Prescription Drug Information: DROSPIRENONE, ETHINYL ESTRADIOL AND LEVOMEFOLATE CALCIUM AND LEVOMEFOLATE CALCIUM (Page 4 of 8)

6.2 Postmarketing Experience

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.

Vascular Disorders

Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, retinal thrombosis, myocardial infarction and stroke), hypertension (including hypertensive crisis)

Hepatobiliary Disorders

Gallbladder disease, liver function disturbances, liver tumors

Immune System Disorders

Hypersensitivity (including anaphylactic reaction)

Metabolism and Nutrition Disorders

Hyperkalemia, hypertriglyceridemia, changes in glucose tolerance or effect on peripheral insulin resistance (including diabetes mellitus)

Skin and Subcutaneous Tissue Disorders

Chloasma, angioedema, erythema nodosum, erythema multiforme

Gastrointestinal Disorders

Inflammatory bowel disease

Musculoskeletal and Connective Tissue Disorders

Systemic lupus erythematosus

7 DRUG INTERACTIONS

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.1 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, rifampin, 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.

Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see Warnings And Precautions (5.2) And Clinical Pharmacology (12.3)].

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.

7.2 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.

COCs Increasing the Plasma Concentrations of CYP450 Enzymes

In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.

Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations [see And Clinical Pharmacology (12.3)].

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 and levomefolate calcium tablets and levomefolate calcium tablets with other drugs that may increase serum potassium concentration [see Warnings And Precautions (5.2) and And Clinical Pharmacology (12.3)].

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.5)].

7.4 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.

7.5 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).

7.6 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 anti-mineralocorticoid activity. Folates may mask vitamin B12 deficiency. [see Warnings And Precautions (5.12) and Drug Interactions (7.2).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.3 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.

8.4 Pediatric Use

Safety and efficacy of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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.

8.5 Geriatric Use

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has not been studied in postmenopausal women and is not indicated in this population.

8.6 Patients with Renal Impairment

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are contraindicated in patients with renal impairment [see Contraindications (4) and Warnings And Precautions (5.2)].

In subjects with creatinine clearance (CLcr) of 50 to 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 to 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 [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are contraindicated in patients with hepatic disease [see Contraindications (4) and Warnings And Precautions (5.4)]. 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 and levomefolate calcium tablets and levomefolate calcium tablets has not been studied in women with severe hepatic impairment.

8.8 Race

No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see Clinical Pharmacology (12.3)].

10 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 anti-mineralocorticoid 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 and levomefolate calcium tablets and levomefolate calcium tablets) were well tolerated after long-term treatment up to 12 weeks.

11 DESCRIPTION

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets provide 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, 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 ascorbic acid, corn starch, croscarmellose sodium, ferric oxide red, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide. The light orange film-coated tablets contain 0.451 mg of levomefolate calcium. The inactive ingredients in the light orange tablets are ascorbic acid, corn starch, croscarmellose sodium, ferric oxide yellow, ferric oxide red, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide.

Drospirenone ((2′,S ,6R ,7R ,8R ,9S ,10R ,13S ,14S ,15S ,16S)-1,3′,4′,6,7,8,9,10,11,12,13,14,15, 16,20,21-Hexadecadydro-10,13-dimethylspirol[17H -dicyclopropa [6,7:15,16] cyclopenta [a] phenanthrene-17, 2′, (5′H)-furan] -3, 5′ (2H) dione is a synthetic progestational compound and has a molecular weight of 366.49 and a molecular formula of C24 H30 O3 .

Ethinyl estradiol 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol is a synthetic estrogenic compound and has a molecular weight of 296.40 and a molecular formula of C20 H24 O2 .

Levomefolate calcium N-{4-[[((6S)-2-amino-3,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-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 C20 H23 CaN7 O6 .

The structural formulas are as follows:

Drospirenone, Ethinyl Estradiol, Levomefolate Calcium
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