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Black Box Warning
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
See full prescribing information for complete Boxed Warning.
* Women over 35 years old who smoke should not use drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use
Overview
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is a contraceptive combination that is FDA approved for the prophylaxis of prevent pregnancy, premenstrual dysphoric disorder (PMDD), acne, folate supplementation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include weight increased, abdominal pain, nausea, vomiting, headache, depression, irritability, labile affect, break-through bleeding, breast tenderness, disorder of menstruation, pain of breast, reduced libido, fatigue.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Dosing information
One tablet PO qd at the same time. The failure rate may increase when pills are missed or taken incorrectly.
To achieve maximum contraceptive and PMDD effectiveness, Beyaz must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered.
How to Start Beyaz
Instruct the patient to begin taking Beyaz either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start).
Day 1 Start
During the first cycle of Beyaz use, instruct the patient to take one pink drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one pink drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium can be taken without regard to meals. If drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is first taken later than the first day of the menstrual cycle, drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
Sunday Start
During the first cycle of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium use, instruct the patient to take one pink drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium can be taken without regard to meals. Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
The patient should begin her next and all subsequent 28-day regimens of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her pink tablets on the next day after ingestion of the last light orange folate tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is started later than the day following administration of the last light orange tablet, the patient should use another method of contraception until she has taken a pink drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium daily for seven consecutive days.
When switching from a different birth control pill
When switching from another birth control pill, drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be started on the same day that a new pack of the previous oral contraceptive would have been started.
When switching from a method other than a birth control pill
When switching from a transdermal patch or vaginal ring, drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be started when the next application would have been due. When switching from an injection, drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should be started on the day of removal.
Withdrawal bleeding usually occurs within 3 days following the last pink tablet. If spotting or breakthrough bleeding occurs while taking drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium , instruct the patient to continue taking drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider.
Although the occurrence of pregnancy is low if drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if pregnancy is confirmed.
The risk of pregnancy increases with each active pink tablet missed. For additional patient instructions regarding missed pills, see the "WHAT TO DO IF YOU MISS PILLS" section in the FDA Approved Patient Labeling. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more light orange tablets, she should still be protected against pregnancy provided she begins taking a new cycle of pink tablets on the proper day.
For postpartum women who do not breastfeed or after a second trimester abortion, start drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium for 7 consecutive days.
Advice in Case of Gastrointestinal Disturbances
In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet.
Folate Supplementation
The U.S. Preventive Services Task Force recommends that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily.1 Consider other folate supplementation that a woman may be taking before prescribing drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium . Ensure that folate supplementation is maintained if a woman discontinues drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium due to pregnancy.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in pediatric patients.
Contraindications
Do not prescribe drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium to women who are known to have the following:
Renal impairment.
Adrenal insufficiency.
A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
Smoke, if over age 35.
Have deep vein thrombosis or pulmonary embolism, now or in the past.
Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35.
Undiagnosed abnormal uterine bleeding.
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past.
Liver tumors, benign or malignant, or liver disease.
Pregnancy, because there is no reason to use COCs during pregnancy.
Warnings
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
See full prescribing information for complete Boxed Warning.
* Women over 35 years old who smoke should not use drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use
Thromboembolic Disorders and Other Vascular Problems
Stop drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if an arterial or venous thrombotic (VTE) event occurs.
Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, Yasmin), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs .
A number of studies have compared the risk of VTE for users of Yasmin (which contains 0.03 mg of EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 1.
This image is provided by the National Library of Medicine.
In addition to these “regulatory studies,” other studies of various designs have been conducted. Overall, there are two prospective cohort studies (see Table 1): the US post-approval safety study Ingenix [Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study) [Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 1), and two from Denmark [Lidegaard 2009, Lidegaard 2011]. There are two case-control studies: the Dutch MEGA study analysis [van Hylckama Vlieg 2009] and the German case-control study [Dinger 2010]. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011] and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1.
Figure : VTE Risk with Yasmin Relative to LNG-Containing COCs (adjusted risk#)
This image is provided by the National Library of Medicine.
(References: Ingenix [Seeger 2007]2, EURAS (European Active Surveillance Study) [Dinger 2007]3, LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011]4, Danish [Lidegaard 2009]5, Danish re-analysis [ Lidegaard 2011]6, MEGA study [van Hylckama Vlieg 2009]7, German Case-Control study [Dinger 2010]8, PharMetrics [Jick 2011]9, GPRD study [Parkin 2011]10)
Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period (see Figure 2). The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.
The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.
Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE.
This image is provided by the National Library of Medicine.
If feasible, stop drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.
COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
Hyperkalemia
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium contains 3 mg of the progestin DRSP, which has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium should not be used in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.
Carcinoma of the Breasts and Reproductive Organs
Women who currently have or have had breast cancer should not use drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium because breast cancer is a hormonally-sensitive tumor.
There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.
Liver Disease
Discontinue drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.
Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.
Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.
High Blood Pressure
For women with well-controlled hypertension, monitor blood pressure and stop drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.
Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC users.
Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium . COCs may decrease glucose tolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.
If a woman taking drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium if indicated.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
Bleeding Irregularities
Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.
Data for drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium show the average number of episodes of bleeding per reference period (90 days) was 3.2 in Cycles 4-6. The average number of bleeding and/or spotting days with drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium was 15.1 days. The intensity of bleeding for drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium based on the ratio of spotting-only days versus total bleeding and/or spotting days was 5.2/15.1 days.
Based on patient diaries from two contraceptive clinical trials of YAZ, 8 to 25% of women experienced unscheduled bleeding per 28-day cycle. A total of 12 subjects out of 1,056 (1.1%) discontinued YAZ due to menstrual disorders including intermenstrual bleeding, menorrhagia, and metrorrhagia.
Women who use drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from YAZ contraception trials for up to 13 cycles, 6 to 10% of women experienced cycles with no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.
If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.
COC Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy.
Discontinue Beyaz if pregnancy is confirmed and initiate a prenatal vitamin containing folate supplementation.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.
Depression
Women with a history of depression should be carefully observed and drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium discontinued if depression recurs to a serious degree.
Interference with Laboratory Tests
The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs .
DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.
Folates may mask vitamin B12 deficiency.
Monitoring
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.
Other Conditions
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
Contraception, Acne and Folate Supplementation Clinical Trials
The data provided reflect the experience with the use of YAZ (3 mg DRSP/0.02 mg EE), in the adequate and well-controlled studies for contraception (N=1,056), for moderate acne vulgaris (N=536) and folate supplementation (N=379).
For contraception, a Phase 3, multicenter, multinational, open-label study was conducted to evaluate safety and efficacy up to one year in 1,027 women aged 17–36 who took at least one dose of YAZ. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of YAZ on carbohydrate metabolism, lipids and hemostasis in 29 women aged 18–35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14–45 with moderate acne vulgarism who took at least one dose of YAZ, evaluated the safety and efficacy during up to 6 cycles. For folate supplementation, the primary efficacy study using drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18–40 who were treated with drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium or YAZ for up to 24 weeks.
Safety data from trials for the indication of PMDD are reported separately due to differences in study design and setting in the OC, Acne and Folate Supplementation studies as compared to the PMDD clinical program.
Two (one parallel and one crossover designed) multicenter, double-blind, randomized, placebo-controlled trials for the secondary indication of treating the symptoms of PMDD evaluated safety and efficacy of YAZ during up to 3 cycles among 285 women aged 18–42, diagnosed with PMDD and who took at least one dose of YAZ.
Adverse Reactions (≥1%) Leading to Study Discontinuation:
Contraception Clinical Trials
Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1.0%).
Of 285 women, 4.6% who used drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium or YAZ discontinued from the clinical trials due to an adverse reaction; no reaction leading to discontinuation occurred in ≥ 1% of women.
The following adverse reactions have been identified during post approval use of YAZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions are grouped into System Organ Classes, and ordered by frequency.
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Oral Contraceptives
Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations.
Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
Effect on DRSP: The main metabolites of DRSP in human plasma are generated without involvement of the CYP system. Inhibitors of this enzyme system are therefore unlikely to influence the metabolism of DRSP.
Effects of Combined Oral Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
In vitro and clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations .
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.
Potential to Increase Serum Potassium Concentration: There is a potential for an increase in serum potassium concentration in women taking drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium with other drugs that may increase serum potassium concentration .
Effects of Folates on Other Drugs
Folates may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs, e.g., antiepileptics (such as phenytoin), methotrexate or pyrimethamine, and may result in a decreased pharmacological effect of the antifolate drug.
Effects of Other Drugs on Folates
Several drugs have been reported to reduce folate concentrations by inhibition of the dihydrofolate reductase enzyme (e.g., methotrexate and sulfasalazine) or by reducing folate absorption (e.g., cholestyramine), or via unknown mechanisms (e.g., antiepileptics such as carbamazepine, phenytoin, phenobarbital, primidone and valproic acid).
Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity. Folates may mask vitamin B12 deficiency.
There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.
The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.
Women who do not breastfeed may start COCs no earlier than four weeks postpartum.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium during labor and delivery.
Nursing Mothers
When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
After oral administration of 3 mg DRSP/0.03 mg EE tablets (Yasmin), about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. * This results in a maximal daily dose of about 0.003 mg DRSP in an infant.
Studies to date indicate there is no adverse effect of folate on nursing infants.
Pediatric Use
Safety and efficacy of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Geriatic Use
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium has not been studied in postmenopausal women and is not indicated in this population.
Gender
There is no FDA guidance on the use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium with respect to specific gender populations.
Race
No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women.
Renal Impairment
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is contraindicated in patients with renal impairment.
In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP concentrations were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium-sparing drugs
Hepatic Impairment
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium is contraindicated in patients with hepatic disease. The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium has not been studied in women with severe hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium in patients who are immunocompromised.
FDA Package Insert for Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium contains no information regarding drug monitoring.
IV Compatibility
There is limited information about the IV Compatibility.
Overdosage
There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
DRSP is a spironolactone analogue which has antimineralocorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.
Levomefolate calcium doses of 17 mg/day (37-fold higher than the levomefolate calcium dose of drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium ) were well tolerated after long-term treatment up to 12 weeks.
Pharmacology
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium
COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.
Structure
Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium (drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets) provides an oral contraceptive regimen consisting of 28 film-coated tablets that contain the active ingredients specified for each tablet below:
24 pink tablets each containing 3 mg DRSP, 0.02 mg EE as betadex clathrate, and 0.451 mg levomefolate calcium
4 light orange tablets each containing 0.451 mg levomefolate calcium
The inactive ingredients in the pink tablets are lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose NF, magnesium stearate NF, hypromellose USP, titanium dioxide USP, talc USP, polyethylene glycol NF, ferric oxide pigment, red NF. The light orange film-coated tablets contain 0.451 mg of levomefolate calcium. The inactive ingredients in the light orange tablets are lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose NF, magnesium stearate NF, hypromellose USP, titanium dioxide USP talc USP, polyethylene glycol NF, ferric oxide pigment, red NF, ferric oxide pigment, yellow NF.
Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3',4',6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa- [6,7:15,16] cyclopenta[a]phenanthrene-17,2'(5H)-furan]-3,5'(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24H30O3.
Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C20H24O2.
Levomefolate calcium (N-[4-[ [(2-amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, calcium salt) is a synthetic calcium salt of L-5-methyltetrahydrofolate (L-5-methyl-THF), which is a metabolite of vitamin B9 and has a molecular weight of 497.5 and a molecular formula of C20H23CaN7O6.
The structural formulas are as follows:
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Pharmacodynamics
Drospirenone is a spironolactone analogue with antimineralocorticoid and antiandrogenic activity. The estrogen in Beyaz is ethinyl estradiol (EE).
Contraception
No specific pharmacodynamic studies were conducted with Beyaz.
Two studies evaluated the effect of 3 mg DRSP / 0.02 mg EE combinations on the suppression of ovarian activity as assessed by measurement of follicle size via transvaginal ultrasound and serum hormone (progesterone and estradiol) analyses during two treatment cycles (21-day active tablet period plus 7-day pill-free period). More than 90% of subjects in these studies demonstrated ovulation inhibition. One study compared the effect of 3 mg DRSP/0.02 mg EE combinations with two different regimens (24-day active tablet period plus 4-day pill-free period vs. 21-day active tablet period plus 7-day pill-free period) on the suppression of ovarian activity during two treatment cycles. During the first treatment cycle, there were no subjects (0/49, 0%) taking the 24-day regimen who ovulated compared to 1 subject (1/50, 2%) using the 21-day regimen. After intentionally introduced dosing errors (3 missed active tablets on Days 1 to 3) during the second treatment cycle, there was 1 subject (1/49, 2%) taking the 24-day regimen who ovulated compared to 4 subjects (4/50, 8%) using the 21-day regimen.
Acne
Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of EE and DRSP increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of DRSP on acne is not known.
Folate Supplementation
Two studies evaluated the impact of Beyaz on plasma folate and RBC folate levels. A randomized, double-blind, active-controlled, parallel group study compared plasma folate and red blood cell (RBC) folate levels during a 24-week treatment with YAZ + 0.451 mg levomefolate calcium as compared to YAZ alone in a U.S. population. 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).
Pharmacokinetics
Absorption
Beyaz and YAZ are bioequivalent with respect to DRSP and EE.
The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of EE is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of Beyaz, which is a combination tablet of DRSP and EE stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1-2 hours after administration of Beyaz.
The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of YAZ, steady state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24h) values of DRSP following multiple dose administration of YAZ (see Table 2).
For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of YAZ, serum Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table 2).
Levomefolate calcium is structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9. Mean baseline concentrations of about 15 nmol/L are reached in populations without folate food fortification under normal nutritional conditions. Orally administered levomefolate calcium is absorbed and incorporated into the body folate pool. Peak plasma concentrations of about 50 nmol/L above baseline are reached within 0.5 – 1.5 hours after single oral administration of 0.451 mg levomefolate calcium.
Steady state conditions for total folate in plasma after intake of 0.451 mg levomefolate calcium are reached after about 8-16 weeks depending on the baseline levels. In red blood cells achievement of steady state is delayed due to the long life-span of red blood cells of about 120 days.
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Food Effect
The rate of absorption of DRSP and EE following single administration of a formulation similar to Beyaz was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.
The effect of food on absorption of levomefolate calcium following administration of Beyaz has not been evaluated.
Distribution
DRSP and EE serum concentrations decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4–5 L/kg.
DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.
Biphasic kinetics is reported for folates with a fast- and a slow-turnover pool.
The fast turnover pool, probably reflecting newly absorbed folate, is consistent with the terminal half-life of approximately 4 – 5 hours after single oral administration of 0.451 mg levomefolate calcium. The slow-turnover pool reflecting turnover of folate polyglutamate has a mean residence time of greater than or equal to 100 days.
Metabolism
The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by CYP3A4.
EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction.
The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.
L-5-methyl-THF is the predominant folate transport form in blood under physiological conditions and during folic acid and levomefolate calcium administration.
Excretion
DRSP serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens.
Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38-47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17-20% of the metabolites were excreted as glucuronides and sulfates.
For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
L-5-methyl-THF is eliminated from the body by urinary excretion of intact folates and catabolic products as well as fecal excretion through a biphasic kinetics process.
Use in Specific PopulationsPediatric Use: Safety and efficacy of Beyaz has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Geriatric Use: Beyaz has not been studied in postmenopausal women and is not indicated in this population.
Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 25-35) when 3 mg DRSP/0.02 mg EE was administered daily for 21 days. Other ethnic groups have not been specifically studied.
Renal Impairment: Beyaz is contraindicated in patients with renal impairment.
The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n=28, age 30-65). All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50–79 mL/min were comparable to those in the control group with CLcr ≥ 80 mL/min. The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30–49 mL/min compared to those in the control group. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium-sparing drugs during the study, mean serum potassium concentrations increased by up to 0.33 mEq/L.
Hepatic Impairment:
Beyaz is contraindicated in patients with hepatic disease.
The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Beyaz has not been studied in women with severe hepatic impairment.
Drug Interactions
Consult the labeling of all concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Oral Contraceptives:Substances diminishing the efficacy of COCs:
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding.
Substances increasing the plasma concentrations of COCs:
Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations.
HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors:
Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Antibiotics:
There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
Effects of Combined Oral Contraceptives on Other Drugs
COCs containing ethinyl estradiol may inhibit the metabolism of other compounds.
COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19, and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.
Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.
Interactions With Drugs That Have the Potential to Increase Serum Potassium Concentration:
There is a potential for an increase in serum potassium concentration in women taking Beyaz with other drugs that may increase serum potassium concentration.
A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group.
Serum potassium concentrations also were measured at multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).
Effects of Folates on Other Drugs
There is a potential that folates such as folic acid and levomefolate calcium may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs (e.g., antiepileptics, methotrexate).
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.
Clinical Studies
Oral Contraceptive Clinical Trial
In the primary contraceptive efficacy study of YAZ (3 mg DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 28-day cycles of use. The age range was 17 to 36 years. The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other. Women with a BMI greater than 35 were excluded from the trial. The pregnancy rate (Pearl Index) was 1.41 (95% CI [0.73 – 2.47]) per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of YAZ in women 35 years of age or younger during cycles in which no other form of contraception was used.
Premenstrual Dysphoric Disorder Clinical Trials
Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the effectiveness of YAZ in treating the symptoms of PMDD. Women aged 18-42 who met DSM-IV criteria for PMDD, confirmed by prospective daily ratings of their symptoms, were enrolled. Both studies measured the treatment effect of YAZ using the Daily Record of Severity of Problems scale, a patient-rated instrument that assesses the symptoms that constitute the DSM-IV diagnostic criteria. * The primary study was a parallel group design that included 384 evaluable reproductive-aged women with PMDD who were randomly assigned to receive YAZ or placebo treatment for 3 menstrual cycles. The supportive study, a crossover design, was terminated prematurely prior to achieving recruitment goals due to enrollment difficulties. A total of 64 women of reproductive age with PMDD were treated initially with YAZ or placebo for up to 3 cycles followed by a washout cycle and then crossed over to the alternate medication for 3 cycles.
Efficacy was assessed in both studies by the change from baseline during treatment using a scoring system based on the first 21 items of the Daily Record of Severity of Problems. Each of the 21 items was rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum score of 126 was possible. In both trials, women who received YAZ had statistically significantly greater improvement in their Daily Record of Severity of Problems scores. In the primary study, the average decrease (improvement) from baseline was 37.5 points in women taking YAZ, compared to 30.0 points in women taking placebo.
Acne Clinical Trials
In two multicenter, double-blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received YAZ or placebo for six 28-day cycles. The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a "clear" or "almost clear" rating on the Investigator's Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented in Table 3:
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Folate Supplementation Clinical Trials
The development program for Beyaz 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 3 and 4 display the results for plasma and RBC folate, respectively, among evaluable subjects in each arm of the study.
Figure : US Study: Mean concentration-time curves (and SD) of plasma folates after daily oral administration of YAZ + levomefolate calcium and YAZ.
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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 : US Study Mean concentration-time curves (and SD) of RBC folates after daily oral administration of YAZ + levomefolate calcium and YAZ
This image is provided by the National Library of Medicine.
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 5 and 6 display the results for plasma and RBC folate, respectively, among evaluable subjects in the levomefolate arm of the study.
Figure : German Study: Mean trough concentration-time curve (and SD) of plasma folates after daily oral administration of Yasmin + levomefolate calcium
This image is provided by the National Library of Medicine.
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 : German Study: Mean concentration-time curves (and SD) of RBC folates after daily oral administration of Yasmin + levomefolate calcium
This image is provided by the National Library of Medicine.
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.
How Supplied
Beyaz (drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets) are available in packages of three blister packs (NDC 50419-407-03).
The film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with Z+ or M+.
Each blister pack (28 film-coated tablets) contains in the following order:
24 round, biconvex, pink, film-coated tablets with embossed “Z+” in a regular hexagon on one side each containing 3 mg drospirenone, 0.02 mg ethinyl estradiol, and 0.451 mg levomefolate calcium
4 round, biconvex, light orange, film-coated tablets with embossed “M+” in a regular hexagon on one side each containing 0.451 mg levomefolate calcium
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
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Precautions with Alcohol
Alcohol-Drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
