The development program for Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and 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 YAZ + 0.451 mg levomefolate calcium as compared to YAZ alone in a U.S. population with 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 4 and 5 display the results for plasma and RBC folate, respectively, among evaluable subjects in each arm of the study. 

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

     Arithmetic mean values based on 4‑ weekly measurements are displayed with arithmetic standard deviations which are shown in only one direction to improve readability. Data are based on per protocol analysis populations. The SD bar shown represents a single SD.

Figure 5 US Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of YAZ + levomefolate calcium and YAZ

    Arithmetic mean values based on 4‑weekly measurements are displayed with arithmetic standard deviations which are shown in only one direction to improve readability. Data are based on per protocol analysis populations. The SD bar shown represents a single SD.

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 without folate food fortification and without concomitant intake of folate supplements were randomized to one of the two treatments. Figures 6 and 7 display the results for plasma and RBC folate, respectively, among evaluable subjects in the levomefolate arm of the study. 

Figure 6 German Study: Mean trough concentration-time curve (and SD) of plasma folates after daily oral administration of Yasmin + levomefolate calcium

    Arithmetic mean values based on biweekly measurements are displayed with arithmetic standard deviations. In the treatment phase, women received Yasmin + levomefolate calcium; in the elimination phase, all women received Yasmin only. Data are based on per protocol analysis populations. The SD bar shown represents a single SD.

Figure 7 German Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of Yasmin + levomefolate calcium

    Arithmetic mean values based on biweekly measurements are displayed with arithmetic standard deviations. In the treatment phase, women received Yasmin + levomefolate calcium; in the elimination phase, all women received Yasmin only. Data are based on per protocol analysis populations. The SD bar shown represents a single SD.

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) daily 1,6.