Clinical Drug Investigation

, Volume 32, Issue 10, pp 673–684

Bioequivalence Evaluation of a Folate-Supplemented Oral Contraceptive Containing Ethinylestradiol/Drospirenone/Levomefolate Calcium versus Ethinylestradiol/Drospirenone and Levomefolate Calcium Alone

  • Herbert Wiesinger
  • Urte Eydeler
  • Frank Richard
  • Dietmar Trummer
  • Hartmut Blode
  • Beate Rohde
  • Konstanze Diefenbach
Original Research Article


Background: Neural tube defects (NTDs) are congenital malformations that occur during early embryonic development. Suboptimal maternal folate status is a well-known risk factor for the occurrence of NTDs, and periconceptional folic acid supplementation has been shown to reduce the risk of NTDs. Folate-supplemented oral contraceptives (OCs) offer a means of improving folate status in women of childbearing potential by increasing their likelihood of having raised folate levels at the time of conception.

Objective: This study aimed to demonstrate bioequivalence of ethinylestradiol (EE), drospirenone and L-5-methyl-tetrahydrofolate (L-5-methyl-THF; active moiety of levomefolate calcium) when taken as a new folate-supplemented OC containing EE/drospirenone/levomefolate calcium, with the respective OC containing EE/drospirenone and a tablet containing levomefolate calcium only.

Methods: This was a randomized, open-label, three-period crossover study carried out at a single centre in Germany. The study included 45 healthy women (age range 18–38 years). The women were randomly assigned to single doses of (i) EE 0.03 mg/drospirenone 3 mg/levomefolate calcium 0.451 mg (SAFYRAL®), (ii) EE 0.03 mg/drospirenone 3 mg (Yasmin®), and (iii) levomefolate calcium 0.451 mg, administered using a crossover design, with one or more menstrual cycle washout between doses. The primary variables were maximum concentrations (Cmax) and area under the concentration versus time curve (AUC) values for EE, drospirenone and L-5-methyl-THF.

Results: The bioavailability of EE and drospirenone was similar after administration of EE/drospirenone/levomefolate calcium and EE/drospirenone. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) for AUC values and Cmax were within the pre-specified range (80.00–125.00%) for bioequivalence for EE and drospirenone in both formulations. The bioavailability of L-5-methyl-THF was similar after administration of EE/drospirenone/levomefolate calcium and levomefolate calcium. The respective GMRs and 90% CIs of baseline-uncorrected and -corrected AUClast (AUC from time zero to time of last measurable concentration) and Cmax were also within the 80.00–125.00% range.

Conclusion: The novel folate-supplemented OC EE/drospirenone/levomefolate calcium is bioequivalent to the established OC Yasmin® (EE/drospirenone components) and to levomefolate calcium (folate component).


  1. 1.
    Botto LD, Moore CA, Khoury MJ, et al. Neural-tube defects. N Engl J Med 1999 Nov 11; 341(20): 1509–19PubMedCrossRefGoogle Scholar
  2. 2.
    Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991 Jul 20; 338(8760): 131–7CrossRefGoogle Scholar
  3. 3.
    Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992 Dec 24; 327(26): 1832–5PubMedCrossRefGoogle Scholar
  4. 4.
    De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, et al. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane database of systematic reviews 2010; (10): CD007950Google Scholar
  5. 5.
    U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009 May 5; 150(9): 626–31CrossRefGoogle Scholar
  6. 6.
    European Surveillance of Congenital Anomalies (EUROCAT). Special report: prevention of neural tube defects by periconceptional folic acid supplementation in Europe. Part IIa: Country specific chapters (Austria to Ireland). 2009a [online]. Available from URL: [Accessed 2012 Apr 1]
  7. 7.
    European Surveillance of Congenital Anomalies (EUROCAT). Special report: prevention of neural tube defects by periconceptional folic acid supplementation in Europe. Part IIb: Country specific chapters (Italy to UK). 2009b [online]. Available from URL: [Accessed 2012 Apr 1]
  8. 8.
    Lamers Y, Prinz-Langenohl R, Bramswig S, et al. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 2006 Jul; 84(1): 156–61PubMedGoogle Scholar
  9. 9.
    Pietrzik K, Lamers Y, Bramswig S, et al. Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women of childbearing age. Am J Clin Nutr 2007 Nov; 86(5): 1414–9PubMedGoogle Scholar
  10. 10.
    Bachmann G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception 2004 Sep; 70(3): 191–8PubMedCrossRefGoogle Scholar
  11. 11.
    Shane B. Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms. Food Nutr Bull 2008 Jun; 29(2 Suppl.): S5–16; discussion S7-9PubMedGoogle Scholar
  12. 12.
    Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010; 49(8): 535–48PubMedCrossRefGoogle Scholar
  13. 13.
    Venn BJ, Green TJ, Moser R, et al. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr 2002 Nov; 132(11): 3353–5PubMedGoogle Scholar
  14. 14.
    Prinz-Langenohl R, Bronstrup A, Thorand B, et al. Availability of food folate in humans. J Nutr 1999 Apr; 129(4): 913–6PubMedGoogle Scholar
  15. 15.
    Blode H, Schurmann R, Benda N. Novel ethinyl estradiol-beta-cyclodextrin clathrate formulation does not influence the relative bioavailability of ethinyl estradiol or coadministered drospirenone. Contraception 2008 Mar; 77(3): 171–6PubMedCrossRefGoogle Scholar
  16. 16.
    Data on file. Fuhrmeister A. Clinical study report number A951. Investigation of the bioequivalence of drospirenone and ethinyl estradiol from two different tablets each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol and its relative bioavailability with reference to an oral suspension in 42 young women. Berlin: Bayer HealthCare Pharmaceuticals; September 1997Google Scholar
  17. 17.
    United States Food and Drug Administration. Guidance for industry. Statistical approaches to establishing bioequivalence. 2001 [online]. Available from URL: [Accessed 2012 Apr 1]
  18. 18.
    Blode H, Klipping C, Richard F, et al. Bioequivalence study of an oral contraceptive containing ethinylestradiol drospirenone/levomefolate calcium relative to ethinyles tradiol/drospirenone and to levomefolate calcium alone. Contraception 2012 Feb; 85(2): 177–84PubMedCrossRefGoogle Scholar
  19. 19.
    Bart S Sr, Marr J, Diefenbach K, et al. Folate status and homocysteine levels during a 24-week oral administration of a folate-containing oral contraceptive: a randomized, double-blind, active-controlled, parallel-group, US-based multicenter study. Contraception 2012 Jan; 85(1): 42–50PubMedCrossRefGoogle Scholar
  20. 20.
    Diefenbach K, Trummer D, Ebert F, et al. Changes in folate levels following a 24-week co-administration of Yasmin and levomefolate calcium 0.451 mg or folic acid 400 mcg (abstract and poster). Eur J Contracept Reprod Health Care 2010; 15(s1): 158–9Google Scholar
  21. 21.
    Hao L, Yang QH, Li Z, et al. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am J Clin Nutr 2008 Aug; 88(2): 448–57PubMedGoogle Scholar
  22. 22.
    Hursthouse NA, Gray AR, Miller JC, et al. Folate status of reproductive age women and neural tube defect risk: the effect of long-term folic acid supplementation at doses of 140 mg and 400 μg per day. Nutrients 2011; 3: 49–62PubMedCrossRefGoogle Scholar
  23. 23.
    Diefenbach K, Trummer D, Ebert F, et al. Changes in folate levels following cessation of Yasmin and levomefolate calcium 0.451 mg or folic acid 400 mcg co-administration (abstract and poster). Eur J Contracept Reprod Health Care 2010; 15(s1): 157–8Google Scholar
  24. 24.
    Cronin M, Schellschmidt I, Dinger J. Rate of pregnancy after using drospirenone and other progestin-containing oral contraceptives. Obstet Gynecol 2009 Sep; 114(3): 616–22PubMedCrossRefGoogle Scholar
  25. 25.
    Venn BJ, Green TJ, Moser R, et al. Comparison of the effect of low-dose supplementation with L-5-methyltetrahy-drofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 2003 Mar; 77(3): 658–62PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Herbert Wiesinger
    • 1
  • Urte Eydeler
    • 2
  • Frank Richard
    • 3
  • Dietmar Trummer
    • 1
  • Hartmut Blode
    • 1
  • Beate Rohde
    • 1
  • Konstanze Diefenbach
    • 1
  1. 1.Bayer HealthCare PharmaceuticalsBerlinGermany
  2. 2.Scope International GmbHHamburgGermany
  3. 3.Nycomed GmbH — A Takeda CompanyKonstanzGermany

Personalised recommendations