Yaz Drug Interactions

Overview: The concurrent administration of oral contraceptives with other may lead to breakthrough bleeding and/or may result in an altered response to either agent (see Table 15 and Table 16). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and nonprescription, before oral contraceptives are prescribed.
Drug-Drug Interactions: See Table 15.

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Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Women on short-term treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of the hormone-containing light pink film-coated tablets in the COC pack, the hormone-free white film-coated tablets should be omitted and the next COC pack be started.
For women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraceptive is recommended.
Several of the anti-HIV/HCV protease inhibitors (eg, ritonavir, telaprevir, boceprevir) and nonnucleoside reverse transcriptase inhibitors (eg, nevirapine) have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase or decrease) in the mean AUC of the estrogen or progestin have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected. Healthcare providers should refer to the label of the individual anti-HIV/HCV protease inhibitor for further drug-drug interaction information.
Strong and moderate CYP3A4 inhibitors such as azole antifungals (eg, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (eg, clarithromycin, erythromycin), diltiazem and grapefruit juice, can increase plasma concentrations of the estrogen or the progestin or both. Increase in DRSP may increase serum potassium levels, possibly increasing the risk of hyperkalemia in high-risk patients (see General under Precautions).
Oral contraceptives may also interfere with the metabolism of other drugs (see Table 16). Accordingly, plasma and tissue concentrations may either increase (eg, cyclosporine) or decrease (eg, lamotrigine). (See Table 16.)

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In clinical studies, 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 (eg, midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (eg, theophylline) or moderately (eg, melatonin and tizanidine).
No formal drug-drug interaction studies have been conducted with ethinyl estradiol/drospirenone.
Interactions With Drugs That Have the Potential to Increase Serum Potassium: There is a potential for an increase in serum potassium in women taking YAZ with other drugs (see Precautions). Of note, occasional or chronic use of NSAID medication was not restricted in any of the YAZ clinical trials.
A drug-drug interaction study of DRSP 3 mg/estradiol 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/estradiol 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 timepoints over 24 hours at baseline and on day 14. On day 14, the ratios for serum potassium C_max and AUC in the DRSP/estradiol group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.080), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).
Drug-Food Interactions: Interactions with food have not been established.
Drug-Herb Interactions: Herbal products containing St. John's wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
Drug-Laboratory Test Interactions: Results of laboratory tests should be interpreted with the knowledge that the patient is taking an oral contraceptive. The following laboratory tests are modified: A. Liver Function Tests: Aspartate serum transaminase (AST): variously reported elevations.
Alkaline phosphatase and gamma glutamine transaminase (GGT): slightly elevated.
B. Coagulation Tests: Minimal elevation of test values reported for such parameters as prothrombin and factors VII, VIII, IX, and X.
C. Thyroid Function Tests: Protein binding of thyroxine is increased as indicated by increased total serum thyroxine concentrations and decreased T₃ resin uptake.
D. Lipoproteins: Small changes of unproven clinical significance may occur in lipoprotein cholesterol fractions.
E. Gonadotropins: LH and FSH levels are suppressed by the use of oral contraceptives. Wait 2 weeks after discontinuing the use of oral contraceptives before measurements are made.
F. Glucose Tolerance: Oral glucose tolerance remained unchanged or was slightly decreased.
Tissue Specimens: Pathologists should be advised of oral contraceptive therapy when specimens obtained from surgical procedures and PAP smears are submitted for examination.
Drug-Lifestyle Interactions: No studies on the effects of YAZ on the ability to drive or use machines have been performed.
Metabolic Interactions: Drospirenone: Metabolism of drospirenone (DRSP) and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Pharmacology: Pharmacokinetics: Metabolism under Actions). 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 and CYP3A4 activity was investigated in clinical pharmacokinetic studies using omeprazole, simvastatin and midazolam as marker substrates. In a 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). 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. Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose levels, DRSP shows little propensity to interact to a significant extent with cytochrome P450 enzymes.
Ethinylestradiol: In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.