Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, emergency contraceptives, ATC code: G03AD01

Machanism of action:
The precise mode of action of levonorgestrel as an emergency contraceptive 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.

Clinical efficacy and safety:
The pregnancy rate was 1.1% (11/976) in an earlier clinical study (Lancet 1998: 352: 428-33) where 750 micrograms of levonorgestrel was taken as two 750 microgram doses with a 12 hour interval.Pregnancy rates appeard to increase with time of start of treatment after intercourse (0.4% [2/450] within 24 hours, 1.2% [4/338] 25-48 hours, 2.7% [5/187] if started between 49 and 72 hours).

Results from a randomized, double-blind clinical study conducted in 2001 (Lancet 2002: 360: 1803-1810) showed 1.34% (16/1 198) pregnancy rate with 1500 microgram
single dose of levonorgestrel /two 750 microgram tablets of levonorgestrel taken at the same time (taken within 72 hours of unprotected sex) (compared with 1.69% [20/11 832] when two 750 microgram tablets were taken 12 hours apart). 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).

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) which means it prevents pregnancy in 99% of situations (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 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      Normal           Overweight      Obese 0 - 18.5         18.5-25          25-30             ≥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          Normal          Overweight        Obese 0 - 18.5             18.5-25         25-30               ≥ 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.

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).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
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 18.5ng/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 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.

Biotransformation
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.

Elimination
Levonorgestrel is not excreted in unchanged form but as metabolites. Levonorgestrel metabolites are excreted in about equal proportions with urine and faeces.

Pharmacokinetics in obese women
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.