Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Generics (UK) Ltd t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, emergency contraceptives
ATC code: G03AD01
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. Ezinelle is not effective once the process of implantation has begun.
Results from a randomised, double-blind clinical study conducted in 2001 (Lancet 2002; 360: 1803-1810) showed that a 1500 microgram single dose of levonorgestrel (taken within 72 hours of unprotected sex) prevented 84% of expected pregnancies (compared with 79% when the two 750 microgram tablets were taken 12 hours apart).
Another study conducted in 1997 (Lancet 1998; 352: 428–33) showed that two 750 microgram doses taken 12 hours apart prevents 85% of expected pregnancies.
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.
Table 1. Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010):
| BMI (kg/m²) | Underweight 0–18.5 | Normal 18.5–25 | Overweight 25–30 | Obese ≥30 |
|---|---|---|---|---|
| N total | 600 | 3952 | 1051 | 256 |
| N pregnancies | 11 | 39 | 6 | 3 |
| Pregnancy rate | 1.83% | 0.99% | 0.57% | 1.17% |
| Confidence interval | 0.92–3.26 | 0.70–1.35 | 0.21–1.24 | 0.24–3.39 |
Table 2. Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010:
| BMI (kg/m²) | Underweight 0–18.5 | Normal 18.5–25 | Overweight 25–30 | Obese ≥30 |
|---|---|---|---|---|
| N total | 64 | 933 | 339 | 212 |
| N pregnancies | 1 | 9 | 8 | 11 |
| Pregnancy rate | 1.56% | 0.96% | 2.36% | 5.19% |
| Confidence interval | 0.04–8.40 | 0.44–1.82 | 1.02–4.60 | 2.62–9.09 |
At the recommended regimen, levonorgestrel is not expected to induce significant modification of blood clotting factors, and lipid and carbohydrate metabolism.
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).
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 levonorgestrel 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.
Animal experiments with levonorgestrel have shown virilisation of female foetuses at high doses.
Preclinical data from conventional studies on chronic toxicity, mutagenicity and carcinogenicity reveal no special hazard for humans, beyond the information included in other sections of the SmPC.
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