Apparent interaction between warfarin and levonorgestrel used for emergency contraception

Emergency contraception with progestogen only (two doses of levonorgestrel 0.75 mg given 12 hours apart and within 72 hours of unprotected intercourse) is better tolerated and more effective than the combined oestrogen-progestogen (Yuzpe) regimen.1 Furthermore, treatment with progestogen only may be preferable to the Yuzpe regimen in women with a known thrombophilic defect or history of thromboembolic events. For women receiving warfarin, drug information cites either no interaction between progestogens and warfarin2 or a reduction in anticoagulant effect.3 We describe an enhanced anticoagulant effect of warfarin after giving a woman levonorgestrel for emergency contraception.

A 35 year old woman with familial type 1 (quantitative) antithrombin deficiency and a history of extensive deep venous thrombosis and pulmonary thromboembolism, attended the clinic after an episode of unprotected intercourse. She was receiving warfarin 7 mg daily for anticoagulation but no other drugs. Her international normalised ratio was 2.1, which was within the therapeutic range (2.0-3.0). She requested emergency contraception. After counselling, she declined the insertion of an intrauterine contraceptive device, preferring the progestogen only regimen. Her international normalised ratio was rechecked three days later and was reported as 8.1. She was advised to discontinue warfarin treatment for two days, at which point her international normalised ratio was 2.5, and then to restart it at a dose of 5 mg once daily. No haemorrhagic problem occurred.

One possible explanation for this enhanced anticoagulant effect is the displacement of warfarin by levonorgestrel from the F1S binding site of human α₁-acid glycoprotein, the main transport protein for drugs in plasma.4 The variant of the F1S binding site comprises part of the F1S/A phenotype of α₁-acid glycoprotein, which is encountered in 50% of the population.

Thus women receiving warfarin treatment may be at risk of an interaction between warfarin and levonorgestrel if they are prescribed the progestogen only regimen because of its apparent safety. The manufacturer of levonorgestrel (Wyeth) has not received any reports describing such an interaction with warfarin. This potential interaction requires prompt investigation, particularly in light of recommendations that emergency contraception be made available over the counter.5 If patients are fully anticoagulated with warfarin, the conventional Yuzpe regimen may be effective without being associated with any increased risk of venous thromboembolism.