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Abstract

Beyaz® (Bayer Healthcare Pharmaceuticals, Berlin, Germany) consists of 28 film-coated tablets: 24 tablets each containing 3 mg drospirenone plus 20 µg ethinylestradiol (EE) and 451 µg levomefolate calcium followed by four tablets, each containing 451 µg levomefolate calcium. It has the same indications of the parent compound 20 µg EE/3 mg drospirenone in a 24/4-day regimen (i.e., contraception, moderate acne, premenstrual dysforic disorder). In addition, the 24-day regimen with 20 µg EE/3 mg drospirenone/levomefolate calcium assure significant increases in red blood cell and plasma folate levels reaching values indicated to be protective in reducing the risk of neural tube defects. A progressive decrease in folate levels has been observed in women taking a 30 µg EE pill fortified with the same dose of levomefolate calcium upon discontinuation. At 4 and 8 weeks following cessation of the oral contraceptive, red blood cell folate levels >906 nmol/l were measured in 85 and 60% of women respectively. Because of this, the folate-containing pill may aid in reducing the risk of neural tube defects in a pregnancy conceived during use or shortly after the discontinuation of the product.

Keywords

Beyaz®drospirenone levomefolate calcium

Progestins with a different pharmacological profile have been developed for hormonal contraception. Drospirenone is a spironolactone derivative [1]. Receptor binding studies revealed that drospirenone fits well into both the binding site of the progesterone and the mineralocorticoid receptors [1 –3]. Moreover, it is a powerful antiandrogen in the Hershberger assay [1 –3]. Antiandrogenic activity, as well as potential effects on testicular steroidogenesis, were also tested in the presence of testicular testosterone secretion in a study in hypophysectomized human chorionic gonadotropin-substituted animals – immature male rats [4]. Human chorionic gonadotropin treatment induced a massive growth of the ventral prostate after hypophysectomy. Cyproterone acetate reversed this stimulation dose dependently. Drospirenone was less active than cyproterone acetate and dienogest, but more potent than Chlormadinone acetate and spironolactone, which is also clinically used as an antiandrogen [4]. Complete inhibition of ovulation and suppression of follicular growth was seen at a daily oral dose of 3 mg in humans [5]. Following oral administration of 3 mg, steady state drospirenone concentrations were reached after 7 days [6].

Drospirenone does not bind to sex hormone-binding globulin or corticosteroid-binding globulin, but binds with 97% efficiency to other serum proteins [7]. The two main metabolites of drospirenone found in human plasma were identified to be the acid form of drospirenone generated by opening of the lactone ring and 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active [7].

The main feature of the combination containing drospirenone plus ethinylestradiol (EE) resides in the ability of the progestin to counteract the effect of EE, a potent synthetic estrogen, on liver synthesis of angiotensinogen leading to aldosterone increase [8]. Due to its antimineralocorticoid properties, the progestin antagonizes the aldosterone effect. Water and salt retention stimulated by estrogens is therefore counteracted by the antimineralocorticoid activity of the progestin. A decrease in extracellular water has been evidenced in normal women and in those with premenstrual symptoms due to water retention [9,10]. Moreover, drospirenone in combination with EE has also shown benefits with respect to body weight. In a 6-month comparative study, Foidart et al. [11] showed that more women in the 30 µg EE/drospirenone cohort lost >2 kg whereas more women in the 30 µg EE/desogestrel group gained >2 kg. These findings were consistent with another large-scale study comparing these two oral contraceptives (OCs) over 13 cycles [12].

At the level of the CNS in ovariectomized rats drospirenone increases the concentrations of β-endorphins [13]. Again, in humans, drospirenone increases the levels of neurosteroids via anxiolytic activity [14].

Drospirenone-containing OCs

At the beginning of the new millennium an OC was developed containing 3 mg drospirenone plus 30 µg EE in a monophasic 21-day regimen. In the subsequent years the dose of EE in this pill has been reduced to 20 µg. Both formulations displayed a high contraceptive efficacy and good cycle control [15 –17]. Additional benefits come from the antimineralocorticoid activity of drospirenone with a decrease of symptoms related to water retention resulting from their use [15,18].

Recently a new combination has been marketed containing 3 mg drospirenone plus 20 µg EE but in a monophasic 24-day regimen (Yaz®, Bayer HealthCare Pharmaceuticals).

This combination has been marketed in Europe, the USA, Latin America and the Asia-Pacific region. A large number of trials indicate that this OC is effective, well tolerated and is associated with good cycle control [19 –21]. In contrast to other OCs characterized by a 21-day regimen followed by a 7 day tablet-free period, the Yaz regimen consists of 24 days of active pills followed by a 4-day hormone-free interval (24/4 regimen). The reduction of the tablet-free period from 7 to 4 days results in a more pronounced ovarian suppression and may reduce the endogenous hormonal fluctuations that occur in this period [22]. Moreover, shortening the hormone-free interval should reduce the risk of escape ovulation when pills are omitted or missed at the beginning of a treatment cycle in clinical practice and it may result in an increase in the contraceptive safety margin [23].

In consideration of all the pharmacological effects displayed by drospirenone, Yaz has been approved for three indications [24]:

The prevention of pregnancy;

The treatment of symptoms of premenstrual dysphoric disorder (PMDD);

The treatment of moderate acne vulgaris.

Data supporting the effectiveness of Yaz in the prevention of unwanted pregnancies come from two 1-year, noncomparative trials (one international and one European). In these trials the contraceptive efficacy of Yaz was assessed in over 13 treatment cycles in 1027 and 1101 healthy women aged 17–36 years. The uncorrected Pearl Index in the international trial was 1.29 and the Pearl Index adjusted for noncompliance was 0.72; in the European trial, the uncorrected Pearl Index was 0.49 providing a contraceptive protection of over 99% [24].

Premenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3–8% of women of reproductive age and characterized by severe mood, behavioral and/or physical symptoms during the luteal phase of their menstrual cycle. While no significant differences between active medication and placebo were found in a randomized, placebo-controlled trial that used a triphasic OC administered for 21 days followed by 7 pills-free days [25], trials that used Yaz demonstrated that this OC formulation was significantly better than placebo for treating women with PMDD [26,27]. Because of the shortened hormone-free interval, Yaz provides more stable levels of exogenous hormones throughout the cycle, thereby reducing the frequency of adverse symptoms during the hormone-free interval. Moreover, drospirenone with its diuretic activity and its activity at the CNS level has been shown to lessen premenstrual bloating, breast pain, depression and irritability [28].

The benefits of Yaz in patients with acne include a reduction in sebum excretion rates and lesion counts. In two large (number of women = 431 and 458) randomized, double-blind, placebo-controlled multicenter trials over six treatment cycles it has been shown that Yaz was generally well tolerated and efficacious in the treatment of moderate acne vulgaris [28,29] [Bayer Healthcare Pharmaceuticals, Unpublished Data].

Folates

Folates are involved in a number of essential functions within the body, including facilitating the healthy development and growth of the fetus in utero. Low maternal folate status is related to a greater risk of adverse pregnancy outcomes, such as neural tube defects (NTDs) and early spontaneous abortion [30 –32].

Folic acid is a B vitamin (B9) found mostly in leafy green vegetables such as spinach, asparagus, orange juice and enriched grains.

Folic acid is absorbed in the proximal small intestine and it is reduced to dihydrofolate and then to tetrahydrofolate (THF) by dihydrofolate reductase, and then metabolized via serine hydroxymethyltransferase and 5,10-methylene-THF reductase to l-5-methyl-THF [33]. l-5-methyl-THF is the biologically active form of folic acid and enters the peripheral circulation. It has limited stability. Because of its limited stability, l-5-methyl-THF cannot be used clinically and its stable calcium salt, levomefolate calcium, was developed.

Levomefolate calcium is the calcium salt of l-5-methyl-THF. Repeated studies have shown that women who get 400 µg daily of folic acid prior to conception and during early pregnancy have a reduced risk that their baby will be born with a serious NTD of up to 100% [34 –37]. NTDs occur when the neural tube fails to close completely within the first 28 days following conception [38]. A meta-analysis performed by Goh et al. [38] in 2006 demonstrated that use of multivitamin supplements provided consistent protection against NTD (random effects odds ratio [OR]:0.67, 95% CI: 0.58–0.77 in case–control studies; OR:0.52, 95% CI: 0.39–0.69 in cohort and randomized controlled studies), cardiovascular defects (OR:0.78, 95% CI: 0.67–0.92 in case–control studies; OR:0.61, 95% CI: 0.40–0.92 in cohort and randomized controlled studies) and limb defects (OR:0.48, 95% CI: 0.30–0.76 in case–control studies; OR:0.57, 95% CI: 0.38–0.85 in cohort and randomized controlled studies). For cleft palate, case–control studies had an OR of 0.76 (95% CI: 0.62–0.93), and cohort and randomized controlled studies had an OR of 0.42 (95% CI: 0.06–2.84); for oral cleft with or without cleft palate, case–control studies had an OR of 0.63 (95% CI: 0.54–0.73), and cohort and randomized controlled studies had an OR of 0.58 (95% CI: 0.28–1.19); for urinary tract anomalies, case–control studies had an OR of 0.48 (95% CI: 0.30–0.76), and cohort and randomized controlled studies had an OR of 0.68 (95% CI: 0.35–1.31); and for congenital hydrocephalus case–control studies had an OR of 0.37 (95% CI: 0.24–0.56), and cohort and randomized controlled studies had an OR of 1.54 (95% CI: 0.53–4.50).

Diet seems to be insufficient in ensuring an adequate intake of folates. Because of this many health organizations recommend supplementation with folates in the periconceptional period. A periconceptional supplementation of 400 μg folic acid daily for at least 1 month prior to conception has been recommended. However, only 10–47% of women are using periconceptional folic acid supplementation [39,40]. A higher dose folic acid supplementation (4.0–5.0 mg/day) is recommended to women in intermediate-to high-risk categories. However, concerns about adverse effects of high levels of folate supplementation have arisen. Potential concerns include masking of vitamin B12 deficiency [41]. Vitamin B12 deficiency produces both an anemia identical to that of folate deficiency but also causes irreversible damage to the CNS and peripheral nervous system. Folic acid will correct the anemia of vitamin B12 deficiency and so delay diagnosis but will not prevent progression to neurological damage. At present there is no evidence to support or refute this possible harm. Moreover, given the low prevalence of vitamin B12 depletion in young women, it seems unlikely that folic acid supplementation in women of childbearing age would result in this side effect [41].

In a public health strategy that was intended to reduce the occurrence of NTDs, some countries implemented mandatory fortification of food with folic acid. After folic acid was added to grain products, a decrease in the occurrence of NTDs by up to 54% was observed in these countries [42 –44]. In the USA, a 19% decrease in NTD prevalence was observed after grain products were fortified with folic acid [42] at an amount intended to provide an additional 100 μg folic acid/day [45]. A reduction in the prevalence of NTDs was also observed in Chile [44]. However, as discussed previously, concerns also arise in this case because of the risk of overdoses when the general population is chronically exposed to a large amount of folic acid.

The addition of acid folic to OCs may help to overcome some of these problems and they could be of benefit to women who become pregnant shortly after discontinuing OCs.

Folic acid and levomefolate calcium are expected to be similarly effective at reducing the risk of NTDs and are comparable in terms of activity [46,47]. Lamers et al. showed that levomefolate calcium is at least as effective as folic acid at reducing plasma homocysteine levels, a risk factor for intrauterine growth retardation, preterm delivery, preeclampsia and NTDs [46]. In a randomized, placebo-controlled, double-blind trial, Venn et al. compared the effects of [6S]-5-methyl-THF (MTHF) and folic acid supplementation for 24 weeks on plasma folate and red cell folate in women aged 18–49 years [47]. Women were randomly assigned to receive a supplement containing [6S]-5-MTHF (113 μg/day), folic acid (100 μg/day) or placebo. Red blood cells incorporate folates during erythropoiesis, and release folates during hemolysis. Because red blood cells have a lifespan of approximately 120 days, red blood cell folate concentrations serve as long-term indicators of folate status. The mean estimated linear increase in plasma folate concentration was 0.3 and 0.4 nmol/l/week in the [6S]-5-MTHF and folic acid groups, respectively. The mean estimated linear increase in red cell folate was 7.4 and 8.3 nmol/l/week in the [6S]-5-MTHF and folic acid groups, respectively. These data sμggest that low-dose [6S]-5-MTHF and folic acid supplementation increase blood folate indices to a similar extent.

Levomefolate calcium may have further theoretical and potential advantages over the intake of folic acid. After ingestion some of the folic acid administered may appear directly in the systemic circulation without biotransformation. An inverse relationship has been described between unmetabolized folic acid and natural killer cell cytotoxicity [48]. Levomefolate calcium seems to overcome some negative features of folic acid as it would obviate the risk that unmetabolized folic acid enters the circulation.

The changes in folate concentrations after daily supplementation with various folate forms and doses in women of childbearing age has been calculated [49 –51]. The folate doses provided were 400 mg/day folic acid and an equimolar amount (416 mg/day) of [6S]-5-MTHF [50] and 800 μg/day folic acid [51]. The results showed that during supplementation with 400 μg/day folic acid or 416 μg/day [6S]-5-MTHF and 800 μg/day folic acid, the red blood cell folates were above the protective concentrations after 8 weeks [50,51]. When folate intake is stopped, folates continue to be present in plasma due to a slow release of folate from tissue stores. It has been calculated that more than 8 weeks would have to pass after cessation of supplementation with either 800 μg/day folic acid, 400 μg/day folic acid or 416 μg/day [6S]-5-MTHF for red blood cell folate concentrations to drop below 906 nmol/l, the folate concentrations thoμght to be optimum for reducing the risk of NTD-affected pregnancy [50].

Drospirenone & the folate-containing pill

Recently Yaz has been fortified with the folate levomefolate calcium. This formulation combines the contraceptive efficacy of OCs and the advantages of drospirenone as well as those of low doses of EE with levomefolate calcium, a compound that may improve the folate status of women of childbearing potential. The new formulation (Beyaz®, Bayer HealthCare Pharmaceuticals) contains 20 μg EE plus 3 mg drospirenone fortified with the folate levomefolate calcium at the dosage of 451 μg (equimolar dose to 400 μg folic acid) for 24 days followed by 451 μg folate levomefolate calcium alone for 4 days.

The fortified OC with levomefolate calcium is approved by the US FDA to:

Prevent pregnancy;

Treat symptoms of PMDD for women who choose to use an OC for contraception;

Treat moderate acne for women at least 14 years old only if the patient desires an OC for birth control;

Raise folate levels in women who choose an OC for contraception.

Data to document the efficacy of Beyaz as a contraceptive and its effects on PMDD and acne come from studies performed with Yaz [28,29] [Bayer Healthcare Pharmaceuticals, Unpublished Data].

The concomitant administration of EE 20 μg plus 3 mg drospirenone and 451 μg levomefolate calcium does not affect the pharmacokinetic profile of the individual components of the pill [Bayer Healthcare Pharmaceuticals, Pers. Comm.]. In other words, the concentrations of both steroids are equivalent to those of women taking EE 20 μg plus 3 mg drospirenone alone. In addition, the pharmacokinetics of l-5-methyl-THF were not affected by the concomitant administration of the drospirenone/EE pill [Bayer Healthcare Pharmaceuticals, Pers. Comm.].

The addition of levomefolate calcium to the pill increases folate levels in users. With the objective of comparing the effects of an OC fortified with 451 μg levomefolate calcium with the same unfortified OC on folate status, Marr et al. performed a randomized, double-blind study conducted across eight centers in the USA [52]. A total of 262 healthy women aged 18–40 years requesting contraception were randomized and were treated for 24 weeks (six cycles). In each treatment cycle, women received 24 days of fortified pill or EE 20 μg plus 3 mg drospirenone alone followed by 4 days of levomefolate calcium alone or placebo, respectively. The red blood cell and plasma folate levels at 4-week intervals until 24 weeks were evaluated. Mean red blood cell folate increased by approximately 40% from baseline reaching values of 1406 ± 440 nmol/l at 24 weeks, above the cut-off for the level associated with maximum prevention of NTDs, in EE 20 μg plus 3 mg drospirenone/levomefolate calcium recipients. In particular, red blood cell folate levels increased up to week 16 of EE 20 μg plus 3 mg drospirenone/levomefolate calcium treatment and remained stable at a concentration of approximately 1400 nmol/l thereafter. Similarly, mean plasma folate increased from 45.0 ± 17.6 nmol/l at baseline to 60.8 ± 19.9 nmol/l at week 24 with EE 20 μg plus 3 mg drospirenone/levomefolate calcium (p < 0.0001 for the between treatment difference at week 24). The increase in plasma folate levels occurred during the first 4–8 weeks of treatment; thereafter, the concentrations remained stable at approximately 60 nmol/l. In parallel, plasma homocysteine levels decreased by week 4 and it remained stable for the remaining duration of the study. In women treated with EE 20 μg plus 3 mg drospirenone only, red blood cell and plasma folate levels remained fairly constant for the entire duration of the study.

Similar results have been obtained by Diefenbach et al. [53] but with a 21/7-day OC containing 30 μg EE plus 3 mg drospirenone. In this study performed in Germany, the pharmacodynamic effect on plasma folate and red blood cell folate levels was assessed during 24 weeks of treatment with 451 μg levomefolate calcium or with 400 μg folic acid, both in combination with 30 μg EE plus 3 mg drospirenone. A total of 172 healthy women aged between 18 and 40 years without folate food fortification and without concomitant intake of folate supplements were randomized to one of the two treatments mentioned above. Following 24 weeks, women on 30 μg EE plus 3 mg drospirenone and levomefolate calcium treatment received a daily dose of 30 μg EE plus 3 mg drospirenone alone in an open-label manner for a further 20 weeks.

A significant and similar increase in red blood cell folates and plasma folate levels were reported with both treatments added to the pill. During treatment, 95% of women treated with 30 μg EE plus 3 mg drospirenone and levomefolate calcium had red blood cell folate levels of ≥906 nmol/l. Red blood cell folate levels remained above the protective concentration of 906 nmol/l in 85, 60, 47, 29 and 9% of women at 4, 8, 10, 12 and 20 weeks, respectively, after stopping 30 μg EE plus 3 mg drospirenone and levomefolate calcium treatment. At the end of the study, red blood cell and plasma folate levels were still above baseline in 89.3 and 41.3% of women in the OC and levomefolate calcium group, respectively. Until the present study, no specific data were available for 20 μg EE plus 3 mg drospirenone and levomefolate calcium.

Conclusion

The use of OCs in combination with folate is an alternative method in women of reproductive age who choose an OC for contraception, for obtaining the recommended amount of folate supplementation. Beyaz assures a significant increase in red blood cell and plasma folate levels, reaching values indicated to be protective in reducing the risk of NTDs. A progressive decrease in folate levels has been observed in women taking a 30 μg EE pill fortified with the same dose of levomefolate calcium after discontinuation. At 4 and 8 weeks following cessation of the OC, red blood cell folate levels ≥906 nmol/l were measured in 85 and 60% of women, respectively. Accordingly, Beyaz is indicated in women who choose to use an OC as their method of contraception to raise folate levels for the purpose of reducing the risk of NTD in a pregnancy conceived during use or shortly after discontinuing the product.

Executive summary

Pharmacological properties of drospirenone

Drospirenone is a spironolactone derivative. It exerts antimineralocorticoid and antiandrogenic activity.

Drospirenone-containing oral contraceptives

For oral contraception, 3 mg drospirenone has been combined with 30 or 20 μg in a monophasic 21-day regimen of ethinylestradiol (EE). Recently, drospirenone was combined with 20 μg EE in a monophasic 24-day regimen.

Clinical efficacy

The 24-day regimen pill displayed a high contraceptive efficacy and good cycle control. Moreover, it has been approved for the treatment of symptoms of premenstrual dysphoric disorder and moderate acne vulgaris.

Folates

Low maternal folate status is related to a greater risk of neural tube defects (NTDs) and early spontaneous abortion.

Pharmacological aspects of folates

After absortion in the proximal small intestine, folic acid is metabolized to l-5-methyl-tetrahydrofolate, the biologically active form of folic acid.

l-5-methyl-tetrahydrofolate cannot be used clinically so its stable calcium salt, levomefolate calcium, was developed.

Daily required doses of folates

It has been shown that 400 μg daily of acid folic (equimolar amount of levomefolate calcium is 451 μg) prior to conception and during early pregnancy reduces the risk of NTDs.

Drospirenone & the folate-containing pill

The 24-day regimen drospirenone pill has been fortified with levomefolate calcium.

Beyaz® consists of 28 film-coated tablets: 24 tablets each containing 3 mg drospirenone plus 20 μg EE and 451 μg levomefolate calcium, followed by four tablets each containing 451 μg levomefolate calcium.

Pharmacokinetic properties

Plasma folate levels in red blood cell and plasma increased, reaching the cutoff level associated with maximum prevention of NTDs.

After cessation of a fortified pill, the red blood cell folate concentrations remain above the protective concentration of 906 nmol/l in 85, 60,47, 29 and 9% of women at 4, 8, 10, 12 and 20 weeks, respectively.

Conclusion

Beyaz assures a significant increase in red blood cell and plasma folate levels reaching values indicated as protective in reducing the risk of NTDs.

Because of the decrease in folate levels after discontinuation, this fortified pill is indicated in women who choose to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of NTD in a pregnancy conceived during use or shortly after discontinuing the product.

Future perspective

The present available data suggest that Beyaz, an OC fortified with levomefolate calcium, is able to ensure levels of folates indicated as protective in reducing the risk of NTDs. However the folate levels decreased shortly after discontinuation of the pill. As a consequence it will be very important to evaluate the possibility of modifying this contraceptive association in an attempt to maintain adequate folate levels for a long time after discontinuation.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Beyaz®: An Oral Contraceptive Fortified with Folate

Abstract

Keywords

Drospirenone-containing OCs

Folates

Drospirenone & the folate-containing pill

Conclusion

Future perspective

Footnotes

References