Tydemy (Page 7 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of DRSP and EE, 0.1 to 2 times the exposure (AUC of DRSP) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of DRSP alone. In a similar study in rats given 10 mg/kg/day DRSP alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day DRSP and EE, 0.8 to 10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of DRSP. Mutagenesis studies for DRSP were conducted in vivo and in vitro and no evidence of mutagenic activity was observed.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of levomefolate. Mutagenesis studies for levomefolate were conducted in vitro and in vivo and no evidence of mutagenic activity was observed.

14 CLINICAL STUDIES

14.1 Oral Contraceptive Clinical Trial

In the clinical efficacy studies of Yasmin® (3 mg DRSP/0.03 mg EE) of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 ± 4.7 years. The age range was 16 to 37 years. The racial demographic was: 83% Caucasian, 1% Hispanic, 1% Black, <1% Asian, <1% other, <1% missing data, 14% not inquired and <1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.

14.2 Folate Supplementation Clinical Trials

The development program for Tydemy (Yasmin® + levomefolate calcium) consisted of two clinical trials.

One study was a multicenter, randomized, double-blind, active-controlled, parallel group US study. Plasma folate and red blood cell folate levels were investigated during a 24-week treatment with 3 mg DRSP/0.02 mg EE (YAZ®) + 0.451 mg levomefolate calcium as compared to YAZ® alone in a U.S. population that consumed folate fortified food. A total of 379 healthy women between 18 and 40 years of age with no restrictions on folate supplementation received YAZ® + levomefolate calcium (N= 285) or YAZ® (N=94). The plasma and RBC folate concentrations at Week 24 were the co-primary endpoints. Figures 3 and 4 display the results for plasma and RBC folate concentrations, respectively, among evaluable subjects in each arm of the study.

Figure 3: US Study: Mean trough concentration-time curves (and SD) of plasma folates after daily oral administration of YAZ® + levomefolate calcium and YAZ®

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Figure 4: US Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of YAZ® + levomefolate calcium and YAZ®

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In the second study, the pharmacodynamic effect on plasma folate, RBC folate, and the profile of circulating folate metabolites was assessed during 24 weeks of treatment with 0.451 mg levomefolate calcium or with 0.4 mg folic acid (equimolar dose to 0.451 mg levomefolate calcium), both in combination with 3 mg DRSP/0.03 mg EE (Yasmin®) followed by 20 weeks of open-label treatment with Yasmin® only (elimination phase). One-hundred and seventy-two healthy women between 18 to 40 years of age from a German population that consumed food without folate fortification and without concomitant intake of folate supplements were randomized to one of the two treatments. Figures 5 and 6 display the results for plasma and RBC folate concentrations, respectively, among evaluable subjects in the levomefolate arm of the study.

Figure 5: German Study: Mean trough concentration-time curve (and SD) of plasma folates after daily oral administration of Yasmin® + levomefolate calcium

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Figure 6: German Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of Yasmin® + levomefolate calcium

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The potential to reduce the incidence of neural tube defects (NTDs) with folate supplementation is well established based on a body of evidence derived from randomized, controlled trials, nonrandomized intervention trials, and observational studies using folic acid. Therefore, the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force recommend that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily1, 6.

15 REFERENCES

  1. US Preventive Services Task Force. Folic Acid for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009;150:626-631.
  2. Seeger, J.D., Loughlin, J., Eng, P.M., Clifford, C.R., Cutone, J., and Walker, A.M. (2007). Risk of thromboembolism in women taking ethinyl estradiol/drospirenone and other oral contraceptives. Obstet Gynecol 110 , 587-593.
  3. Dinger, J.C., Heinemann, L.A., and Kuhl-Habich, D. (2007). The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 75 , 344-354.
  4. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011.
  5. Lidegaard, O., Lokkegaard, E., Svendsen, A.L., and Agger, C. (2009). Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 339 , b2890.
  6. Lidegaard, O., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E., and Lokkegaard, E. (2011).Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343 , d6423.
  7. Van Hylckama Vlieg, A., Helmerhorst, F.M., Vandenbroucke, J.P., Doggen, C.J., and Rosendaal, F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339 , b2921.
  8. Dinger, J., Assmann, A., Mohner, S., and Minh, T.D. (2010). Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care 36 , 123-129.
  9. Jick, S.S., and Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 342 , d2151.
  10. Parkin, L., Sharples, K., Hernandez, R.K., and Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 342 , d2139.
  11. Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41(No. RR-14).

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