Source: Health Products Regulatory Authority (IE) Revision Year: 2019 Publisher: Laboratoire HRA Pharma, 200 avenue de Paris, 92320 CHATILLON, France
Pharmacotherapeutic group: EMERGENCY CONTRACEPTIVES
ATC code: G03AD01
The primary mechanism of action is blockade and/or delay of ovulation via suppression of the luteinizing hormone (LH) peak. Levonorgestrel interferes with the ovulatory process only if it is administered before the onset of the LH surge. Levonorgestrel has no emergency contraceptive effect when administered later in the cycle.
In clinical trials, the proportion of pregnancies avoided after the use of levonorgestrel varied from 52% (Glasier, 2010) to 85% (Von Hertzen, 2002) of expected pregnancies. Efficacy appears to decline with time after intercourse.
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. For pharmacokinetic studies in obese women see section 5.2.
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 used regimen, levonorgestrel is not expected to induce significant modifications 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).
After oral administration of 1.5 mg levonorgestrel, the plasma terminal half-life of the product is estimated to 43 hours. The maximal plasma concentration of levonorgestrel (approximately 40 nmol/l) is reached within 3 hours.
Levonorgestrel is hydroxylated in the liver and the metabolites are excreted as glucuronide conjugates.
Bioavailability of oral levonorgestrel is approximately 100 percent. In the plasma, it is strongly bound to SHBG. Levonorgestrel is eliminated via kidney (60-80%) and liver (40-50%).
A pharmacokinetic study showed that total levonorgestrel concentrations are decreased in obese women (BMI ≥30 kg/m²) (approximately 50% decrease in Cmax and AUC0-24), compared to women with normal BMI (<25 kg/m²) (Praditpan et al., 2017). Another study also reported a decrease of total levonorgestrel Cmax by approximately 50% between obese and normal BMI women, while doubling the dose (3 mg) in obese women appeared to provide plasma concentration levels similar to those observed in normal women who received 1.5 mg of levonorgestrel (Edelman et al., 2016). The clinical relevance of these data is unclear.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, beyond the information included in other sections of the SmPC. Animal experiments with levonorgestrel have shown virilization of female fetuses at high doses.
A preclinical study conducted in mice showed no effect on fertility in the progeny of treated dams. Two studies investigating the consequence of exposure to levonorgestrel on the development of pre-embryos before implantation, showed that levonorgestrel had no adverse effects on fertilisation and the in vitro growth of mouse pre-embryos.
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