CLINICAL PHARMACOLOGY
Mechanism of Action
Emergency contraceptive pills are not effective if a woman is already pregnant. Plan B One-Step is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.
Pharmacokinetics
Absorption
Following a single dose administration of Plan B One-Step in 30 women under fasting conditions, maximum plasma concentrations of levonorgestrel of 19.1 ng/mL were reached at 1.7 hours. See Table 2.
Table 2. Pharmacokinetic Parameter Values Following Single Dose Administration of Plan B One-Step (levonorgestrel) tablet 1.5 mg to 30 Healthy Female Volunteers under Fasting Conditions
| Mean (± SD) |
| Cmax (ng/mL) |
AUCt (ng·hr/mL)
|
AUCinf (ng·hr/mL)
|
Tmax (hr)
|
t1/2 (hr) |
Levonorgestrel |
19.1
(9.7) |
294.8
(208.8) |
307.5
(218.5) |
1.7
(1.0-4.0) |
27.5
(5.6) |
Cmax = maximum concentration AUCt = area under the drug concentration curve from time 0 to time of last determinable concentration AUCinf = area under the drug concentration curve from time 0 to infinity Tmax = time to maximum concentration t1/2 = elimination half life
|
Effect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of Plan B One-Step has not been evaluated.
Distribution
The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.
Metabolism
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates 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 16βhydroxylevonorgestrel. 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.
Excretion
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
Specific Populations
Pediatric
This product is not intended for use in the premenarcheal population, and pharmacokinetic data are not available for this population.
Geriatric
This product is not intended for use in postmenopausal women, and pharmacokinetic data are not available for this population.
Race
No formal studies have evaluated the effect of race. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both Plan B and the Yuzpe regimen (another form of emergency contraception). There was a non-statistically significant increased rate of pregnancy among Chinese women in the Plan B One-Step trial. The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown [see USE IN SPECIFIC POPULATIONS (8.6)].
Hepatic Impairment
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Plan B One-Step.
Renal Impairment
No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B One-Step.
Drug-Drug Interactions
No formal drug-drug interaction studies were conducted with Plan B One-Step [see DRUG INTERACTIONS (7)].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity: There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for 2 years at approximately 5 µg/day, to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 µg/kg/day. In another 7 year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.
Genotoxicity: Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.
Fertility: There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.
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