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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 ethinyl estradiol has been reported to increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol 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. It has been reported that once daily co-administration of drospirenone 3 mg and ethinyl estradiol 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days to a premenopausal women resulted in a moderate increase of drospirenone systemic exposure. The exposure of ethinyl estradiol was reported to increase mildly (see PRECAUTIONS).
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 reported 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 consistent effects of antibiotics on plasma concentrations of synthetic steroids has not been reported.
Effects of Combined Oral Contraceptives on Other Drugs: COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been reported 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: It has been reported that administration of a hormonal contraceptive containing ethinyl estradiol 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 report an inhibitory potential of drospirenone 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 3 mg and ethinyl estradiol 0.03 mg combination with other drugs that may increase serum potassium concentration (see PRECAUTIONS and PHARMACOLOGY under Actions).
A drug-drug interaction study of drospirenone 3 mg/estradiol 1 mg versus placebo was reported in 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 drospirenone/estradiol treatment group relative to baseline were reported to be 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were reported to be 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 drospirenone/estradiol group to those in the placebo group were reported to be 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group was reported to develop hyperkalemia (serum potassium concentrations > 5.5 mEq/L).
Concomitant Use with HCV Combination Therapy - Liver Enzyme Elevation: Do not co-administer drospirenone 3 mg and ethinyl estradiol 0.03 mg combination with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see PRECAUTIONS). Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been reported in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
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. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity (see PRECAUTIONS and previous text).
