Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 or dual CYP450 3A4 and P-glycoprotein (P-gp) inhibitors may significantly increase the plasma concentrations of docetaxel, which is a substrate of both CYP450 3A4 and P-gp. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a suspected interaction with amiodarone was described in a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy who developed increasing abdominal discomfort and skin lesions during 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab. A subsequent switch to docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. In another case report, a 79-year-old man was hospitalized with fever, diarrhea, and grade 4 stomatitis and neutropenia after receiving a third cycle of docetaxel (35 mg/m2 on days 1 and 8 every 21 days) for metastatic androgen-independent prostate cancer while on dronedarone therapy (400 mg twice daily), which had been commenced 24 days earlier due to recurrence of atrial fibrillation. Docetaxel was still detectable in a plasma sample taken 24 days after it was last administered, at a concentration of approximately 2.4 ng/mL, even though its terminal half-life is about 12 hours. Unfortunately, the patient died after deterioration of his condition and multiple infectious complications. The authors of these case reports propose that, in addition to CYP450 3A4 inhibition, P-gp inhibition due to amiodarone and dronedarone may also have contributed to the interaction.

MANAGEMENT: Concomitant use of docetaxel with CYP450 3A4 inhibitors, particularly potent inhibitors or dual CYP450 3A4 and P-gp inhibitors such as itraconazole, ketoconazole, posaconazole, conivaptan, ceritinib, idelalisib, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics, should generally be avoided. Some authorities recommend avoiding concomitant use of docetaxel during and for 2 weeks after treatment with itraconazole. If concomitant use is required, a reduced dosage of docetaxel should be considered. Based on extrapolation from the pharmacokinetic study in 7 cancer patients, a 50% reduction in the docetaxel dose may be reasonable. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

MONITOR: Coadministration with inhibitors of CYP450 3A4 or dual CYP450 3A4 and P-glycoprotein (P-gp) inhibitors may increase the plasma concentrations of docetaxel, which is a substrate of both CYP450 3A4 and P-gp. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 g/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a suspected interaction with amiodarone was described in a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy who developed increasing abdominal discomfort and skin lesions during 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab. A subsequent switch to docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. In another case report, a 79-year-old man was hospitalized with fever, diarrhea, and grade 4 stomatitis and neutropenia after receiving a third cycle of docetaxel (35 mg/m2 on days 1 and 8 every 21 days) for metastatic androgen-independent prostate cancer while on dronedarone therapy (400 mg twice daily), which had been commenced 24 days earlier due to recurrence of atrial fibrillation. Docetaxel was still detectable in a plasma sample taken 24 days after it was last administered, at a concentration of approximately 2.4 ng/mL, even though its terminal half-life is about 12 hours. Unfortunately, the patient died after deterioration of his condition and multiple infectious complications. The authors of these case reports propose that, in addition to CYP450 3A4 inhibition, P-gp inhibition due to amiodarone and dronedarone may also have contributed to the interaction.

MANAGEMENT: Caution is advised if docetaxel is prescribed in combination with CYP450 3A4 inhibitors or dual CYP450 3A4 and P-gp inhibitors. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paresthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea. Dosage reduction of docetaxel may be required if an interaction is suspected.

MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. Data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir) or is nephrotoxic.

MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may significantly increase the plasma concentrations of docetaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel AUC increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%.

MANAGEMENT: The use of docetaxel in combination with grapefruit and grapefruit juice should generally be avoided. If concomitant use is required, a reduced dosage of docetaxel should be considered, particularly if used with large amounts of grapefruit juice, and therapeutic drug monitoring of docetaxel considered per local treatment protocols. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.