It was established that the efficacy of levonorgestrel (LNG), a standard oral hormonal agent for emergency contraception (EC), is limited during the post-ovulation period.¹ In an attempt to search for efficacious EC options in regulating post-ovulary processes, researchers from the University of Hong Kong’s Faculty of Medicine (HKUMed) evaluated the effects of piroxicam (PXM), a cyclo-oxygenase (COX) inhibitor, as a co-treatment with LNG in improving EC efficacy.¹

Oral hormonal emergency contraception (EC) has been the most widely adopted method to prevent unwanted pregnancies.¹ In Hong Kong, currently available oral EC options include levonorgestrel (LNG) and ulipristal acetate (UPA).¹ As a second-generation progestin, LNG exhibits agonism towards progesterone receptors (PRs), limiting luteinizing hormone (LH) surge, thereby disrupting the ovulatory process, rather than having an effect on implantation.^1,2 Therefore, LNG is effective only when taken before ovulation.¹ Similarly, UPA also did not have a significant effect under post-ovulation settings.¹ Therefore, the efficacy of currently available oral EC methods was somewhat limited.¹

Previous clinical studies had suggested that cyclo-oxygenase (COX) inhibitors may possess a synergistic effect when administered with oral EC methods, thereby producing optimal outcomes in regulating both ovulatory and post-ovulatory processes.¹ Hence, a Hong Kong- based randomized double-blinded trial was conducted to investigate the efficacy of piroxicam (PXM), a COX inhibitor, in facilitating favorable EC outcomes when co-administered with LNG.¹

In this block-randomized, double-blind, placebo-controlled trial, 860 adult women who requested for oral EC within 72 hours after unprotected sexual intercourse at the Family Planning Association of Hong Kong between 2018 and 2022 were randomized 1:1 to receive either 40mg of PXM (n=430) or placebo (n=430) along with their LNG treatment (1.5 mg).¹ At 1-2 weeks after the next expected menstrual period, follow-up involving pregnancy testing and assessment of bleeding events was conducted.¹

The primary endpoint was contraceptive efficacy measured by the percentage of pregnancies prevented based on the number of expected pregnancies in each treatment group.¹ The number of expected pregnancies of each group was determined by the Trussell’s model, based on the daily probabilities of pregnancy relative to the first day of bleeding in a cycle.^1,3 Secondary endpoints included pregnancy rate after taking EC, bleeding pattern deviations of the subsequent menstruation, and occurrence of adverse events.¹  

For the primary outcome, a significantly higher percentage of pregnancies prevented was reported in the PXM group when compared to the placebo group (94.7% vs. 63.4%; p<0.0001), with a risk difference of 31.3% (95% CI: 26.1%-36.3%).¹ Whereas for secondary outcomes, the PXM group demonstrated a significantly lower overall pregnancy rate compared to the placebo group (0.2% vs. 1.7%; OR=0.20; 95% CI: 0.02-0.91; p=0.036).¹ In terms of bleeding patterns of the next menstrual period, both groups exhibited similar and statistically insignificant deviations from the previous menstrual pattern (p=0.14), accompanied with an identical reported incidence of non-menstrual spotting or bleeding within 6 days following intake of EC for both groups (39%).¹ However, the PXM group was associated with a significant perceived reduced in menstrual blood loss when compared to the placebo group (24% vs 16%; p_trend= 0.019).¹

For the safety outcomes, PXM exhibited a desirable safety profile when it was co-administered with LNG, with both treatment groups exhibiting comparable incidence of adverse events with no statistical significance.¹ The most frequently reported adverse events (with frequencies >5%) were fatigue or weakness, nausea, lower abdominal pain, dizziness, and headache in both groups.¹

In summary, the findings of this study demonstrated that the co-administration of PXM with LNG offered improvements in EC efficacy without inducing disruption in subsequent menstrual patterns and potentiating adverse events under post-ovulation settings.¹ Therefore, PXM co-administration could be considered where LNG is selected for EC.¹