News in brief: Dabigatran; Antibiotics and COC; Prescription kitchen

What is dabigatran?

Dabigatran is an oral direct thrombin inhibitor anticoagulant that is now approved in New Zealand for the prevention of stroke in patients with atrial fibrillation and for short-term use to prevent thromboembolism after hip or knee replacement surgery. It therefore provides an alternative to warfarin or enoxaparin (Clexane) for these indications. Dabigatran (Pradaxa) will be listed on the Pharmaceutical Schedule, without restriction. The listing date will be confirmed in the next few months.

What is dabigatran used for

At this stage, dabigatran looks promising as a new anticoagulant medicine. Studies show that it is as effective as warfarin for preventing stroke in patients with atrial fibrillation and as effective as enoxaparin for prophylaxis of thromboembolism after hip and knee surgery, with similar rates of bleeding.^1,2,3 For some patients dabigatran may be a more convenient option, especially compared to warfarin, because it does not require intensive laboratory monitoring. In addition, other advantages of dabigatran include:^4,5

• A more rapid onset of action - patients are fully anti-coagulated within 36 hours
• A more rapid return to normal coagulation after discontinuation (48 hours)
• A wider therapeutic window with a more predictable effect on coagulation irrespective of age, ethnicity and weight (warfarin often has an unpredictable effect, individual variation and a narrow therapeutic window)
• A fixed daily dose is taken unlike the variable dose often required for warfarin. However, for stroke prevention patients should be aware that it is a twice daily dose.
• A lower interaction rate with other medicines and with food when compared to warfarin

However, despite these potential advantages, dabigatran should still be used cautiously because it is a new medicine and its use in clinical practice is not well known in New Zealand. Clinical experience and data on longer term safety is lacking. For example, although dabigatran was approved for use in Canada in 2008 for the prevention of thromboembolism, it has only as recently as October 2010 been approved for stroke prevention in patients with atrial fibrillation.⁶ Similarly, dabigatran has been approved for use in the USA for stroke prevention since October 2010.⁷ An increased risk of a rare adverse event has not been ruled out. Although not altering the conclusions of the study, re-evaluation of the database for the RE-LY trial, has identified 81 new events that included four patients with clinical myocardial infarction (MI), 28 patients with silent MI and 69 further events of major haemorrhage.⁸

Further information on dabigatran will appear in a future edition of Best Practice Journal. An information sheet is available here.

References

1. Connolly S, Ezekowitz M, Yusuf A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139-51.
2. Eriksson B, Dahl O, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacment: a randomised, double-blind, non-inferiority trial. Lancet 2007;370(9591):949-56.
3. Eriksson B, Dahl O, Rosencher N, et al. Oral dabigatran etexilate vs. Subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacment: the RE-MODEL randomised trial. J Thromb Haemost 2007;5(11):2178-85.
4. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011;49(5):761-72.
5. Bendel SD, Bona R, Baker WL. Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. Adv Ther 2011;[Epub ahead of print].
6. Health Canada. Pradax product monograph. 2010. Available from: www.hc-sc.gc.ca (Accessed May 2011).
7. U.S. Food and Drug Administration. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. FDA New Release Oct. 19, 2010. Available from: www.fda.gov (Accessed May 2011).
8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875-6.

International recommendations now advise that the majority of broad-spectrum antibiotics do not affect the contraceptive effectiveness of the combined oral contraceptive.^1,2 No change in advice has as yet been announced in New Zealand.

The implication of the new recommendations is that women taking a combined oral contraceptive, who require treatment with an antibiotic for three weeks or less*², no longer need to use additional precautions to prevent pregnancy. However, women should still be advised about the importance of correct contraceptive practice during periods of illness, e.g. if vomiting or diarrhoea occur.

This change in advice does not apply:

• To every antibiotic - patients taking antibiotics that induce liver enzymes, e.g. rifampicin and rifabutin, DO require additional precautions (see below)
• If an antibiotic causes vomiting or diarrhoea - patients should be advised to follow the “seven day rule”

Background to the changes

It has been standard practice for many years for doctors to advise patients who are taking a combined oral contraceptive that antibiotics affect its efficacy and that they must observe the ‘”seven day rule” when taking antibiotics. The “seven day rule” refers to advice to use other methods of contraception, e.g. condoms, or to abstain from sexual intercourse, for the duration of antibiotic treatment and the following seven days.

The theory supporting this approach was based on the potential for antibiotics to reduce the gastrointestinal flora responsible for increasing the reabsorption of oestrogens from the gastrointestinal tract (see below). A reduction in gastrointestinal flora, could therefore result in a reduction in circulating hormone levels required for effective contraception.³ However, the validity of this theory has been debated by specialists in women’s health as there is no evidence that confirms this potential interaction.^1,2,3

In 2009, the World Health Organisation, changed its recommendation to state that most broad spectrum antibiotics do not affect the contraceptive effectiveness of combined oral contraceptives and that no restriction on use is required when using these medicines at the same time.¹ This recommendation was adopted by the Centers for Disease Control and Prevention in the United States in 2010. In January 2011, the Faculty of Sexual and Reproductive Healthcare in the United Kingdom also changed its advice in support of this recommendation and the latest edition of the British National Formulary (BNF) includes this updated advice.^2,4

Evidence for the change in advice

There is a lack of evidence that antibiotic use reduces the efficacy of the combined oral contraceptive.² Studies have not shown a decrease in the levels of ethinyloestradiol or any effect on gonadotrophin concentration with antibiotic use.²

A recent case-crossover study showed no association between contraceptive failure and antibiotic use in women taking combined oral contraceptives.³ Although the authors state that an increase in risk of contraceptive failure cannot be ruled out due to limitations of the study design, they conclude that antibiotics have a limited effect on the metabolism of the combined oral contraceptive.

Other studies, that indirectly support the lack of a causal relationship between antibiotic use and contraceptive failure, include evidence that:^1,2

• Combined oral contraceptive efficacy is not reduced in women who have had a colectomy and ileostomy, and therefore have no enterohepatic circulation of ethinyloestradiol.
• Reports of pregnancies in women taking antibiotics have included women taking high doses of a combined oral contraceptive, e.g. containing 30 µg or more of ethinyloestradiol. Low dose combined oral contraceptives containing 20 µg ethinyloestradiol are effective contraceptive agents so it seems unlikely that the theoretical small reduction in ethinyloestradiol concentration resulting from reduced enterohepatic circulation would be the cause of contraceptive failure in women taking higher doses.
• Reports of pregnancies have occurred in women taking erythromycin and fluconazole which actually increase levels of ethinyloestradiol.
• Study results may be confounded by other reasons for contraceptive failure, e.g. missed pills, antibiotic induced vomiting and diarrhoea.

Contraceptive advice for women using enzyme inducing antibiotics

The BNF recommends that an alternative method of contraception is always required for women using combined oral contraceptives and rifampicin or rifabutin.⁴

Induction of cytochrome P-450 enzymes explains the proven interaction with theses antibiotics,² which are potent enzyme inducing drugs.

If rifampicin or rifabutin is required (either short or long-term) the recommended strategy is for the woman to change to an alternative method of contraception that is not affected by enzyme inducers.^2,4 Options include injectable or implantable progestogens, an intrauterine contraceptive device or a levonorgestrel intrauterine system. If an enzyme inducer is required short term (i.e. less than two months) a practical solution would be to temporarily stop the combined oral contraceptive and administer a one-off depot medroxyprogesterone acetate (DMPA) injection to cover the treatment course and the following 28 days.

A less favoured approach is to increase the dose of the combined oral contraceptive to give 50 μg or more of ethinyloestradiol to account for the increased metabolism and also recommending the use of condoms as an additional precaution.⁵ This combination may be considered as an option if the enzyme inducing medicine is for short-term use (< two months) but is not recommended if the enzyme inducer is required for a longer term. Women taking an enzyme inducing medicine must continue to take a higher dose of combined oral contraceptive and use additional precautions for the time they are taking an enzyme inducer and for four weeks after finishing the course.^2,4

For further information about other important drug interactions with combined oral contraceptives see: “Combined oral contraceptive: issues for current users” BPJ 12 (Apr 2008).