May 29, 2017
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Seasonale

"The widespread use of oral contraceptives (OCs), particularly in the United States and certain countries in the European Union (EU), where they were introduced earlier than elsewhere, is fueling the continued decline in death rates from ovarian c"...

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Seasonale




CLINICAL PHARMACOLOGY

Mechanism Of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with SEASONALE.

Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of SEASONALE in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. EE is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of EE is approximately 43%.

Following continuous dosing with once-daily administration of SEASONALE tablets, plasma concentrations of levonorgestrel and EE reached steady-state within 7 days. The mean plasma pharmacokinetic parameters for SEASONALE under fasting conditions in normal healthy women following once-daily administration of one levonorgestrel/EE combination tablet for 10 days are summarized in Table 5.

Table 5: Mean ±SD Pharmacokinetic Parameters Under Fasting Conditions in Healthy Women Following 10 Days Administration of One Tablet of SEASONALE (n=44)

Analyte AUC0-24 Cmax Cmin Cavga Tmax
Levonorgestrel 54.6 ± 16.5 ng*hr/mL 5.0 ± 1.5 ng/mL 1.6 ± 0.5 ng/mL 2.3 ± 0.7 ng/mL 1.4 ± 0.7 hours
Ethinyl estradiol 935.5 ± 346.9 pg*hr/mL 106.1 ± 41.2 pg/mL 18.5 ± 9.4 pg/mL 38.9 ± 14.4 pg/mL 1.6 ± 0.6 hours
a Cavg = AUC0-24/24

Food Effect

The effect of food on the rate and the extent of levonorgestrel and EE absorption following oral administration of SEASONALE has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and EE are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 -99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. EE is about 95 -97% bound to serum albumin. EE does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of levonorgestrel/EE oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by EE, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of EE involves formation of EE-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed EE by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of EE hydroxylation. Hydroxylation at the 4-, 6-, and 16-positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of SEASONALE was about 30 hours.

EE is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of EE after a single dose of SEASONALE was found to be about 15 hours.

Clinical Studies

In a 12-month, multicenter, randomized, open-label clinical trial, 456 women aged 18-40 were studied to assess the safety and efficacy of SEASONALE, completing 809 91-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (77%), African-American (11%), Hispanic (7%), Asian (2%), and Other (3%).

There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 84 to 304 pounds, with a mean weight of 157 pounds and a median weight of 147 pounds. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 29% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 8% were new starts.

The pregnancy rate (Pearl Index [PI]) in the 397 women aged 18-35 years was 1.98 pregnancies per 100 women-years of use (95% CI: 0.54 to 5.03), based on 4 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.

Last reviewed on RxList: 4/19/2017
This monograph has been modified to include the generic and brand name in many instances.

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