Drospirenone-containing combined oral contraceptives and risk of venous thromboembolism

HSA would like to update healthcare professionals on the outcome of recent studies investigating the risk of venous thromboembolism (VTE) associated with the use of drospirenone-containing combined oral contraceptives (COCs).

The drospirenone-containing COCs available locally are Yasmin® and Yaz®, which are marketed by Bayer (South East Asia) Pte Ltd. Both Yasmin® and Yaz® contain ethinylestradiol in addition to drospirenone. They were licensed in Singapore since June 2003 and December 2008, respectively as birth control pills, with Yaz® also indicated for use in the treatment of moderate acne problem in selected groups of female patients.

Recent studies on drospirenone-containing COCs and risk of VTE

In April 2011, the British Medical Journal published two articles citing an increased risk of VTE in women using drospirenone-containing COCs.1,2 Both were observational database studies, which showed a two- to three-fold increased risk of VTE in women taking drospirenone-containing COCs compared to levonorgestrel-containing COCs.

In the nested case-control study by Parkin et al,1 the odds ratio for non-fatal idiopathic VTE among women (aged 15 to 44 years) using drospirenone-containing COCs compared to levonorgestrel-containing COCs was 3.3 (95% CI, 1.4 to 7.6). However, the absolute risk of VTE in these women was low, with a crude incidence rate of 23.0 per 100,000 woman years (95% CI, 13.4 to 36.9) in current users of drospirenone-containing COCs, and 9.1 per 100,000 woman years (95% CI, 6.6 to 12.2) in current users of levonorgestrel-containing COCs.

The second study was a case-control study by Jick & Hernandez.2 In this study, the odds ratio for VTE among women (aged 15 to 44 years) using drospirenone-containing COCs was 2.3 (95% CI, 1.6 to 3.2). However, the absolute risk of VTE was still small, with the incidence rates for VTE being 30.8 per 100,000 person-years (95% CI, 25.6 to 36.8) among women taking drospirenone-containing COCs and 12.5 per 100,000 person-years (95% CI, 9.61 to 15.9) among women taking levonorgestrel-containing COCs. Women younger than 30 years of age who used drospirenone-containing COCs appeared to be at an increased risk of VTE (odds ratio 3.7; 95% CI, 2.0 to 6.9).

Other available studies

Prior to this, there were four major studies conducted that involved drospirenone-containing COCs. Two were large post-market surveillance studies undertaken by the company (EURAS3 and Ingenix4) and two were observational studies carried out by academics (Lidegaard et al5 and van Hylckama Vlieg et al6). The post-market surveillance studies did not demonstrate a difference in the VTE incidences for COCs containing drospirenone in comparison to those containing levonorgestrel or other progestogens. In contrast, the observational studies concluded that COCs have a differential VTE risk based on the progestogen component. However, the difference between the results of EURAS and those of the Lidegaard and van Hylckama Vlieg studies was plausibly due to the impact of bias and residual confounding.

Actions taken by regulatory agencies

The EMA's Pharmacovigilance Working Party (PhVWP), in its May 2011 plenary meeting, announced that it had completed a review of all available data including recent publications and information on additional analyses regarding the risk of VTE associated with drospirenone-containing COCs. The assessment has not changed the conclusion that the risk of VTE with any COC (including those containing drospirenone) is very small. The PhVWP concluded that the data have shown that drospirenone-containing COCs are associated with a higher VTE risk than levonorgestrel-containing COCs and that the risk may be similar to that for COCs containing desogestrel or gestodene. The PhVWP recommended that the product information for all drospirenone-containing COCs should be updated to reflect these conclusions.

The US Food and Drug Administration (FDA) and Health Canada are currently reviewing the studies published in the British Medical Journal (as described above) and will look at all currently available information in their benefit-risk assessment of drospirenone-containing COCs.

Local Situation

HSA has been closely reviewing and monitoring the association of VTE with use of drospirenone-containing COCs. Based on the latest information available, HSA has concluded that the benefit-risk profile of Yasmin® and Yaz® remains positive when used according to its licensed indications. Currently, Yasmin® and Yaz® are contraindicated in the presence or a history of VTE. Additional warnings on VTE, including risk factors for VTE, are in the process of being updated in the local package inserts of both products.

To date, two suspected local reports of thrombosis associated with the use of drospirenone-containing COCs have been received. The first case described a patient who developed pulmonary thrombosis approximately seven months after taking Yasmin® for birth control and the second was a patient who developed superior sagittal venous sinus thrombosis approximately five months after taking Yaz® for dysfunctional uterine bleeding.

HSA's advisory

Healthcare professionals are reminded that any prescribing decision should take into account each patient's relevant medical history and any associated risk factors and contraindications. All COCs, including Yasmin® and Yaz®, should be prescribed with caution to obese women (BMI > 30), or those with a higher baseline risk of VTE for other reasons.

In addition, healthcare professionals are advised to educate their patients on the signs and symptoms of VTE (persistent leg oedema, leg pain or tenderness, angina, or sudden shortness of breath) and to seek immediate medical attention if they experience such symptoms.

Healthcare professionals are also strongly encouraged to report adverse events involving drospirenone-containing COCs to the Vigilance Branch of HSA.

References

1. Parkin et al. BMJ 2011;340:d2139

2. Jick & Hernandez. BMJ 2011;340:d2151

3. Dinger et al. Contraception 2007;75:344-354

4. Seeger et al. Obstet Gynecol 2007;110:587-593

5. Lidegaard et al. BMJ 2009;339:b2890

6. van Hylckama Vlieg et al. BMJ 2009;339:b2921