound to albumin but not to sex hormone-binding globulin.
The metabolism of norelgestromin takes place in the liver and is via transformation into levonorgestrel (conversion of the C3 oxime into a ketone) as well as hydroxylation and conjugation. However, because norelgestromin is used parenterally, first-pass metabolism in the liver and gastrointestinal tract that normally occurs with oral administration are avoided. The biological half-life of norelgestromin is 17 to 37 hours. The metabolites of norelgestromin, along with those of ethinyl estradiol, are eliminated in the urine and feces.

## Chemistry

Norelgestromin, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime, is a synthetic estrane steroid and a derivative of testosterone. It is a racemic mixture of E and Z isomers, which have approximately the same activity. Norelgestromin is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins. It is the C3 oxime derivative of levonorgestrel and the C17β deacetyl derivative of norgestimate and is also known as levonorgestrel 3-oxime and as 17β-deacetylnorgestimate. A related progestin is norethisterone acetate oxime (17α-ethynyl-19-nortestosterone 3-oxime 17β-acetate).

## History

Norelgestromin was introduced for medical use in 2002.

## Society and culture
### Generic names

Norelgestromin is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name. The combined ethinyl estradiol and norelgestromin contraceptive patch is also known by its developmental code name RWJ-10553.

### Brand names

Norelgestromin is marketed under the brand names Evra, Ortho Evra, Xulane, and others, all in combination with ethinylestradiol.

### Availability

Norelgestromin is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, Asia, and elsewhere in the world. It is not listed as being marketed in Australia, New Zealand, Japan, South Korea, China, India, or certain other countries.

## Research

A transdermal gel formulation of norgelstromin and ethinyl estradiol was under development by Antares Pharma for use as a method of birth control with the code name AP-1081 but development was discontinued.