Ortho Evra (Ethinyl Estradiol; Norelgestromin)
Ethinyl Estradiol; Norelgestromin
Brand name: Ortho Evra™
Classification:
Hormones and Hormone Modifiers
- Non-oral combination contraceptives
Description: Ethinyl estradiol; norelgestromin (also known as deacetylnorgestimate), trade name Ortho Evra® is a hormonal contraceptive. Unlike combination hormonal oral contraceptives (OCs), Ortho Evra® is a transdermal patch system with once-a-week dosing. The patch is worn for one week and replaced on the same day of the week for 3 consecutive weeks, with the 4th week ‘patch-free.’ Ethinyl estradiol is an estrogen commonly found in combination hormonal contraceptives. Norelgestromin is a progestin of high progestational, slight estrogenic, and low androgenic activity; this drug is the primary active metabolite produced following oral administration of norgestimate. The progestin has little effect on serum lipoproteins and has very little negative effect on carbohydrate metabolism. When compared to OCs, the ethinyl estradiol; norelgestromin contraceptive patch provides similar clinical contraceptive efficacy rates (99% effective). There is no epidemiologic data available to determine whether the safety and efficacy of transdermal delivery of these hormones differs from that of OCs. However, it should be noted that the pharmacokinetic profile for the Ortho Evra® transdermal patch is different from the profile for oral contraceptives; overall exposure (i.e., AUC and steady-state concentrations) for ethinyl estrogen is higher for transdermal patch users while peak concentrations are lower. In general, women are exposed to approximately 60% more estrogen when using the transdermal patch. In addition, inter-subject variability in women using the transdermal patch is high, and some women may be exposed to even higher concentrations of estrogen. It is possible that increased estrogen exposure may be associated with an increased risk of serious adverse events. Practitioners prescribing Ortho Evra® should be familiar with the information relating to the standard risks and benefits of combined oral hormonal contraceptives; the risk of higher estrogen exposure with the transdermal patch should be balanced against the chance of conception if an oral contraceptive pill is not taken daily. The FDA approved this first transdermal contraceptive on November 20, 2001. The transdermal system is expected to improve patient acceptability and compliance with hormonal contraception. On February 17 2006, Johnson & Johnson reported the results of 2 epidemiologic studies in women using the Ortho Evra® transdermal patch. In the first study, the results indicate that women naive to hormonal contraception using the transdermal patch are not at increased risk of venous thromboembolism (VTE) when compared to women taking a daily oral contraceptive containing norgestimate and ethinyl estradiol 35 mcg. Interim results from a second objective of this study indicate that there is not an increased risk of stroke or heart attack in Ortho Evra® users. In the second study, which is similar in design to the first, the interim results also do not indicate an increased risk of stroke or heart attack; however, in women using the Ortho Evra® transdermal patch, the risk of VTE is increased 2-fold. Further analyses, including the risk factors for those patients at increased risk of VTE, are ongoing.
Mechanism of Action: The primary action of a combined hormonal contraceptive containing an estrogen and progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In pharmacodynamic studies comparing the actions of ethinyl estradiol; norelgestromin (Ortho Evra™) transdermal patch to OCs, transdermal delivery more completely suppressed follicular development. Viscosity of the cervical mucus also increases with hormonal contraceptive use, preventing penetration of sperm; an alteration in endometrial tissue also occurs. When hormonal contraception is discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology.
Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention.
Progestins are classified according to their progestational, estrogenic and androgenic properties. Norelgestromin combines high progestational activity with low androgenicity. Progestins in general can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins, like norelgestromin, have only slight effects on carbohydrate metabolism and are less likely to aggravate sebaceous glands and acne.
Serious adverse events to combined hormonal contraception, like thrombosis, have long been associated with the estrogen component but the specific progestin in the combined contraceptive may also have some effect. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects of hormonal contraception can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
 Ortho Evra Transdermal Patch (Film, Extended Release 20;150 mcg/24hr;mcg/24hr)
Pharmacokinetics: Ethinyl estradiol; norelgestromin is applied to the skin in the form of a transdermal delivery system. Following transdermal patch application, both norelgestromin and ethinyl estradiol (EE) reach a plateau by approximately 48 hours; pooled data from 3 clinical studies demonstrate that steady-state is reached within 2 weeks of application. The mean steady-state concentrations for norelgestromin and EE are 0.305 - 1.53 ng/ml and 11.2 - 137 pg/ml, respectively. In multiple dose studies, AUC for both norelgestromin and EE increase over time; pharmacokinetic parameters reach steady-state conditions during cycle 3. Results from a study of consecutive norelgestromin and EE transdermal patch wear for 7 days and 10 days indicate that serum concentrations of norelgestromin and EE drop slightly during the first 6 hours after patch replacement, but recover within 12 hours. By day 10 of patch administration, both norelgestromin and EE concentrations have decreased by approximately 25% compared to day 7 concentrations. When compared to a daily oral contraceptive containing norelgestromin 250 mcg and EE 35 mcg, overall exposure to norelgestromin and EE is higher in patients treated with the transdermal patch. Of interest, exposure to estrogen is significantly higher in women using the patch with estrogen AUC and steady-state concentrations approximately 55% and 60% higher, respectively. Conversely, Cmax for EE is about 35% higher for the oral contraceptive. In addition, inter-subject variability for the pharmacokinetic parameters is higher for patients using the transdermal patch compared with patients taking the oral contraceptive. The mean pharmacokinetic profiles of the 2 products (i.e., oral contraceptive and the transdermal patch) are different; direct comparisons between these parameters should be used cautiously.
Absorption from the abdomen, buttock, upper outer arm and upper torso (excluding breast) were equivalent to one another in pharmacokinetic studies. All 4 application sites for the EE; norelgestromin patch may be considered therapeutically equivalent. The absorption of norelgestromin and EE following application of the patch was also studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. There were no significant treatment effects on steady-state concentrations or AUC of norelgestromin when compared to normal wear. For EE, slight increases in these values were observed due to sauna, whirlpool and treadmill; however, the values were within the reference range. There was no significant effect of cold water on these parameters.
After absorption, norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of sex hormone-binding globulin (SHBG), a marker of estrogenic activity. Changes in SHBG concentrations are higher in patients using the EE; norelgestromin transdermal patch when compared to the oral contraceptive (334% for the transdermal patch vs. 200% for the oral contraceptive).
Because of transdermal administration, first-pass metabolism (via the gastrointestinal tract and/or liver) of norelgestromin and EE that would be expected with oral administration is avoided. Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinylestradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. The metabolites of EE are eliminated by renal and fecal pathways. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract upon elimination and then undergo entero-hepatic recycling. Norelgestromin is also metabolized in the liver; metabolites may subsequently undergo glucuronide and sulfate conjugation before elimination via renal and fecal pathways. Following removal of the patch, the half-lives for norelgestromin and EE are approximately 28 hours and 17 hours, respectively, and serum levels of norelgestromin and EE reach very low or non-measurable levels within 3 days.
Special Populations: Serum concentrations of ethinyl estradiol; norelgestromin may be reduced in patients who are morbidly obese and may lead to reduced efficacy. Race has no effect on pharmacokinetics. No formal studies were conducted to evaluate the pharmacokinetic parameters of this patch in females with renal or hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function, and hormonal contraceptives are contraindicated in active liver disease or severe hepatic impairment.
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[ Revised 4/7/2006 2:03:00 PM ]
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