Wednesday, November 27, 2013

Obese patients and emergency contraception

In a story featured on NPR yesterday, news of additional warning information on labeling for oral emergnecy contraception in Europe has raised questions as to why similar label changes have not yet occured in the USA. The story focuses on a recent meta-analysis [1] that describes the effectiveness of the oral emergency contraceptives levonorgestrel (Plan B) and ulipristal acetate (Ella). In this case, I must agree with the FDA, that there is not enough data to make a change in the labeling, and further analysis needs to take place.

The meta-analysis was comprised of 2 studies randomizing patients to either agent 72 hours and 120 hours (levornorgestrel significantly looses efficacy after 96 hours) after unprotected intercouse, respectively. In each study, only patients who followed up were included. In total, of the 3445 patients included, there were 60 pregnancies, of which, 38 occured in patients who recieved levonorgestrel and 22 who recieved ulipristal. Despite this small number of pregnancies, a large amount of analysis was conducted. In short, while ulipristal was associated with a significantly reduced risk of pregnancy, both agents were associated with a reduced efficacy at higher BMIs (>30)- levornorgestrel had the greates loss of effectiveness. But again, the numbers were quite small; 6 pregnancies of 227 patients with BMI >30 who were randomized to ulipristal and 14 of 242 with BMI >30 randomized to levonorgestrel. Converting BMI to weight, levonorgestrel appeared to be less effective in patients who weighed >70 kg, and ulipristal loosing effectiveness in patients weighing >88kg. When reviewing each study individually,[2,3] ulipristal was non-inferior to levonorgestrel, and there were no investigations into the effect of of BMI or weight. However, upon each meta-analysis conducted, ulipristal was consistently shown to be superior. Before too much skeptecism creeps in, and investigation into the funding sources of these studies (when they're even disclosed), it is worth investigating the pharmacokinetic theory that may exist.

In obese patients, there are a number of assumptions regarding what pharmacokinetic and pharmacodynamic changes occur. The only agreement is that changes do occur. Most of the data we use to dose medications in obese patients are either 1) computer modeled over-simplifications with assumed variables or 2) based on social definitions (like ideal body weight) that were never intended to be used for medication dosing purposes. But, in general, it is assumed that a lipophilic drug with a large volume of distribution (for example; levonorgestre; Vd of 1.8 L/kg) would be predicted to have lower plasma concentrations due to higher volume of adipose tissue, thustly, lower efficacy. However, the PK data with levonorgestrel demonstrates that there is no change in Vd in obese patients, but rather, an increase in AUC (total exposure), longer half-life, longer time to steady state and decreased hypothalamic-pituitary-ovarian inhibition.[4]

Despite these observations, according to the latest Cochrane analysis, there is no change in effectiveness of OC with increasing BMI.[5] Important to note, however, is that these studies are analyzing long term OC use- not emergency OC.

Extrapolating the PK data to emergency OC use, one could theorize that with a larger AUC, and longer time to steady-state, a one time dose may loose effectiveness. What is equally unclear is the impact of increasing the dose. It is clear that the effect of decreased effectiveness is not exclusive to ulipristal,[6] and should not be considered an alternative in obese patients (as described in the NPR piece), copper IUDs would be considered as an alternative.

1] Glasier A, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception 84 (2011) 363–367
2] Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006;108:1089–97
3] Glasier A, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized noninferiority trial and meta-analysis. Lancet 2010;375:555–62 
4]Edelman A, Carlson N, Cherala G, et al. Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity. Contraception. 2009 August; 80(2): 119–127
5]Lopez LM, Grimes DA, Chen M, et al. Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev. 2013 Apr 30;4:CD008452. doi: 10.1002/14651858
6]Moreau C, Trussell J.Results from pooled Phase III studies of ulipristal acetate for emergency contraception. Contraception 86 (2012) 673–680