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Pharmacology: Pharmacodynamics: The precise mode of action of levonorgestrel is not known.
At the recommended regimen, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase, when the likelihood of fertilisation is the highest. Levonorgestrel is not effective once the process of implantation has begun.
Efficacy: It was estimated from the results of an earlier clinical study, that 750 micrograms of levonorgestrel (taken as two 750 microgram doses with a 12 hour interval) prevents 85% of expected pregnancies. Efficacy appears to decline with time of start of treatment after intercourse (95% within 24 hours, 85% 24-48 hours, 58% if started between 48 and 72 hours).
Results from a recent clinical study showed that two 750 microgram tablets of levonorgestrel taken at the same time (and within 72 hours of unprotected sex) prevented 84% of expected pregnancies. There was no difference between pregnancy rates in case of women who were treated on the third or the fourth day after the unprotected act of intercourse (p>0.2).
There is limited and inconclusive data on the effect of high body weight/high BMI on the contraceptive efficacy. In three WHO studies no trend for a reduced efficacy with increasing body weight/BMI was observed (Table 1), whereas in the two other studies (Creinin et al., 2006 and Glasier et al., 2010) a reduced contraceptive efficacy was observed with increasing body weight or BMI (Table 2). Both meta-analyses excluded intake later than 72 hours after unprotected intercourse (i.e. off-label use of levonorgestrel) and women who had further acts of unprotected intercourse. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageAt the recommended regimen, levonorgestrel is not expected to induce significant modification of blood clotting factors, and lipid and carbohydrate metabolism.
Paediatric population: A prospective observational study showed that out of 305 treatments with levonorgestrel emergency contraceptive tablets, seven women became pregnant resulting in an overall failure rate of 2.3%. The failure rate in women under 18 years (2.6% or 4/153) was comparable to the failure rate in women 18 years and over (2.0% or 3/152).
Pharmacokinetics: Orally administered levonorgestrel is rapidly and almost completely absorbed.
The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of single dose of 1.5 mg levonorgestrel maximum drug serum levels of 18.5 ng/ml were found at 2 hours.
After reaching maximum serum levels, the concentration of levonorgestrel decreased with a mean elimination half-life of about 26 hours.
Levonorgestrel is not excreted in unchanged form but as metabolites. Levonorgestrel metabolites are excreted in about equal proportions with urine and faeces. The biotransformation follows the known pathways of steroid metabolism, the levonorgestrel is hydroxylated in the liver and the metabolites are excreted as glucuronide conjugates.
No pharmacologically active metabolites are known.
Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG). Only about 1.5% of the total serum levels are present as free steroid, but 65% are specifically bound to SHBG.
The absolute bioavailability of levonorgestrel was determined to be almost 100% of the dose administered.
About 0.1% of the maternal dose can be transferred via milk to the nursed infant.
