Levonorgestrel and ethinyl estradiol

The sections below provide information on substances for which data on drug interactions with CHCs are available. There is little information available about the clinical effect of most drug interactions that may affect CHCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested. Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with CHCs or the potential for metabolic enzyme or transporter system alterations. No drug-drug interaction studies were conducted with TYBLUME.

Enzyme inducers (e.g., CYP3A4) : May decrease the effectiveness of TYBLUME or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with TYBLUME. ( 7.1 , 7.2 )

7.1 Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the Plasma Concentration of CHCs and Potentially Diminishing the Efficacy of CHCs Table 3 Significant Drug Interactions Involving Substances That Affect CHCs a Induction potency of St. John's wort may vary widely based on preparation. Metabolic Enzyme Inducers Clinical effect Concomitant use of CHCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of CHCs [see Clinical Pharmacology (12.3) ] .

Decreased exposure of the estrogen and/or progestin component of CHCs may potentially diminish the effectiveness of CHCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with CHCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, primidone, phenylbutazone, rifabutin, rufinamide, topiramate, products containing St.

John's wort, and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of CHCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Decreased exposure of the estrogen component of CHCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the CHC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction.

Substances increasing the systemic exposure of CHCs: Co-administration of atorvastatin or rosuvastatin and CHCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice The effect of grapefruit juice on CYP3A4 enzymes (e.g., strong vs. moderate inhibition) depends on its brand, concentration, and preparation. , or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of CHCs.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).

In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when CHCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

7.2 Effects of Combined Hormonal Contraceptives on Other Drugs Table 4 provides significant drug interaction information for drugs co-administered with TYBLUME. Table 4 Significant Drug Interaction Information for Drugs Co-Administered with CHCs Lamotrigine Clinical effect Concomitant use of CHCs with lamotrigine may significantly decrease systemic exposure of lamotrigine due to induction of lamotrigine glucuronidation [see Clinical Pharmacology (12.3) ]. Decreased systemic exposure of lamotrigine may reduce seizure control. Prevention or management Dose adjustment may be necessary. Consult the approved product labeling for lamotrigine.

Thyroid Hormone Replacement Therapy or Corticosteroid Replacement Therapy Clinical effect Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin [see Warnings and Precautions (5.11) ]. Prevention or management The dose of replacement thyroid hormone or cortisol therapy may need to be increased. Consult the approved product labeling for the therapy in use. [See Warnings and Precautions (5.11) ]. Other Drugs Clinical effect Concomitant use of CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam.

Concomitant use with ethinyl estradiol-containing CHCs may increase systemic exposure of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole). Prevention or management The dosage of drugs that can be affected by this interaction may need to be increased. Consult the approved product labeling for the concomitantly used drug.

7.3 Effect on Laboratory Tests The use of CHCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

7.4 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation CHCs are contraindicated for use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ]. Discontinue TYBLUME prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TYBLUME can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, TYBLUME should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.