Pharmacology: Mode of action: COCs 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 in the endometrium (which reduce the likelihood of implantation).
Pharmacodynamics, clinical efficacy: When taken consistently and correctly, the probable failure rate of COCs is 0.1% per year; however, the failure rate during typical use is 5% per year for all types of oral contraceptives. The efficacy of most methods of contraception depends upon the reliability with which they are used. Method failure is more likely if COC tablets are missed.
The following noncontraceptive health benefits related to the use of COCs are supported by epidemiological studies that largely utilized COC formulations containing doses exceeding 35 μg of EE or 50 μg of mestranol.
Effects on menses: Improved menstrual cycle regularity; Decreased blood loss and decreased incidence of iron-deficiency anemia; Decreased incidence of dysmenorrhea.
Effects related to inhibition of ovulation: Decreased incidence of functional ovarian cysts; Decreased incidence of ectopic pregnancies.
Other noncontraceptive health benefits: Decreased incidence of fibroadenomas and fibrocystic disease of the breast; Decreased incidence of acute pelvic inflammatory disease; Decreased incidence of endometrial cancer; Decreased incidence of ovarian cancer; Decreased severity of acne.
Oral Contraception: The contraceptive effect of the hormonal components contained in Loette is based on the interaction of various factors, the most important of which are the inhibition of ovulation (by suppression of gonadotropin release) and changes in the cervical mucus (which increase the difficulty of sperm penetration into the uterus). Additionally, changes in the endometrium reduce the likelihood of implantation.
Acne: Acne treatment with Loette is based on estrogen-induced increases in sex hormone binding globulin (SHBG). Because testosterone binds to SHBG, bioavailable testosterone is reduced. In addition, Loette suppresses gonadotropin production, leading to decreased ovarian production of androgens, including androstenedione. Serum levels of 3 α-androstanediol glucuronide (a marker of peripheral 5 α- reductase activity) are also reduced. These biochemical changes produced by the co-administration of levonorgestrel and ethinyl estradiol are associated with improvement of acne in otherwise healthy women.
Clinical Studies: Oral Contraception: An open-label multicenter phase III clinical study was conducted in 1,447 women receiving Loette. Of 7,720 cycles of exposure evaluable for efficacy, a total of 5 pregnancies were reported. This represents an overall user-efficacy (typical userefficacy) pregnancy rate of 0.84 per 100 woman-years. This rate includes patients who did not take the drug correctly. Cycle control was also evaluated by analyzing cycle characteristics such as duration and intensity of withdrawal bleeding and the incidence of breakthrough bleeding and amenorrhea. A total of 7,508 cycles were valid for cycle control analysis; the overall incidence of intermenstrual bleeding was low. Breakthrough bleeding alone and spotting alone occurred during 4.3% and 12.1% of cycles, respectively. Breakthrough bleeding and spotting occurred in 11.0% of the cycles, while breakthrough bleeding and/or spotting occurred in 27.3% of the cycles. Overall, 2.6% of cycles were amenorrheic. The length of withdrawal bleeding was 3 to 7 days in 86% of cycles, and the mean intensity was light for the most common episode length (4 to 6 days). The mean cycle length, excluding cycle 1, was 29.1 days, and 90% of the cycles ranged in duration from 26 to 30 days.
Acne: Two (2) randomised, double blind, placebo-controlled, 6-cycle, multicenter, phase III clinical studies were done to evaluate the efficacy and safety of levonorgestrel/ethinylestradiol (LNG/EE) 100 μg/20 μg for the treatment of moderate acne. Study 1 was conducted at 12 sites in the United States and at 1 site in Canada and Australia, and study 2 was conducted at 18 sites in the United States. Patients in studies 1 and 2 were randomly assigned to receive 28-day packs of either LNG/EE or placebo tablets. Those in the LNG/EE group received active tablets for 21 consecutive days and inert tablets for the subsequent 7 days. The study medication was taken for up to 6 cycles during the studies. Moderate acne was defined in the Clinical Trials as a total facial count of 6-200 non-inflammatory lesions (comedones), 10-75 inflammatory lesions (papules and pustules) and 0-5 nodules.
In both studies, LNG/EE treatment consistently produced greater mean reductions in lesion counts than placebo treatment. Generally, the differences between treatment groups became apparent at cycles 2 or 3 and increased over time, becoming significant at cycles 4, 5, or 6. The combined clinical global assessment results showed that a significantly greater percentage of patients in the LNG/EE treatment group than in the placebo group rated clear or mild at end of study (EOS).
Pharmacokinetics: Levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract. It is subject to minimal first-pass metabolism and is almost completely bioavailable following oral administration. Levonorgestrel is primarily metabolized by reduction of the A-ring followed by glucuronidation. The majority of an oral dose of levonorgestrel is eliminated as conjugates of glucuronide or sulfate with considerably smaller portions appearing as free metabolites. Approximately 43-45% of levonorgestrel is eliminated in the urine and approximately 32% in the feces.
After a single dose of Loette, maximum plasma concentrations (Cmax) of levonorgestrel of 2.8 ± 0.9 ng/ml (mean ± SD) are reached at 1.6 ± 0.9 hours. The area under the curve (AUC0-∞ is 35.2 ± 12.8 ngr/ml after a single dose. Following 21 days of Loette therapy, steady state Cmax values of 6.0 ± 2.7 ng/ml are attained at 1.5 ± 0.5 hours after the daily dose. The minimum plasma concentrations of levonorgestrel at steady state are 1.9 ± 1.0 ng/ml. The AUC0-24 at steady state is 68.3 ± 32.5 ng·hr/ml. The mean AUC0-∞ for levonorgestrel after a single dose is significantly lower than the mean AUC0-24 at steady state. In addition, sex hormonebinding globulin (SHBG) levels increased significantly from day 1 (57 ± 18 nmol/l) to day 21 (93 ± 40 nmol/l), induced by the daily administration of ethinylestradiol. Therefore, the non-linear kinetics of levonorgestrel are due to an increase in binding of levonorgestrel to SHBG. The elimination half-life for levonorgestrel in combination with ethinylestradiol is approximately 36 ± 13 hours at steady state.
Ethinylestradiol is rapidly and almost completely absorbed from the gastrointestinal tract. Ethinylestradiol undergoes extensive first-pass metabolism. The mean bioavailability is about 43% with marked interindividual variation. Ethinylestradiol is highly bound to albumin and induces an increase in the plasma concentration of SHBG. Ethinylestradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronide or sulfate. Conjugated ethinylestradiol is excreted in bile and is subject to enterohepatic recirculation.
After a single dose of Loette, Cmax values of ethinylestradiol of 62 ± 21 pg/ml are reached at 1.5 ± 0.5 hours. The AUC0-∞ is 653 ± 227 pg·hr/ml after a single dose. Following at least 6 daily doses of Loette treatment, steady state Cmax values of ethinylestradiol are 77 ± 30 pg/ml and are reached at 1.3 ± 0.7 hours. The AUC0-24 at steady state is 604 ± 231 pg·hr/ml. Following 21 days of treatment, steady state Cmax values of ethinylestradiol of 82 ± 33 pg/ml are reached at 1.4 ± 0.6 hours after the daily dose. The minimum plasma concentrations of ethinylestradiol at steady state are 10.5 ± 5.1 pg/ml. The AUC0-24 at the end of 21 days of treatment is 776 ± 308 pg·hr/ml. The elimination half-life of ethinylestradiol in combination with levonorgestrel is 18 ± 4.7 hours at steady state.
Toxicology: Preclinical safety data: None.