Published: March 2002
Publications
Venous Thromboembolism with Diane 35™ and Estelle 35™
Information on this subject has been updated. Read the most recent information.
Prescriber Update 23(1): 2-3
March 2002
Dr Ruth Savage, Medical Assessor, Centre for Adverse Reactions Monitoring, Dunedin
The Medicines Adverse Reactions Committee reminds prescribers to confine the use of Diane 35/35 ED™ and Estelle 35/35 ED™ to women with polycystic ovary syndrome, hirsutism, androgenic alopecia and pronounced acne. A recent case-control study has found a four-fold increase in the risk of venous thromboembolism with oral contraceptives containing cyproterone acetate compared with a second generation oral contraceptive. Similar risk estimates have been found in previous smaller studies. From all these studies, it is concluded that the risk of venous thromboembolism with cyproterone-containing contraceptives is at least as great as with third generation oral contraceptives.
Higher risk of VTE with cyproterone-containing OCs vs a second generation OC
A new case-control study of venous thromboembolism (VTE) and combined oral contraceptives (OCs), using the UK General Practice Research Database (GPRD), was published in October 2001.1 The intention of this study was to assess the risk of VTE in women taking OCs containing cyproterone acetate and ≤ 35 mcg of ethinyloestradiol (CPA/EE) compared with women taking levonorgestrel and ≤ 35 mcg ethinyloestradiol (LN/EE), a second generation OC.
Cohorts of 24,401 women taking CPA/EE and 75,000 women taking LN/EE were identified from the GPRD. Twenty-six women from these cohorts who had a confirmed diagnosis of deep vein thrombosis or pulmonary embolism (PE) were identified as cases. Matched controls were drawn from the same cohorts. The relative risk of VTE for women taking CPA/EE was 3.9 (95% CI 1.1-13.4) compared with those taking LN/EE.1
The background incidence of VTE in women aged 15-44 years not using combined OCs is 0.5-1 case per 10,000 woman-years.2 In users of second generation OCs, the incidence of VTE has been estimated at about 2 per 10,000 woman-years of use and 3-4 per 10,000 for women taking third generation OCs.2 Using these figures and the GPRD study,1 the incidence of VTE for women taking OCs containing cyproterone can be estimated at about 8 per 10,000 woman-years.
Previous studies support recent findings
Two earlier studies3,4 raised concerns about the risk of VTE with cyproterone-containing contraceptives. However, the numbers of cases and controls taking CPA/EE in these studies were very small so firm conclusions could not be drawn. The World Health Organisation (WHO) study3 provided the first evidence of a difference in risk of VTE between second and third generation OCs. Within this study there were nine cases and three controls using CPA/EE. The risk of VTE with this preparation was five times greater than with LN/EE. The table below compares the relative risks of VTE with combined OCs in the WHO3 and GPRD1 studies. This table also shows that the increased risk with CPA/EE is similar to that found with third generation OCs (i.e. those containing desogestrel or gestodene).
Relative risk (odds ratio) of VTE with cyproterone-containing and third generation OCs compared with second generation OCs
| Study | OC progestogen (a = 2nd generation b = 3rd generation) |
Adjusted odds ratio | 95% CI |
|---|---|---|---|
| WHO3 | levonorgestrela | 1.0 | reference group |
| desogestrel or gestodeneb | 2.7 | 1.6 - 4.6 | |
| cyproterone | 5.1 | 1.3 - 20.3 | |
| GPRD1 | levonorgestrela | 1.0 | reference group |
| cyproterone | 3.9 | 1.1 - 13.4 |
The second investigation4 was a New Zealand study of fatal PE, which included two case patients who had been exposed to CPA/EE (neither of these deaths was reported to CARM). Despite this small number and a resulting wide confidence interval, the risk estimate of 17.6 (95% CI 2.7-113.0) compared with no OC use was similar to the estimate of 14.9 in the WHO study3 and 13.3 which can be derived from the GPRD study.1
CARM has received 15 reports of pulmonary embolism with CPA/EE
In New Zealand, the brands of cyproterone-containing oral contraceptives currently available are Diane 35/35 ED™ and Estelle 35/35 ED™. Up until January 2001 CARM had received 13 reports of VTE occurring in women taking CPA/EE. Ten of these 13 women had developed PE. In February 2001, VTE with Diane 35/35 ED was classified as an adverse reaction of current concern. From February 2001 until November 2001, CARM received five more reports of PE. None of these 18 cases was fatal. The indications, where known, were contraception in ten patients, acne in five and irregular menstruation in two. Estelle 35/35 ED were added to the list of adverse reactions of current concern in October 2001.
No evidence that indications for CPA/EE falsely elevate risk estimates
Obesity is more prevalent in women with androgenic disorders and CPA/EE is indicated in these women. It has been argued that because obesity is associated with an increased risk of VTE, use in these indications would account for the increased risk observed with CPA/EE rather than a true increase in thrombogenicity compared with other OCs. In the GPRD study1 adjusting the results for a history of hirsutism, acne, polycystic ovary disease and asthma, as well as body mass index and smoking, did not change the risk estimate.
Prescribe only to women with androgen-dependent disorders
The evidence presented indicates that combined OCs containing cyproterone are at least as likely as third generation OCs to cause VTE. The Medicines Adverse Reactions Committee reminds prescribers to confine the prescribing of Diane 35/35 ED and Estelle 35/35 ED to women with polycystic ovary syndrome, hirsutism, androgenic alopecia and pronounced acne, and as contraception in women with these conditions.5,6 All patients currently on these medicines should be reviewed for the appropriateness of this therapy. Both new and current patients should be fully advised of the risks of VTE. When prescribing Diane 35/35 ED or Estelle 35/35 ED, observe the contraindications, precautions and risk factors for VTE. Where these medicines are being used for contraception, follow the Ministry of Health advice7 on the prescribing of combined OCs.
The patient information leaflet on OCs and blood clots has been updated, and can be obtained from the Medsafe web site (www.medsafe.govt.nz/Consumers/leaflets/oralcontraceptives.htm). Copies are also available free of charge from Wickliffe: phone (04) 496 2277, fax (03) 479 0979, e-mail pubs@health.govt.nz or post an order to the Ministry of Health, c/- Wickliffe Ltd, PO Box 932, Dunedin.
Product information in the form of consumer medicine information (CMI) is also available for consumers. This can be downloaded from the Medsafe web site (www.medsafe.govt.nz/Consumers/cmi/d/diane35.htm or www.medsafe.govt.nz/Consumers/cmi/d/diane35ED.htm).
Competing interests (author): none declared.
Correspondence to Dr Ruth Savage, CARM, PO Box 913, Dunedin.
References
- Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001;358:1427-1429.
- The European Agency for the Evaluation of Medicinal Products (EMEA). EMEA committee for proprietary medicinal products (CPMP) Public Assessment Report. Combined oral contraceptives and venous thromboembolism. 28 September 2001. http://www.emea.eu.int/pdfs/human/regaffair/0220101en.pdf
- WHO Collaborative Study of Steroid Hormone Contraception and Cardiovascular Disease. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-1588.
- Parkin L, Skegg DCG, Wilson M, Herbison GP, Paul C. Oral contraceptives and fatal pulmonary embolism. Lancet 2000;355:2133-2134.
- Schering NZ Ltd. Diane 35 and Diane 35 ED data sheet 8 November 2000. www.medsafe.govt.nz/Profs/Datasheet/d/diane35+35edtab.htm
- Douglas Pharmaceuticals Ltd. Estelle 35 and Estelle 35 ED data sheet 16 July 2001. www.medsafe.govt.nz/Profs/Datasheet/e/Estelle3535EDtab.htm
- Ministry of Health (Medsafe). Advice on the use of combined oral contraceptives. March 2002 www.medsafe.govt.nz/Profs/PUarticles/OCadvice2002.htm
