(see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.phenobarbitalContraindicated (1)phenobarbital will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. phenytoinContraindicated (1)phenytoin will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. pioglitazoneMonitor Closely (1)pioglitazone will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Advise women to use alternative method of contraception or back-up method when moderate or weak enzyme inducer is used with combination contraceptives. Back-up contraception should be continued for 28 days after discontinuing medication to ensure contraceptive reliability. pitolisantMonitor Closely (1)pitolisant will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Pitolisant is a borderline/weak inducer of CYP3A4. Monitor sensitive CYP3A4 substrates for reduced effectiveness if coadministered.posaconazoleMonitor Closely (1)posaconazole will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.prednisoneMonitor Closely (1)prednisone will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Advise women to use alternative method of contraception or back-up method when moderate or weak enzyme inducer is used with combination contraceptives. Back-up contraception should be continued for 28 days after discontinuing medication to ensure contraceptive reliability. pretomanidSerious - Use Alternative (1)dienogest/estradiol valerate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.primidoneContraindicated (1)primidone will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. quinidineMonitor Closely (1)quinidine will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.quinupristin/dalfopristinMonitor Closely (1)quinupristin/dalfopristin will decrease the level or effect of dienogest/estradiol valerate by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. An alternate or additional form of birth control may be advisable during concomitant use.ranolazineMonitor Closely (1)ranolazine will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.rifabutinContraindicated (1)rifabutin will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. rifapentineContraindicated (1)rifapentine will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. ritonavirMonitor Closely (1)ritonavir will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Significant changes (increase or decrease) in plasma levels of estrogen and progestin have been seen when HIV protease inhibitors are administered. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.saquinavirMonitor Closely (1)saquinavir will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Significant changes (increase or decrease) in plasma levels of estrogen and progestin have been seen when HIV protease inhibitors are administered. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.siltuximabMonitor Closely (1)siltuximab, dienogest/estradiol valerate. Other (see comment). Use Caution/Monitor. Comment: CYP450 activity in the liver is down regulated by infection and inflammation stimuli including cytokines (eg, IL-6); inhibition of IL-6 by siltuximab may restore CYP450 enzymatic activity; caution if coadministered with CYP substrates that have a narrow therapeutic index.somapacitanMonitor Closely (1)dienogest/estradiol valerate will decrease the level or effect of somapacitan by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Oral estrogens may reduce serum insulin-like growth factor I (IGF-1) response to growth hormone (GH) analogs. Higher GH dose may be requiredsomatrogonMonitor Closely (1)dienogest/estradiol valerate will decrease the level or effect of somatrogon by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Oral estrogens may reduce serum insulin-like growth factor I (IGF-1) response to growth hormone (GH) analogs. Higher GH dose may be requiredsomatropinMonitor Closely (1)dienogest/estradiol valerate will decrease the level or effect of somatropin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Oral estrogens may reduce serum insulin-like growth factor I (IGF-1) response to growth hormone (GH) analogs. Higher GH dose may be requiredSt John's WortContraindicated (1)St John's Wort will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy. streptomycinMonitor Closely (1)streptomycin will decrease the level or effect of dienogest/estradiol valerate by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. An alternate or additional form of birth control may be advisable during concomitant use.sugammadex sodiumSerious - Use Alternative (1)sugammadex sodium decreases effects of dienogest/estradiol valerate by receptor binding competition. Avoid or Use Alternate Drug. In vitro binding studies showed that sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, a sugammadex bolus dose is considered to be equivalent to missing dose(s) of hormonal contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day of sugammadex, or the patient has a transdermal or implant hormonal contraceptive, the patient must use an additional, nonhormonal contraceptive method or back-up method of contraception (eg, condoms and spermicides) for the next 7 days.tamoxifenMonitor Closely (1)tamoxifen will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.ticarcillinMonitor Closely (1)ticarcillin will decrease the level or effect of dienogest/estradiol valerate by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. An alternate or additional form of birth control may be advisable during concomitant use.tipranavirMonitor Closely (1)tipranavir will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Significant changes (increase or decrease) in plasma levels of estrogen and progestin have been seen when HIV protease inhibitors are administered. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache. topiramateMonitor Closely (1)topiramate will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Advise women to use alternative method of contraception or back-up method when moderate or weak enzyme inducer is used with combination contraceptives. Back-up contraception should be continued for 28 days after discontinuing medication to ensure contraceptive reliability. tranexamic acid oralContraindicated (1)tranexamic acid oral, dienogest/estradiol valerate. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Coadministration of tranexamic acid oral and combination hormonal contraceptives increases thrombotic risk.valoctocogene roxaparvovecMonitor Closely (1)dienogest/estradiol valerate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.verapamilMonitor Closely (1)verapamil will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache. warfarinMonitor Closely (1)dienogest/estradiol valerate increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for potential adverse effects such as nausea, irregular uterine bleeding, breast tenderness and headache. >10% Headache, including migraines (13.2%) 1-10% Metrorrhagia and irregular menstruation (8%) Breast pain, discomfort, or tenderness (6.6%) Nausea or vomiting (6.5%) Acne (3.9%) Weight gain (2.85) <1% Venous thromboembolism Jaundice or cholestasis Gallbladder disease Depression Black Box Warnings Cigarette smoking Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use This risk increases with age (>35 yr) and heavy smoking (15 or more cigarettes/day) Advise women who use hormonal oral contraceptives not to smoke Contraindications Pregnancy Hypersensitivity Breast Cancer, or another estrogen- or progestin-sensitive cancer A high risk of arterial or venous thromboembolic disorders Undiagnosed uterine bleeding Cautions Poorly metabolized with hepatic impairment Use caution in patients with history of migraine, seizure disorder, Not recommended for women smokers >35 years Oral contraceptives can reduce production of milk in breastfeeding mothers Evaluate significant change in headaches and discontinue therapy if indicated Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should choose an alternate oral contraceptive due to the possibility of decreased contraceptive efficacy Discontinue therapy if jaundice occurs Not for administration for women with uncontrolled hypertension or hypertension with vascular disease Monitor prediabetic and diabetic women receiving therapy Consider an alternate contraceptive method for women with uncontrolled dyslipidemia Evaluate uterine bleeding or amenorrhea Thromboembolic disease may occur; stop therapy for at least 4 weeks before and through 2 weeks after major surgery; initiate therapy no sooner than 4 weeks after delivery, in women who are not breastfeeding Safety and efficacy not established for BMI >30 kg/m² CDC guidelines recommend waiting at least 3 weeks following vaginal birth or 6 weeks after cesarean section to decrease risk for venous thromboembolism before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum) should not use combined hormonal contraceptives (MMWR July 7, 2011) Breast cancer Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk; studies do not show an association between ever (current or past) use of COCs and risk of breast cancer Some studies report a small increase in risk of breast cancer among current or recent users(<6 months since last use) and current users with longer duration of COC use A woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early-onset menstruation before age 12, late-onset menopause, after age 55, first child after age 30, nulliparity 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 insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy; oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use; if the patient has not adhered to