Levomefolate Calcium: A Component in FDA-approved Oral Contraceptive

General Description

Levomefolate calcium, a key component in a new FDA-approved combination oral contraceptive, plays a crucial role in preventing pregnancy, treating premenstrual dysphoric disorder, and moderate acne vulgaris. It is designed to increase folate levels, reducing the risk of neural tube defects in potential pregnancies. Its pharmacokinetics involve absorption into the body's folate pool, steady-state achievement in plasma and red blood cells, and elimination via urinary and fecal excretion. Clinical trials have demonstrated its efficacy in contraception, raising folate levels, treating premenstrual dysphoric disorder, and reducing acne lesions, making it a significant advancement in combination oral contraceptives.

Figure 1. Levomefolate calcium

Overview of the market

Levomefolate calcium, a key ingredient in a new combination oral contraceptive approved by the FDA in September 2010, plays an essential role in preventing pregnancy and treating premenstrual dysphoric disorder (PMDD) and moderate acne vulgaris. This pill contains drospirenone (DRSP), ethinyl estradiol (EE), and levomefolate calcium, following its predecessor's formulation of DRSP 3 mg and EE 20 µg. What sets this oral contraceptive apart is the inclusion of levomefolate calcium. This compound is designed to increase folate levels, thereby reducing the risk of neural tube defects in a pregnancy conceived while taking or shortly after discontinuing the product. Thus, this is the only oral contraceptive that not only prevents pregnancy but also enhances the safety of potential future pregnancies. The use of levomefolate calcium demonstrates a significant advancement in combination oral contraceptives, offering a dual benefit of contraception and neural tube defect prevention. ¹

Pharmacokinetics

Levomefolate calcium, a key component in a combination oral contraceptive, exhibits specific pharmacokinetics. Structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9, it is absorbed orally and incorporated into the body folate pool. Peak plasma concentrations are reached within 0.5-1.5 hours after a single oral administration of 0.451 mg levomefolate calcium, with levels around 50 nmol/L above baseline. Steady-state conditions for total folate in plasma are achieved after 8-16 weeks, depending on baseline levels. However, steady state in red blood cells (RBCs) is delayed due to their long lifespan of about 120 days. Folate kinetics demonstrate a fast- and slow-turnover pool, reflecting newly absorbed folate and turnover of folate polyglutamate respectively. The metabolism of levomefolate calcium results in L-5-methyl-THF, the predominant folate transport form in blood. It is eliminated through urinary excretion of intact folates and catabolic products, as well as fecal excretion in a biphasic kinetics process. ¹

Clinical efficacy

Levomefolate calcium, a bioactive form of folic acid, demonstrates clinical efficacy in several areas when used in combination with oral contraceptives containing drospirenone and ethinyl estradiol. In contraception, its efficacy is inferred from trials of drospirenone/ethinyl estradiol without levomefolate calcium. The Pearl Index, a measure of contraceptive effectiveness, was calculated as 1.29 and adjusted to 0.72 after accounting for patient compliance issues. Levomefolate calcium has also been shown to raise folate levels. Studies have demonstrated similar increases in plasma and Red Blood Cell (RBC) folate levels when compared with folic acid supplements. Moreover, even after discontinuation of the treatment, RBC and plasma folate levels remained above baseline in a significant number of subjects. The oral contraceptive containing drospirenone/ethinyl estradiol/levomefolate calcium has been approved for the treatment of premenstrual dysphoric disorder a severe form of premenstrual syndrome. Double-blind, placebo-controlled trials have demonstrated significant improvement in premenstrual dysphoric disorder symptoms. Finally, two large randomized, double-blind, placebo-controlled trials have demonstrated the effectiveness of the oral contraceptive containing drospirenone/ethinyl estradiol/levomefolate calcium in the treatment of moderate acne vulgaris. These studies showed a significant reduction in both inflammatory and non-inflammatory acne lesions, as well as improvement in overall skin appearance. ²

Reference

1. Rapkin RB, Creinin MD. The combined oral contraceptive pill containing drospirenone and ethinyl estradiol plus levomefolate calcium. Expert Opin Pharmacother. 2011;12(15):2403-2410.

2. Wiesinger H, Eydeler U, Richard F, et al. Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone. Clin Drug Investig. 2012;32(10):673-684.