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BMJ. 2000 December 2; 321(7273): 1382.
PMCID: PMC27541
Drug points

Apparent interaction between warfarin and levonorgestrel used for emergency contraception

J Ellison, A J Thomson, and I A Greer
Department of Obstetrics and Gynaecology

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.

Footnotes

 Competing interests: None declared.

References

1. Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet. 1998;352:428–433. [PubMed]
2. Crowther NR, Holbrook AM, Kenwright R, Kenwright M. Drug interactions among commonly used medications. Can Fam Physician. 1997;43:1972–1981. [PMC free article] [PubMed]
3. British national formulary, No 39. Bath: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2000. Appendix 1: interactions; p. 614.
4. Herve F, Duche J-C, d'Athis P, Marche C, Barre J, Tillement J-P. Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human α1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on α1-acid glycoprotein. Pharmacogenetics. 1996;6:403–415. [PubMed]
5. Royal College of Obstetricians and Gynaecologists and the Faculty of Family Planning and Reproductive Health Care. Joint statement on emergency hormonal contraception. London: RCOG; 1995.

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