Interactions with Letrozole
If you are currently being treated with any of the following medications, you should not use Letrozole without reading these interactions.
Coadministration with modafinil may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil is a modest inducer of CYP450 3A4 in vitro, and pharmacokinetic studies suggest that its effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, felodipine, lovastatin, midazolam, nifedipine, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, verapamil). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.
GENERALLY AVOID: Coadministration with St. John's wort may alter the pharmacokinetics of antineoplastic agents that are substrates of the CYP450 3A4 isoenzyme (e.g., bexarotene, bortezomib, busulfan, cyclophosphamide, dasatinib, docetaxel, doxorubicin, etoposide, exemestane, ifosfamide, imatinib, irinotecan, letrozole, paclitaxel, sorafenib, sunitinib, tamoxifen, temsirolimus, teniposide, thiotepa, toremifene, tretinoin, vinca alkaloids). The mechanism is induction of CYP450 3A4 metabolism by constituents of St. John's wort, which is expected to reduce the systemic levels and pharmacologic effects of many of these agents. In contrast, some agents such as cyclophosphamide and ifosfamide are prodrugs that are converted to active metabolites by CYP450 3A4, thus pharmacologic effects may be enhanced by St. John's wort. However, clinical data are currently limited.
GENERALLY AVOID: Theoretically, estrogen-containing drugs may negate the pharmacologic effects of aromatase inhibitors in the treatment of hormone-dependent breast cancer. Aromatase inhibitors induce a state of estrogen deprivation in postmenopausal women by inhibiting the conversion of androgens to estrogens in adrenal and ovarian tissues, thus estrogen administration would be expected to reverse their therapeutic effects.
MONITOR CLOSELY: Coadministration of thalidomide with glucocorticoids and/or antineoplastic agents in the treatment of malignancy may potentiate the risk of thromboembolism. The exact mechanism is unknown but likely multifactorial. Thalidomide alone has been associated with the development of deep-vein thrombosis (DVT), and malignancy itself is also a common cause. In a study of 100 patients receiving induction chemotherapy (combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin) for multiple myeloma, the addition of thalidomide was associated with an increased incidence of DVT compared to chemotherapy without thalidomide (28% vs. 4%). Administration of thalidomide was safely resumed in 75% of patients after initiation of appropriate anticoagulation therapy. In another study, 9 of 21 (43%) patients with metastatic renal cell carcinoma (RCC) receiving gemcitabine, 5-FU, and thalidomide developed venous thromboembolism, including one case of fatal cardiac arrest. This rate is substantially higher than the 3% rate observed in a group of 125 patients previously treated at the same institution with similar regimens of gemcitabine and 5-FU but without thalidomide. It is also higher than the 9% rate (12 of 140 patients) the investigators found in a review of published data from five RCC trials that used thalidomide therapy without concomitant cytotoxic therapy. Another study found a significant association of DVT with exposure to doxorubicin in patients receiving thalidomide. Specifically, 31 of 192 (16%) multiple myeloma patients treated with DT-PACE (a regimen of dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) developed DVT, while only 1 of 40 (2.5%) did so on DCEP-T (similar to DT-PACE but without doxorubicin). The time to DVT was also significantly decreased with doxorubicin exposure. In a pooled analysis of 39 prospectively monitored clinical trials involving 1784 thalidomide-treated patients, the incidence of thromboembolism was 5% when thalidomide was used as a single agent, 13% when combined with corticosteroids (8% to 26% has been reported in individual studies with dexamethasone), and 17% when combined with chemotherapy. Among thalidomide-treated patients with multiple myeloma, thromboembolism rates ranged from a low of 1/30 among those treated with concomitant cyclophosphamide, etoposide, and cisplatin to a high of about 1/3 in those treated with doxorubicin-containing regimens.
MONITOR: Coadministration of sirolimus or tacrolimus with other drugs that are also metabolized by CYP450 3A4 may result in elevated plasma concentrations of the macrolide immunosuppressant and/or the coadministered drug(s). The mechanism is decreased drug clearance due to competitive inhibition of CYP450 3A4 activity. Although clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of the drugs should be considered.
MONITOR: Coadministration with aprepitant may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) and the CYP450 3A4 substrate dexamethasone (20 mg orally on day 1 and 8 mg on days 2 through 5) resulted in an increase in the area under the plasma concentration-time curve (AUC) of dexamethasone by 2.2-fold on days 1 and 5. Similarly, aprepitant increased the AUC of methylprednisolone (125 mg intravenously on day 1 and 40 mg orally on days 2 and 3) by 1.34-fold on day 1 and 2.5-fold on day 3. The effect of aprepitant on the pharmacokinetics of CYP450 3A4 substrates is expected to be greater when the substrates are administered orally as opposed to intravenously and may be altered following prolonged administration.
MONITOR: Coadministration with conivaptan may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by conivaptan. In pharmacokinetic studies with drugs that are primarily metabolized by CYP450 3A4 such as midazolam, simvastatin, and amlodipine, conivaptan has increased systemic exposure (AUC) by 2- to 3-fold.
MONITOR: Coadministration with dasatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by dasatinib, which is a time-dependent inhibitor of the isoenzyme. In a pharmacokinetic study of 54 healthy subjects, administration of simvastatin with a single 100 mg dose of dasatinib increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of simvastatin by 37% and 20%, respectively, compared to administration without dasatinib.
MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.
MONITOR: Coadministration with lapatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 2C8 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein efflux transporter. The mechanism is decreased clearance via these routes due to inhibition by lapatinib.
MONITOR: Coadministration with telithromycin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by telithromycin.