Prescription Drug Information: DROSPIRENONE, ETHINYL ESTRADIOL AND LEVOMEFOLATE CALCIUM AND LEVOMEFOLATE CALCIUM (Page 3 of 8)

5.2 Hyperkalemia

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets contains 3 mg of the progestin DRSP, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are contraindicated 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. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see Clinical Pharmacology (12.3)].

5.3 Carcinoma of the Breasts and Reproductive Organs

Women who currently have or have had breast cancer should not use drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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.

5.4 Liver Disease

Discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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.

5.5 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.6 High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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.

5.7 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.8 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets. 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.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.9 Headache

If a woman taking drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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.

5.10 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 and levomefolate calcium tablets and levomefolate calcium tablets show the average number of episodes of bleeding per reference period (90 days) was 3.2 in Cycles 4 to 6. The average number of bleeding and/or spotting days with drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets was 15.1 days. The intensity of bleeding for drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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 and levomefolate calcium tablets and levomefolate calcium tablets 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.

5.11 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 drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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 [see Use In Specific Populations (8.1)].

5.12 Depression

Women with a history of depression should be carefully observed and drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets discontinued if depression recurs to a serious degree.

5.13 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 [see Drug Interactions (7.2)].

DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.

Folates may mask vitamin B12 deficiency.

5.14 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.

5.15 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.

6 ADVERSE REACTIONS

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

  • Serious cardiovascular events and stroke [see Boxed Warning andWarnings And Precautions (5.1)]
  • Vascular events [see Warnings And Precautions (5.1)]
  • Liver disease [see Warnings And Precautions (5.4)]

Adverse reactions commonly reported by COC users are:

  • Irregular uterine bleeding
  • Nausea
  • Breast tenderness
  • Headache

6.1 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 to 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 to 35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14 to 45 with moderate acne vulgaris 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 and levomefolate calcium tablets and levomefolate calcium tablets was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18 to 40 who were treated with drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets or YAZ® for up to 24 weeks.

The adverse reactions seen across the 3 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥2% of users) were: headache/migraine (5.9%), menstrual irregularities (including vaginal hemorrhage [primarily spotting], metrorrhagia and menorrhagia) (4.1%), nausea/vomiting (3.5%), and breast pain/tenderness (3.2%).

PMDD Clinical Trials

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 to 42, diagnosed with PMDD and who took at least one dose of YAZ®.

Common adverse reactions (≥2% of users) were: menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%).

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%).

Acne Clinical Trials:

Of 536 women, 5.4% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was menstrual irregularities (including menometrorrhagia, menorrhagia, metrorrhagia and vaginal hemorrhage) (2.2%).

Folate Clinical Trial:

Of 285 women, 4.6% who used drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets or YAZ® discontinued from the clinical trials due to an adverse reaction; no reaction leading to discontinuation occurred in ≥ 1% of women.

PMDD Clinical Trials:

Of 285 women, 11.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were: nausea/vomiting (4.6%), menstrual irregularity (including vaginal hemorrhage, menorrhagia, menstrual disorder, menstruation irregular and metrorrhagia) (4.2%), fatigue (1.8%), breast tenderness (1.4%), depression (1.4%), headache (1.1%), and irritability (1.1%).

Serious Adverse Reactions

Contraception Clinical Trials:

Migraine and cervical dysplasia

Acne Clinical Trials:

None reported in the clinical trials

Folate Supplementation Clinical Trial:

Cervix carcinoma stage 0

PMDD Clinical Trials:

Cervical dysplasia

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