Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
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. Levonorgestrel is not effective once the process of implantation has begun.
Results from the randomised, double-blind clinical studies conducted in 1998, 2001 and 2010 showed that 1500 microgram levonorgestrel (taken within 72 hours of unprotected sex) prevented 85%, 84%, 97% of expected pregnancies, respectively.
The pregnancy rate (number of observed pregnancies in women taking EC/total number of women taking EC) was 1.1%, 1.34%, and 0.32%, respectively. Prevented fraction appeared to decrease and pregnancy rates appeared to increase with time of start of treatment after unprotected intercourse, highest efficacy is reached when EC is taken within 24 hours after intercourse. Efficacy appears to decrease with increasing time from unprotected intercourse.
Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010) showed that the pregnancy rate of levonorgestrel is 1.01% (59/5 863) (compared to an expected pregnancy rate of about 8% in the absence of emergency contraception) see Table 1.
Table 1. Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010):
| Levonorgestrel dose | Treatment delay in days | Prevented fraction (95% CI)* | Pregnancy rate | |
|---|---|---|---|---|
| Von Hertzen, 1998 | 0.75 mg (two doses taken 12 h apart) | Day 1 (≤ 24 h) | 95% | 0.4% |
| Day 2 (25-48 h) | 85% | 1.2% | ||
| Day 3 (49-72 h) | 58% | 2.7% | ||
| All women | 85% | 1.1% | ||
| Von Hertzen, 2002 | 1.5 mg (single dose) | 1-3 days | 84% | 1.34% |
| 0.75 mg (two doses taken together) | 1-3 days | 79% | 1.69% | |
| Dada, 2010 | 1.5 mg (single dose) | 1-3 days | 96.7% | 0.40% |
| 0.75 mg (two doses taken together) | 1-3 days | 97.4% | 0.32% | |
| Meta-analysis of all three WHO studies | - | - | 1.01% | |
* CI: confidence interval (compared to an expected pregnancy rate of about 8% in the absence of emergency contraception)
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 2), 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 3). 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 2. 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 3. 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 absolute bioavailability of levonorgestrel was determined to be almost 100% of the dose administered.
The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of one tablet of Levonelle 1500 maximum drug serum levels of levonorgestrel of 18.5 ng/ml were found at 2 hours.
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.
About 0.1% of the maternal dose can be transferred via milk to the nursed infant.
The biotransformation follows the known pathways of steroid metabolism, the levonorgestrel is hydroxylated by liver enzymes mainly by CYP3A4 and its metabolites are excreted after glucuronidation by liver glucuronidase enzymes. (See section 4.5).
No pharmacologically active metabolites are known.
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.
A pharmacokinetic study showed that 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 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.
Animal experiments with levonorgestrel have shown virilisation of female fetuses at high doses.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenicity potential beyond the information included in other section of the SPC.
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