Drug Safety

, Volume 27, Issue 13, pp 1001–1018 | Cite as

Safety of a New Oral Contraceptive Containing Drospirenone

  • Lothar A.J. Heinemann
  • Jürgen Dinger
Review Article


New chemical entities must undergo rigorous, and preferably independent, safety and efficacy assessments before entry into the market. This is also true for oral contraceptives (OCs) given their extensive usage by healthy women and the safety concerns highlighted by the so-called ‘third generation pill scare’ in Europe a decade ago. This scare heightened patient and physician awareness of the increased risk of thromboembolic complications (mainly venous thromboembolism [VTE]) associated with OC use.

Yasmin® (ethinylestradiol 30μg/drospirenone 3mg [EE/DRSP]) is a novel OC that was demonstrated in clinical phase I–III studies to be highly effective in preventing pregnancy and to have a good safety profile. Nonetheless, clinical trials are not usually sufficiently powered to detect rare adverse events such as VTE to enable comparison with other OCs, which could allay fears and concerns about their inherent risks. Therefore, an extensive assessment of the VTE risk associated with EE/DRSP has been undertaken by reviewing data from the clinical development programme, postmarketing surveillance and spontaneous worldwide reporting, as well as information from other sources.

Spontaneous worldwide reporting has revealed a VTE reporting rate of 5.1/100 000 women-years with EE/DRSP use. In contrast, 3-year interim results from a large, controlled, prospective postmarketing surveillance study suggest a VTE rate of 61/100 000 women-years for EE/DRSP, which is similar to the rates of 60/100 000 and 73/100 000 women-years for levonorgestrel-containing OCs and other OCs, respectively. When placed in context with potential biases and confounding factors that would inflate the perceived risk of VTEs with a novel OC, the VTE rate with EE/DRSP does not highlight any safety concerns. Furthermore, the risk of VTE with EE/DRSP or other OCs is far less than that associated with pregnancy and delivery (up to 800/100 000 women-years) or than other risks of daily living.

Available data indicate that EE/DRSP is not associated with any increased risk of other serious adverse events such as hyperkalaemia, cardiac arrhythmia or birth defects. Nonetheless, caution should be exerted in prescribing EE/DRSP to women with conditions that predispose to hyperkalaemia.

Overall, the safety data with EE/DRSP and other OCs indicate that these products have no negative impact on the risk of VTE (and other adverse events) in women who receive OCs for contraception.


Reporting Rate Spontaneous Reporting Drospirenone Risk Management Programme Preferential Prescribe 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Heinemann is the principal investigator of the EURAS study. This independently designed and monitored study was funded by an unconditional grant from Schering AG, Berlin, Germany. Dr Dinger is an employee of Schering AG, Berlin, Germany. The authors would like to thank David Cutler for editorial support in the preparation of this manuscript.


  1. 1.
    Heinemann LA. The changing scene: an unnecessary pill crisis. Hum Reprod Update 1999; 5: 746–55PubMedCrossRefGoogle Scholar
  2. 2.
    World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346: 1582–8Google Scholar
  3. 3.
    Spitzer WO, Lewis MA, Heinemann LA, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ 1996; 312: 83–8PubMedCrossRefGoogle Scholar
  4. 4.
    Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589–93PubMedCrossRefGoogle Scholar
  5. 5.
    Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346: 1593–6PubMedCrossRefGoogle Scholar
  6. 6.
    Lewis MA, MacRae KD, Kuhl-Habichl D, et al. The differential risk of oral contraceptives: the impact of full exposure history. Hum Reprod 1999; 14: 1493–9PubMedCrossRefGoogle Scholar
  7. 7.
    Vandenbroucke JP, Helmerhorst FM, Bloemenkamp KW, et al. Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol 1997; 177: 887–91PubMedCrossRefGoogle Scholar
  8. 8.
    Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323: 131–4PubMedCrossRefGoogle Scholar
  9. 9.
    Crosignani PG, La Vecchia C. Concordant and discordant effects on cardiovascular risks exerted by oestrogen and progestogen in women using oral contraception and hormone replacement therapy: ESHRE Capri Workshop Group. Hum Reprod Update 1999; 5: 681–7PubMedCrossRefGoogle Scholar
  10. 10.
    Spitzer WO, Faith JM, MacRae KD. Myocardial infarction and third generation oral contraceptives: aggregation of recent studies. Hum Reprod 2002 Sep; 17(9): 2307–14PubMedCrossRefGoogle Scholar
  11. 11.
    Schwarz T, Siegert G, Oettler W, et al. Venous thrombosis after long-haul flights. Arch Intern Med 2003; 163: 2759–64PubMedCrossRefGoogle Scholar
  12. 12.
    Heinemann LA, on behalf of the European Active Surveillance Study Group. The European Active Surveillance Study on oral contraceptive prescribing practice, benefits and safety (EURAS): the study protocol. LAMSO 2001; 2: DOI 10.1072/L0204323Google Scholar
  13. 13.
    Heinemann LA, Assmann A, on behalf of the EURAS Group. The European Active Surveillance Study on oral contraceptive prescribing practice, benefits and safety (EURAS): a work in progress report. LAMSO 2001; 2: DOI 10.1072/L0211331Google Scholar
  14. 14.
    The European Active Surveillance Study on prescribing practice, benefits and safety [online]. Available from URL: [Accessed 2004 Sep 3]Google Scholar
  15. 15.
    Lewis MA, Heinemann LA, MacRae KD, et al. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. The Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception 1996; 54: 5–13PubMedCrossRefGoogle Scholar
  16. 16.
    van Lunsen HW. Recent oral contraceptive use patterns in four European countries: evidence for selective prescribing of oral contraceptives containing third-generation progestogens. Eur J Contracept Reprod Health Care 1996; 1: 39–45PubMedCrossRefGoogle Scholar
  17. 17.
    Heinemann LA, Lewis MA, Assmann A, et al. Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives? Pharmacoepidemiol Drug Saf 1996; 5: 285–94PubMedCrossRefGoogle Scholar
  18. 18.
    Jamin C, de Mouzon J. Selective prescribing of third generation oral contraceptives (OCs). Contraception 1996; 54: 55–6PubMedCrossRefGoogle Scholar
  19. 19.
    Jamin C, Benifla JL, Madelenat P. The role of selective prescribing in the increased risk of VTE associated with thirdgeneration oral contraceptives. Hum Reprod Update 1999; 5: 664–71PubMedCrossRefGoogle Scholar
  20. 20.
    Kuhl H. Comparative pharmacology of newer progestogens. Drugs 1996; 51: 188–215PubMedCrossRefGoogle Scholar
  21. 21.
    Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000; 62: 29–38PubMedCrossRefGoogle Scholar
  22. 22.
    Spitzer WO. The 1995 pill scare revisited: anatomy of a nonepidemic. Hum Reprod 1997; 12: 2347–57PubMedCrossRefGoogle Scholar
  23. 23.
    Heinemann LA, Lewis MA, Assmann A, et al. Case-control studies on venous thromboembolism: bias due to design? A methodological study on venous thromboembolism and steroid hormone use. Contraception 2002; 65: 207–14PubMedCrossRefGoogle Scholar
  24. 24.
    Heinemann LA, Garbe E, Farmer R, et al. Venous thromboembolism and oral contraceptive use: a methodological study of diagnostic suspicion and referral bias. Eur J Contracept Reprod Health Care 2000; 5: 183–91PubMedCrossRefGoogle Scholar
  25. 25.
    Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33Google Scholar
  26. 26.
    Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605–13PubMedCrossRefGoogle Scholar
  27. 27.
    Farmer RD, Lawrenson RA, Thompson CR, et al. Populationbased study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–8PubMedCrossRefGoogle Scholar
  28. 28.
    Rubig A. Drospirenone: a new cardiovascular-active progestin with antialdosterone and antiandrogenic properties. Climacteric 2003; 6Suppl. 3: 49–54PubMedGoogle Scholar
  29. 29.
    Preston RA, Alonso A, Panzitta D, et al. Additive effect of drospirenone/17-beta-estradiol in hypertensive postmenopausal women receiving enalapril. Am J Hypertens 2002; 15: 816–22PubMedCrossRefGoogle Scholar
  30. 30.
    Schurmann R, Holler T, Benda N. Estradiol and drospirenone for climacteric symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled study of the safety and efficacy of three dose regime. Climacteric 2004; 7: 189–96PubMedCrossRefGoogle Scholar
  31. 31.
    Warming L, Ravn P, Nielsen T, et al. Safety and efficacy of drospirenone used in a continuous combination with 17betaestradiol for prevention of postmenopausal osteoporosis. Climacteric 2004; 7: 103–11PubMedCrossRefGoogle Scholar
  32. 32.
    Data on file, Schering AG, 2004Google Scholar
  33. 33.
    European Agency for the Evaluation of Medicinal Products. Combined oral contraceptives and venous thromboembolism. The European Agency for the Evaluation of Medicinal Products Committee for Proprietary Medicinal Products (CPMP) public assessment report. London, 2001 Sep 28 [online]. Available from URL: 2001 [Accessed 2004 Sep 8]Google Scholar
  34. 34.
    Lewis MA. The Transnational Study on Oral Contraceptives and the Health of Young Women: methods, results, new analyses and the healthy user effect. Hum Reprod Update 1999; 5: 707–20PubMedCrossRefGoogle Scholar
  35. 35.
    Suissa S, Blais L, Spitzer WO, et al. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997; 56: 141–6PubMedCrossRefGoogle Scholar
  36. 36.
    Suissa S, Spitzer WO, Rainville B, et al. Recurrent use of newer oral contraceptives and the risk of venous thromboembolism. Hum Reprod 2000; 15: 817–21PubMedCrossRefGoogle Scholar
  37. 37.
    Sheldon T. Dutch GPs warned against new contraceptive pill. BMJ 2002; 324: 869PubMedCrossRefGoogle Scholar
  38. 38.
    Oelkers W. Antimineralocorticoid activity of a novel oral contraceptive containing drospirenone, a unique progestogen resembling natural progesterone. Eur J Contracept Reprod Health Care 2002; 7Suppl. 3: 19–26; discussion 42–3PubMedGoogle Scholar
  39. 39.
    Oelkers W, Helmerhorst FM, Wuttke W, et al. Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers. Gynecol Endocrinol 2000; 14: 204–13PubMedCrossRefGoogle Scholar
  40. 40.
    van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea. Cutis 2002; 69: 2–15PubMedGoogle Scholar
  41. 41.
    Thorneycroft IH, Gollnick H, Schellschmidt I. Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment. Cutis, 2004; 74: 123–30PubMedGoogle Scholar
  42. 42.
    Guido M, Romualdi D, Giuliani M, et al. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004; 89: 2817–23PubMedCrossRefGoogle Scholar
  43. 43.
    Sidney S, Petitti DB, Soff GA, et al. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception 2004; 70: 3–10PubMedCrossRefGoogle Scholar
  44. 44.
    Adverse drug reaction database. London: Medicines and Healthcare Products Regulatory Agency, 1995Google Scholar
  45. 45.
    Moride Y, Haramburu F, Requejo AA, et al. Under-reporting of adverse drug reactions in general practice. Br J Clin Pharmacol 1997; 43: 177–81PubMedCrossRefGoogle Scholar
  46. 46.
    Stephens MD. Underreporting. In: Stephens MD, Talbot JC, Routledge PA, editors. Detection of new adverse drug reactions. 4th ed. London: MacMillan Reference Ltd, 1998: 4–8Google Scholar
  47. 47.
    Machin D, Campbell MJ. Statistical tables for design of clinical trials. Oxford: Blackwell Scientific Publications, 1987Google Scholar
  48. 48.
    XYZ & Others v Schering Health Care Limited, Organon Laboratories Limited, John Wyeth & Brother Limited (High Court of Justice, Queen’s Bench, case no. 0002638, 29 July 2002)Google Scholar
  49. 49.
    Karara AH, Zhang P, Blode H, et al. Effect of drospirenone/estradiol combination product on the serum potassium of mildly hypertensive postmenopausal women maintained on enalapril maleate [abstract no. 45]. J Clin Pharmacol 2001; 41: 1024Google Scholar
  50. 50.
    Danish Health Registers [online]. Available from URL: [Accessed 2004 Sep 3]Google Scholar
  51. 51.
    Lidegaard O. Thrombotic diseases in young women and the influence of oral contraceptives. Am J Obstet Gynecol 1998; 179: S62–7PubMedCrossRefGoogle Scholar
  52. 52.
    Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25- year population-based study. Arch Intern Med 1998; 158: 585–93PubMedCrossRefGoogle Scholar
  53. 53.
    Lidegaard O. Øjvind Lidegaard homepage [online]. Available from URL: [Accessed 2004 Sep 3]
  54. 54.
    US National Center for Injury Prevention and Control. United States National Center for Injury Prevention and Control: 2001/2002 data [online]. Available from URL: [Accessed 2004 Jun 30]Google Scholar
  55. 55.
    Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002; 162: 2197–202PubMedCrossRefGoogle Scholar
  56. 56.
    Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–35Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Center for Epidemiology & Health Research (ZEG)BerlinGermany
  2. 2.Schering AGBerlinGermany

Personalised recommendations