Alesse (Ethinyl Estradiol; Levonorgestrel)
Brand Name(s): Alesse®-21, Alesse®-28, Aviane™-28, Enpresse® Triphasic, Lessina™-28, Levlen®, Levlite™, Levora®, Lutera™, Nordette®, Preven™, Seasonale®, Tri-Levlen®, Triphasil®-28, Trivora® | Enpresse™ 28 | Portia™ | Triphasil®-21
Classification:
Hormones and Hormone Modifiers
Description: Ethinyl estradiol and levonorgestrel are used together as an oral contraceptive agent. Ethinyl estradiol is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. Levonorgestrel is the most widely prescribed contraceptive progestin worldwide. Levonorgestrel has high progestational and androgenic activity, and negatively affects serum lipoproteins. LDL cholesterol is increased, and HDL cholesterol is lowered. Low-dose estrogen formulations (e.g., Alesse®, Aviane™, Lessina™ and Levlite™) are available. Levonorgestrel containing combination products can be used in the US as a postcoital ‘emergency’ contraceptive, and one product, Preven™, is FDA approved for this purpose. The FDA has explicitly declared all levonorgestrel containing combination products to be safe and effective for this use. In Europe and South Africa, 4-pill strips identical to Preven™ in dosage are marketed for emergency contraception. From clinical studies involving over 5000 women, the pooled failure rate of levonorgestrel containing combination products for postcoital contraception is around 3%. Levonorgestrel containing oral contraceptive combinations were first approved by the FDA in 1982. The Preven™ emergency contraceptive kit was approved by the FDA in September 1998. A new ‘continuous dosage’ product of ethinyl estradiol; levonorgestrel, Seasonale®, can be taken continuously for 84 days and was FDA approved for routine contraception in September 2003; this regimen allows women to have less withdrawal bleeds (menstrual periods) per year. A second continuous dosage product Seasonique™ received an ‘approvable’ letter as an oral contraceptive by the FDA in August of 2005; Seasonique™ is similar to Seasonale® in that ethinyl estradiol; levonorgestrel is taken continuously for 84 days; however, with Seasonique™, the final 7 days of the three month cycle contain low-dose ethinyl estradiol rather than inert tablets. The FDA has indicated that the drug will be approved once additional data supporting its use are available.
Mechanism of Action: The primary action of the combination of an estrogen with a 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 addition, viscosity of the cervical mucus increases with hormonal contraceptive use, preventing penetration of sperm. Alteration in endometrial tissues also occurs. When traditional regimens of oral contraception are 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.
The mechanism for postcoital oral contraception is not well understood. Evidence exists at several stages of the reproductive cycle. Most of the scientific evidence suggests that inhibition or delay of ovulation is the primary mechanism of action. However, fertilization, embryo transport, or implantation may be disrupted as secondary mechanisms. Postcoital regimens will not interrupt an established (implanted) pregnancy. It is important to note that postcoital contraception is not intended to replace traditional oral contraceptive use. Long term effects of frequent, repetitive use of emergency contraceptive regimens are unknown.
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, and lack of estrogen is now recognized as a risk factor for myocardial infarction. 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. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate sebaceous gland hyperresponsiveness to androgens and lead to acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
Pharmacokinetics: Following oral administration in the third cycle of use, 83% of ethinyl estradiol survives absorption and first pass through the liver. Levonorgestrel is approximately 100% bioavailable. Both hormones are widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). Levonorgestrel is strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG).
Alesse 28 Tablets(Tab 0.02;0.1 mg;mg)
Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate. 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. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling.
Levonorgestrel undergoes hydroxylation and then conjugation to sulfate and glucuronide salts. Sulfation is the major metabolic pathway. No entero-hepatic recycling occurs.
Excretion of the oral contraceptive steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is 8 - 13 hours for levonorgestrel and 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormones that allows for once-daily administration.
[1 of 20 - Click here to see more photos]
[ Revised 5/1/2006 4:41:00 PM ]
Related entries
Monthly Archives
Syndicate
Allergies
