RECLIPSEN- desogestrel and ethinyl estradiol
Watson Pharma, Inc.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
RECLIPSEN™ Tablets provide an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18, 19- dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)- trien-20-yne-3, 17, diol). Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, corn starch, povidone, stearic acid and vitamin E. RECLIPSEN also contains 7 green tablets containing the following inactive ingredients: anhydrous lactose, D&C Yellow No. 10, FD&C Blue No. 2, magnesium stearate and microcrystalline cellulose.
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 changes in the endometrium which reduce the likelihood of implantation.
Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity91,92. The relevance of this latter finding in humans is unknown.
Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.
In the third cycle of use after a single dose of RECLIPSEN™, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC0-∞ ) is 33,858 ± 11,043 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL•hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of RECLIPSEN, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of RECLIPSEN, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24 , at steady state is 1,117 ± 302 pg/mL•hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.
The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.
RECLIPSEN™ Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.
In a clinical trial with RECLIPSEN, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.
|TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES.|
|% of Women Experiencingan Unintended Pregnancywithin the First Year of Use||% of WomenContinuing Useat One Year 3|
|Method(1)||Typical Use 1 (2)||Perfect Use 2 (3)||(4)|
|Copper T 380A||0.8||0.6||78|
|Norplant and Norplant-2||0.05||0.05||88|
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected
intercourse reduces the risk of pregnancy by at least 75%.9
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10
Source: Trussel J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, ContraceptiveTechnology: Seventeenth Revised Edition. New York, NY; Irvington Publishers, 1998.
|1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.|
|2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.|
|3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.|
|4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.|
|5 Foams, creams, gels, vaginal suppositories, and vaginal film.|
|6 Cervical mucus (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the post-ovulatory phases.|
|7 With spermicidal cream or jelly.|
|8 Without spermicides.|
|9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 4 yellow pills).|
|10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.|
RECLIPSEN has not been studied for and is not indicated for use in emergency contraception.