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Indication
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This product is contraindicated for use with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine, because this product can increase the blood concentration of the above drugs, resulting in prolonged Q-T interval and occasional torsade de pointes. This product is contraindicated for use with rifampicin, carbamazepine and phenobarbital, the latter of which can significantly reduce the blood concentration of this product. This product cannot be used in combination with ergot alkaloids (ergotamine, dihydroergotamine). Ergot alkaloids are substrates of CYP3A4. When the two are used together, the increased blood concentration of ergot drugs can lead to ergot poisoning. When sirolimus is used in combination with voriconazole, the blood concentration of the former may increase significantly, so these two drugs cannot be used at the same time. This product is contraindicated for use with ritonavir (400 mg each time, once every 12 hours). When healthy subjects were given ritonavir (400 mg each time, once every 12 hours) and voriconazole at the same time, the blood concentration of voriconazole was significantly reduced. Ritonavir 100 mg each time, once every 12 hours is used to inhibit CYP3A, thereby increasing the concentration of other antiretroviral drugs, but the effect of this dosing regimen on the concentration of voriconazole has not been studied. This product is prohibited from being used simultaneously with efavirenz. When the two are used simultaneously, the blood concentration of voriconazole is significantly reduced, while the blood concentration of efavirenz is significantly increased. This product is prohibited from being used simultaneously with rifabutin. When the two are used together, the blood concentration of voriconazole is significantly reduced, while the blood concentration of rifabutin is significantly increased. Unless otherwise specified, drug interaction studies were conducted in healthy male volunteers. Multiple doses were administered, 200 mg orally each time, twice a day, until steady-state concentrations were reached. These research results are also of reference significance for other populations and other routes of administration. This section describes the effects of other drugs on voriconazole, the effects of voriconazole on other drugs, and the interactions between the two drugs. The first and second parts of the interaction are described in the following order: prohibited co-use; dose adjustment and close clinical and/or biological monitoring are required when co-use; and finally, no obvious pharmacokinetic interaction, but may be beneficial to clinical treatment. Effects of other drugs on voriconazole Voriconazole is metabolized by cytochrome P450 isoenzymes, including CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes can increase or decrease the blood concentration of voriconazole, respectively. Rifampicin (CYP450 inducer): When co-administered with rifampicin (600 mg once a day), the Cmax (peak blood concentration) and AUC (area under the concentration-time curve during the dosing interval) of voriconazole were reduced by 93% and 96%, respectively. Therefore, it is prohibited to co-administer this product with rifampicin. Carbamazepine and phenobarbital (potential CYP450 inducers): Although not studied, carbamazepine and phenobarbital may significantly reduce the plasma concentration of voriconazole, so this product is contraindicated for co-administration with these two drugs. Cimetidine (nonspecific CYP450 inhibitor and can increase gastric acid pH): When co-administered with cimetidine (400 mg twice daily), the Cmax and AUC of voriconazole increased by 18% and 23%, respectively. No dose adjustment of this product is required for co-administration of the two. Ranitidine (increases gastric acid pH): Ranitidine (150 mg twice daily) had no significant effect on the Cmax and AUC of voriconazole. Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor, 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on the Cmax and AUC of voriconazole. Effects of voriconazole on other drugs Voriconazole inhibits the activity of cytochrome P450 isoenzymes, including CYP2C19, CYP2C9 and CYP3A4. Therefore, this product may increase the blood concentration of drugs metabolized by CYP45O isoenzymes. Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied, voriconazole is contraindicated for co-administration with terfenadine, astemizole, cisapride, pimozide or quinidine. Because this product can increase the blood concentration of the above drugs, resulting in prolonged Q-T interval and occasional torsade de pointes ventricular tachycardia. Sirolimus (CYP3A4 substrate): When co-administered with voriconazole, the Cmax and AUC of sirolimus (single dose of 2g) increased by 556% and 1014%, respectively. Therefore, the co-administration of these two drugs is contraindicated. Ergot alkaloids (CYP3A4 substrates): Although not studied, the blood concentration of ergot alkaloids (ergotamine and dihydroergotamine) may increase when used in combination with voriconazole, resulting in ergot poisoning. Therefore, the combination of voriconazole and ergot alkaloids is contraindicated. Cyclosporine (CYP3A4 substrate): In stable renal transplant patients, voriconazole can increase the Cmax and AUC of cyclosporine by at least 13% and 70%, respectively. When patients who have been treated with cyclosporine start using this product, it is recommended that their cyclosporine dose be halved and the blood concentration of cyclosporine be closely monitored. Increased cyclosporine concentrations can cause renal toxicity. After discontinuation of this product, the concentration of cyclosporine still needs to be closely monitored, and the dose of cyclosporine can be increased if necessary. Tacrolimus (CYP3A4 substrate): When used in combination with voriconazole, the Cmax and AUC of tacrolimus (single dose 0.1 mg/kg) increased by 117% and 221%, respectively. When patients who have been treated with tacrolimus begin to use this product, it is recommended that the dose of tacrolimus be reduced to 1/3 of the original dose and blood concentrations be closely monitored. Increased tacrolimus concentrations can cause renal toxicity. After discontinuation of this product, the concentration of tacrolimus still needs to be closely monitored, and the dose of tacrolimus can be increased if necessary. Oral anticoagulants: Warfarin (CYP2C9 substrate): When voriconazole (twice a day, 300 mg each time) is used in combination with warfarin (single dose 30 mg), the prothrombin time can be extended by up to 93%. Therefore, when the two are used in combination, it is recommended to closely monitor the prothrombin time. Other oral anticoagulants, such as phenylprocoumon and acenocoumarol (CYP2C9 and CYP3A4 substrates): Although not studied, the blood concentration of coumarin may increase when coumarins are used in combination with voriconazole, thereby prolonging the prothrombin time. If patients are taking voriconazole and coumarin preparations at the same time, the prothrombin time needs to be closely monitored and the dose of the anticoagulant should be adjusted accordingly. Sulfonylureas (CYP2C9 substrates): Although not studied, voriconazole may increase the blood concentration of sulfonylurea drugs (such as tolbutamide, glipizide, glyburide) when used simultaneously, thus causing hypoglycemia. Therefore, close monitoring of blood sugar is recommended when the two are used in combination. Statins (CYP3A4 substrates): Although not studied clinically, in vitro tests (human liver microsomes) have shown that voriconazole inhibits the metabolism of lovastatin. Therefore, the co-administration of voriconazole and statins may increase the blood concentration of statins metabolized by CYP3A4. Increased blood concentrations of statins may cause rhabdomyolysis, and it is recommended that the dose of statins should be adjusted when the two are co-administered. Benzodiazepines (CYP3A4 substrates): Although not clinically studied, voriconazole has been shown to inhibit the metabolism of midazolam in vitro (liver microsomes). Therefore, voriconazole may increase the blood concentration of benzodiazepines (midazolam and triazolam) metabolized by CYP3A4 and prolong the duration of sedation. It is recommended to adjust the dose of benzodiazepines when the two drugs are co-administered. Vinca alkaloids (CYP3A4 substrates): Although not studied, the blood concentrations of vinca alkaloids (vincristine and vinblastine) may still increase when used in combination with voriconazole, resulting in neurotoxicity. Prednisone (CYP3A4 substrate): When used in combination with voriconazole, the Cmax and AUC of prednisone (single dose 60 mg) increased by 11% and 34%, respectively. No dose adjustment is required when the two are used in combination. Digoxin (P-glycoprotein-mediated transport): Voriconazole has no significant effect on the Cmax and AUC of digoxin (0.25 mg once a day). Mycophenolic acid (UDP-glucuronyltransferase substrate): Voriconazole has no significant effect on the Cmax and AUCtau of mycophenolic acid (1g single dose). Drug interactions Phenytoin (CYP2C9 substrate and strong inducer of CYP450): The simultaneous use of phenytoin and voriconazole should be avoided as much as possible unless the benefits outweigh the risks after weighing them. Phenytoin once a day, 300 mg each time, can reduce the Cmax and AUC of voriconazole by 49% and 69% respectively; voriconazole twice a day, 400 mg each time (see Dosage and Administration) can increase the Cmax and AUC of phenytoin (once a day, 300 mg each time) by 67% and 81% respectively. Therefore, when the two are used together, it is recommended to closely monitor the blood concentration of phenytoin. When used in combination with phenytoin, the maintenance dose of voriconazole needs to be appropriately adjusted. For oral administration, the dose of voriconazole is adjusted from 200 mg twice a day to 400 mg twice a day; if the patient weighs less than 40 kg, the dose is increased from 100 mg twice a day to 200 mg twice a day. For intravenous infusion, the dose is adjusted to 5 mg/kg twice a day. See Dosage and Administration. Rifabutin (CYP450 inducer): Avoid the combination of rifabutin and voriconazole unless the benefits outweigh the risks. When rifabutin (300 mg once daily) and voriconazole (200 mg twice daily) are used simultaneously, the Cmax and AUC of voriconazole are reduced by 69% and 78%, respectively. When voriconazole is administered twice daily, 350 mg each time, and is co-administered with rifabutin, its Cmax and AUC are 96% and 68% of those when it is used alone (200 mg twice daily), respectively. When voriconazole is administered twice daily, 400 mg each time, and is co-administered with rifabutin, its Cmax and AUC are 104% and 87% higher than those when it is used alone (200 mg twice daily), respectively; at the same time, the Cmax and AUC of rifabutin are increased by 195% and 331%, respectively. When rifabutin is used simultaneously with voriconazole, it is recommended to increase the maintenance dose of voriconazole. For oral administration, the dose is adjusted from 200 mg twice a day to 350 mg twice a day; if the patient weighs less than 40 kg, the dose is increased from 100 mg twice a day to 200 mg twice a day. For intravenous infusion, the dose is adjusted to 5 mg/kg twice a day. And monitor complete blood counts and adverse events of rifabutin (such as uveitis). Omeprazole (CYP2C19 inhibitor, CYP2C19 and CYP3A4 substrate): When used simultaneously with omeprazole (single dose of 40 mg per day), the Cmax and AUC of voriconazole increased by 15% and 41%, respectively. No dose adjustment of voriconazole is required. When used in combination with voriconazole, the Cmax and AUC of omeprazole increased by 116% and 280%, respectively. Therefore, when patients who are taking omeprazole start taking voriconazole, it is recommended to halve the dose of omeprazole. Voriconazole also inhibits the metabolism of other proton pump inhibitor drugs that are CYP2C19 substrates. Indinavir: (CYP3A4 substrate and inhibitor): The Cmax, Cmin (blood trough concentration) and AUC of voriconazole, as well as the Cmax and AUC of indinavir, were not significantly affected by the simultaneous use of indinavir (800 mg 3 times a day) and voriconazole. Other HIV protease inhibitors (CYP3A4 inhibitors): In vitro studies have shown that voriconazole has an inhibitory effect on the metabolism of HIV protease inhibitors (such as saquinavir, amprenavir and nelfinavir), and protease inhibitors can also inhibit the metabolism of voriconazole. However, the results of in vitro studies alone cannot predict the situation in the human body after the two drugs are used together. Therefore, the efficacy and/or toxicity of the drugs must be monitored when these two drugs are used simultaneously. Non-nucleoside reverse transcriptase inhibitors (NNRTIs, CYP3A4 substrates, CYP3A4 inhibitors, or CYP450 inducers): In vitro studies have shown that delavirdine and efavirenz may inhibit voriconazole metabolism. Although not studied, efavirenz and nevirapine may induce voriconazole metabolism, and voriconazole may also inhibit NNRTI metabolism. Due to the lack of in vivo studies, the efficacy and/or toxicity of the drugs should be closely monitored when the two are used together. |
United States
