Voriconazole tablets

Mechanism of action: The mechanism of action of voriconazole is to inhibit the demethylation of 14α-sterol mediated by cytochrome P450 in fungi, thereby inhibiting the biosynthesis of ergosterol. In vitro tests have shown that voriconazole has a broad-spectrum antifungal effect. This product has antibacterial effects on Candida species (including fluconazole-resistant Candida krusei, Candida glabrata and Candida albicans resistant strains) and has a bactericidal effect on all tested Aspergillus fungi. In addition, voriconazole also has a bactericidal effect on other pathogenic fungi in vitro, including fungi with low sensitivity to existing antifungal drugs, such as Actinomyces and Fusarium. Animal experiments have found that the minimum inhibitory concentration value of voriconazole is related to its efficacy. However, in clinical studies, there is no correlation between the minimum inhibitory concentration and clinical efficacy, and there seems to be no correlation between the blood concentration of the drug and the clinical efficacy. This is a characteristic of azole antifungal drugs. Microbiology: Clinical trials have shown that voriconazole has clinical efficacy (improvement or cure, see the clinical experience section below) against Aspergillus, including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, and Aspergillus nidulans; Candida, including Candida albicans, and some Candida dubliniensis, Candida glabrata, C. inconspicua, Candida krusei, Candida parapsilosis, Candida tropicalis, and Candida guillimonda; Actinomyces, including Mycoplasma apiaceum and Mycoplasma prolificum, and Fusarium. Other fungal infections that respond to voriconazole (usually cured or improved) include Alternaria, Blastomyces dermatitidis, Blastomyces head, Cladosporium, Coccidioides immitis, Otocorona, Cryptococcus neoformans, Acanthophorum spp., Exophialium spinulosum, Chromosporium persei, Madura mycetoma, Paecilomyces, Penicillium, including Penicillium manifestum, Xylella fastidiosa, Scopulariopsis brevis, and Trichosporon, including Trichosporon albus infections. In vitro studies have observed that voriconazole has antimicrobial activity against the following clinically isolated fungi, including Acremonium, Alternaria, Diplodia, Cladosporium, Cladophialophora, Cladophialophora spp., and Histoplasma capsulatum. Voriconazole at 0.05-2 μg/ml can inhibit most strains. In vitro studies have shown that voriconazole has antimicrobial activity against Curvularia and Sporothrix, but its clinical significance is unclear. Before treatment, specimens should be collected for fungal culture, and other relevant laboratory tests (serological tests and histopathological examinations) should be performed to isolate and identify pathogens. Anti-infection treatment must be carried out before obtaining the results of culture and other laboratory tests, but once the results are obtained, the medication regimen should be adjusted accordingly. Clinical strains with reduced sensitivity to voriconazole have been found. However, an increase in the minimum inhibitory concentration value does not necessarily lead to clinical treatment failure. There are also patients with clinically effective treatments for infections caused by other azole-resistant strains. Due to the complexity of the patients enrolled in clinical trials, it is difficult to determine the relationship between in vitro antibacterial activity and clinical treatment outcomes. The critical concentration of voriconazole in drug sensitivity tests has not yet been established. Resistance: There is no sufficient research on the in vitro resistance of Candida, Aspergillus, Actinomyces and Fusarium to voriconazole. It is currently unknown how the resistance of various fungi in the antibacterial spectrum of voriconazole develops. Fungi with reduced sensitivity to fluconazole and itraconazole may also have reduced sensitivity to voriconazole, suggesting that cross-resistance may exist among these azole drugs. The relationship between cross-resistance and clinical efficacy has not been fully established. If isolates from clinical cases show cross-resistance, other antifungal drugs may need to be switched for treatment. Preclinical safety data: Repeated dose toxicity studies suggest that the target organ of voriconazole is the liver. Similar to other antifungal drugs, the plasma exposure when hepatotoxicity occurs in experimental animals is equivalent to the exposure achieved by therapeutic doses in humans. Experiments in rats, mice and dogs have found that voriconazole can also induce microlesions in the adrenal glands. Other routine studies on safety pharmacology, reproductive toxicity and potential carcinogenicity have not found voriconazole to be particularly harmful to humans. Reproductive studies have shown that voriconazole is teratogenic in rats and embryotoxic in rabbits at systemic exposures equivalent to those achieved by therapeutic doses in humans. In pre- and post-partum studies, exposures below those achieved with human therapeutic doses prolonged gestation and delivery in rats, resulting in dystocia leading to maternal death and decreased perinatal survival. Similar to other azole antifungal drugs, the mechanism by which voriconazole affects delivery is likely species-specific, including reduced estradiol levels. In preclinical data for the excipient sodium thiobutyl ether-β-cyclodextrin (SBECD), repeated-dose toxicity studies showed that SBECD primarily affects urethral epithelial cell cavitation and activation of macrophages in the liver and lungs. Since positive results were obtained in the guinea pig maximization test (GMPT), prescribers should be aware of the potential for allergy to intravenous preparations. Genotoxicity and reproductive toxicity studies have shown that the excipient SBECD is not particularly hazardous to humans. No studies on the carcinogenicity of SBECD have been conducted. One of the impurities in SBECD is an alkylating mutagen, which has evidence of carcinogenicity in rodents, so it should be considered that this impurity has the potential to cause carcinogenesis in humans. Based on the above study results, the course of intravenous preparations should not exceed 6 months. Clinical experience: In this section, clinical efficacy is evaluated as cure and improvement. Aspergillus infection - efficacy of voriconazole in patients with poor prognosis of aspergillosis Voriconazole has bactericidal effect on Aspergillus in vitro. An open, randomized, multicenter study compared the efficacy and survival benefit of voriconazole and amphotericin B in 277 immunocompromised patients with acute invasive aspergillosis, with a course of 12 weeks. The global overall response rate was 53% and 31% in the treatment group and control group, respectively (complete or partial recovery of abnormal symptoms and signs at baseline and imaging/bronchoscopy). The 84-day survival rate in the treatment group was significantly higher than that in the control group. In addition, voriconazole has a significant advantage in both time to death and time to discontinuation due to toxicity, which is clinically and statistically significant. This study confirms the results of an earlier prospective study. The latter study subjects were patients with risk factors for poor prognosis, including graft-versus-host disease, especially intracranial infection (usually with a mortality rate of 100%), who achieved good results after treatment with this product. This study included patients with brain, sinus, lung and disseminated aspergillosis in patients with underlying diseases such as bone marrow transplantation, solid organ transplantation, hematological malignancies, cancer or AIDS. Severe refractory candidal infections This study included 55 patients with severe refractory candidal infections (including candidemia, disseminated and other invasive candidiasis) who had previously been treated with antifungal treatment, especially fluconazole, but none of them worked. Twenty-four patients responded to voriconazole treatment (15 cured and 9 improved). Among patients infected with non-albicans Candida albicans strains resistant to fluconazole, 3/3 of Candida krusei (cured) and 6/8 of Candida glabrata (5 cured and 1 improved) were effectively treated. Limited drug sensitivity data also support clinical efficacy. Infections with Actinomyces and Fusarium Voriconazole is effective for the following rare fungal infections: Actinomyces: In the voriconazole-treated group, 16 of the 28 patients with Mycoplasma apical infection were effectively treated (6 were cured and 10 were improved); 2 of the 7 patients with Mycoplasma multiflora infection were effectively treated (both were improved). In addition, 1 of the 3 patients with mixed (more than 1 pathogen, including Actinomyces) infection was effectively treated. Fusarium: Among the 17 patients in the voriconazole-treated group, 7 were effective (3 were cured and 4 were improved). Among these 7 patients, 3 had eye infections, 1 had sinus infections, and 3 had disseminated infections. Another 4 patients had mixed infections including Fusarium spp., of which 2 were effectively treated. Most of the patients with the above rare pathogen infections were ineffective or intolerant to the existing antifungal treatment. Treatment course: In clinical trials, 561 patients received voriconazole for more than 12 weeks, and 136 patients received voriconazole for more than 6 months. Pediatric medication experience Voriconazole was used to treat 61 pediatric patients with confirmed or highly suspected invasive fungal infections, aged 9 months to 15 years, including 34 patients aged 2-12 years and 20 patients aged 12-15 years. Most patients (57/61) had used other antifungal drugs, but all failed. Five children aged 12-15 years were included in the therapeutic study, and the rest received voriconazole treatment in placebo. The underlying diseases of these children included hematological malignancies, aplastic anemia (27 cases) and chronic granulomatous disease (14 cases). Aspergillosis was the most common fungal infection (43/61; 70%).

Voriconazole. Chemical name: (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

This product is a film-coated tablet, which appears white to off-white after removing the coating.

Treatment of invasive aspergillosis. Treatment of severe invasive infections caused by Candida species resistant to fluconazole (including Candida krusei). Treatment of severe infections caused by Actinomyces and Fusarium species. This product should be used primarily to treat progressive, potentially life-threatening infections in immunocompromised patients.

First give a loading dose (first 24 hours) - patients weighing ≥40kg: give once every 12 hours, 400mg each time (applicable to the first 24 hours); patients weighing <40kg: give once every 12 hours, 200mg each time (applicable to the first 24 hours). Then give a maintenance dose (24 hours after the start of medication) - patients weighing ≥40kg: give twice a day, 200mg each time; patients weighing <40kg: give twice a day, 100mg each time.

The most common adverse events in the treatment trials were visual disturbances, fever, rash, nausea, vomiting, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory dysfunction. The most common adverse events related to treatment that led to discontinuation included increased liver function test values, rash, and visual disturbances.

This product is contraindicated in patients with a known history of hypersensitivity to voriconazole or any of the excipients.

Precautions for children: The safety and efficacy of voriconazole in children under 12 years old have not been established. In the therapeutic study, a total of 22 patients with invasive aspergillosis aged 12-18 years were enrolled and given a maintenance dose of voriconazole, i.e. 4 mg/kg once every 12 hours. Twelve patients (55%) were treated effectively. In the therapeutic study, the pharmacokinetic properties of voriconazole in adolescents were rarely studied. Precautions for pregnancy and lactation: Pregnant women There is currently insufficient data on the use of voriconazole in pregnant women. Animal experiments have shown that this product has reproductive toxicity (see preclinical safety data), but the potential risk to humans has not been determined. Voriconazole should not be used in pregnant women unless the benefits to the mother significantly outweigh the potential toxicity to the fetus. Women of childbearing age Women of childbearing age should take effective contraceptive measures during the use of voriconazole. There is no data on the secretion of voriconazole in breast milk for lactating women. Unless the benefits clearly outweigh the risks, lactating women should not use voriconazole. Elderly precautions: In multiple-dose treatment studies, 9.2% of patients were aged 65 years and 1.8% were aged 75 years. A study conducted in healthy volunteers showed that the total exposure (AUC) and peak blood concentration (Cmax) of elderly men were higher than those of younger men. Analysis of pharmacokinetic data of 552 patients in 10 voriconazole treatment studies showed that after intravenous or oral administration of voriconazole, the blood concentration of elderly patients was about 80%-90% higher than that of younger patients. However, the overall safety of the elderly is similar to that of young people, so there is no need to adjust the dose.

Unless otherwise noted, drug interaction studies were conducted in healthy male volunteers. Multiple doses were administered orally, 200 mg twice daily, until steady-state concentrations were reached. These study 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. Parts 1 and 2 of the interaction are described in the following order: prohibited co-administration; dose adjustment and close clinical and/or biological monitoring are required when co-administered; and finally, there is no obvious pharmacokinetic interaction, but it 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 used in combination with rifampicin (600 mg once daily), the Cmax (peak plasma concentration) and AUCτ (area under the concentration-time curve during the dosing interval) of voriconazole decreased by 93% and 96%, respectively. Therefore, the combination of this product with rifampicin is prohibited (see [Contraindications]). Carbamazepine and phenobarbital (potential strong CYP450 inducers): Although not studied, carbamazepine and phenobarbital may significantly reduce the plasma concentration of voriconazole, so the combination of this product with these two drugs is prohibited (see [Contraindications]). Cimetidine (non-specific CYP450 inhibitor, and can increase the pH of gastric acid): When used in combination with cimetidine (400 mg twice daily), the Cmax and AUCτ of voriconazole increased by 18% and 23%, respectively. No dosage adjustment is required for the combination of the two. Ranitidine (increases gastric acid pH): Ranitidine (twice daily, 150 mg each time) had no significant effect on the Cmax and AUCτ of voriconazole. Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor, twice daily, 1 g each time) and azithromycin (once daily, 500 mg each time) had no significant effect on the Cmax and AUCτ 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 plasma concentrations 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 (see [Contraindications]). Sirolimus (CYP3A4 substrate): When co-administered with voriconazole, the Cmax and AUCτ of sirolimus (single dose of 2g) increased by 556% and 1014%, respectively. Therefore, the co-administration of these two drugs is prohibited (see [Contraindications]). Ergot alkaloids (CYP3A4 substrate): Although not studied, the blood concentration of ergot alkaloids (ergotamine and dihydroergotamine) may increase when co-administered with voriconazole, resulting in ergot poisoning. Therefore, the co-administration of voriconazole and ergot alkaloids is prohibited (see [Contraindications]). Cyclosporine (CYP3A4 substrate): In stable renal transplant patients, voriconazole can increase the Cmax and AUCτ 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 the dose of cyclosporine be halved and the blood concentration of cyclosporine be closely monitored. Increased cyclosporine concentrations can cause nephrotoxicity. 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 AUCt of tacrolimus (single dose 0.1 mg/kg) increased by 117% and 221%, respectively. When patients who have been treated with tacrolimus start using this product, it is recommended that the dose of tacrolimus be reduced to 1/3 of the original dose and the blood concentration be closely monitored. Increased tacrolimus concentrations can cause nephrotoxicity. 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 anticoagulant warfarin (CYP2C9 substrate): When voriconazole (twice daily, 300 mg each time) is used in combination with warfarin (single dose of 30 mg), the prothrombin time can be extended by up to 93%. Therefore, when the two are used together, 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 use 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 still increase the blood concentration of sulfonylurea drugs (such as tolbutamide, glipizide, glyburide) when used simultaneously, thereby causing hypoglycemia. Therefore, it is recommended to closely monitor blood sugar when the two are used together. Statins (CYP3A4 substrates): Although not clinically studied, in vitro tests (human liver microsomes) have shown that voriconazole inhibits the metabolism of lovastatin. Therefore, the combination of voriconazole and statins may increase the blood concentration of statins metabolized by CYP3A4. Increased blood concentrations of statins may cause rhabdomyolysis. It is recommended that the dose of statins should be adjusted when the two are used together. 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 metabolized by CYP3A4 (such as midazolam and triazolam) and prolong the duration of sedation. It is recommended to adjust the dose of benzodiazepines when the two drugs are used together. Vinca alkaloids (CYP3A4 substrates): Although not studied, there is a possibility that the plasma concentrations of vinca alkaloids (vincristine and vinblastine) may be increased when co-administered with voriconazole, resulting in neurotoxicity. Prednisone (CYP3A4 substrate): The Cmax and AUCτ of prednisone (single dose of 60 mg) increased by 11% and 34%, respectively, when co-administered with voriconazole. No dose adjustment is required when the two are co-administered. Digoxin (P-glycoprotein-mediated transport): Voriconazole had no significant effect on the Cmax and AUCτ of digoxin (0.25 mg once daily). Mycophenolic acid (UDP-glucuronyltransferase substrate): Voriconazole had no significant effect on the Cmax and AUCτ of mycophenolic acid (single dose of 1 g). Drug Interactions Phenytoin (CYP2C9 substrate and strong inducer of CYP450): Avoid using phenytoin and voriconazole at the same time unless the benefits outweigh the risks after weighing. Phenytoin once a day, 300 mg each time, can reduce the Cmax and AUCτ of voriconazole by 49% and 69%, respectively; voriconazole twice a day, 400 mg each time (see [Usage and Dosage]), can increase the Cmax and AUCτ 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 increased to 5 mg/kg twice a day. See [Dosage and Administration]. Rifabutin (CYP450 inducer): The combination of rifabutin and voriconazole should be avoided as much as possible unless the benefits outweigh the risks after weighing. When rifabutin (300 mg once a day) and voriconazole (200 mg twice a day) are used simultaneously, the Cmax and AUCτ of voriconazole are reduced by 69% and 78%, respectively. When voriconazole is administered twice a day at 350 mg each time and combined with rifabutin, its Cmax and AUCτ are 96% and 68% of those when the drug is used alone (200 mg twice a day), respectively. Voriconazole was administered twice daily, 400 mg each time, and combined with rifabutin, and its Cmax and AUCτ were 104% and 87% higher than when it was used alone (200 mg twice a day); at the same time, the Cmax and AUCτ of rifabutin increased by 195% and 331%, respectively. When rifabutin is used simultaneously with voriconazole, it is recommended to increase the maintenance dose of voriconazole. If it is administered orally, 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. If it is administered intravenously, the dose is adjusted to 5 mg/kg twice a day. It is also recommended to closely monitor the complete blood count and adverse events of rifabutin (such as uveitis). Omeprazole (CYP2C19 inhibitor, CYP2C19 and CYP3A4 substrate): When used simultaneously with omeprazole (single dose 40 mg daily), the Cmax and AUCτ of voriconazole increased by 15% and 41%, respectively. No dose adjustment of voriconazole is required. When used in combination with voriconazole, the Cmax and AUCτ of omeprazole increased by 116% and 280%, respectively. Therefore, when patients who are currently taking omeprazole start taking voriconazole, it is recommended to halve the dose of omeprazole. Voriconazole also has an inhibitory effect on the metabolism of other proton pump inhibitor drugs that are CYP2C19 substrates. Indinavir: (CYP3A4 substrate and inhibitor): When indinavir (800 mg three times a day) and voriconazole were used simultaneously, the Cmax, Cmin (trough blood concentration) and AUCτ of voriconazole and the Cmax and AUCτ of indinavir were not significantly affected. Other HIV protease inhibitors (CYP3A4 inhibitors): In vitro studies have shown that voriconazole inhibits 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 (NNRTI) (CYP3A4 substrates, CYP3A4 inhibitors or CYP450 inducers): In vitro studies have shown that delavird and efavirenz can inhibit the metabolism of voriconazole. Although not studied, efavirenz and nevirapine may induce voriconazole metabolism, and voriconazole may also inhibit the metabolism of NNRTIs. In the absence of in vivo studies, the efficacy and/or toxicity of the drugs should be closely monitored when the two drugs are used together.

Keep tightly closed.

50 mg x 2 tablets

24 months

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