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Voriconazole (Vorizol) Instructions
Common name: Voriconazole
Trade name: Vorizol
All names: Voriconazole, Vivan, Voriconazole, Vorizol

Indications:
This product is a broad-spectrum triazole antifungal drug with the following indications: treatment of invasive aspergillosis. Treatment of severe invasive infections caused by fluconazole-resistant Candida species (including Candida krusei). Treats serious infections caused by Actinomyces species and Fusarium species.

Usage and Dosage:
Give loading dose first (first 24 hours) - patients weighing ≥40 kg: administer 400 mg once every 12 hours (applicable to the first 24 hours); patients weighing <40 kg: administer 200 mg once every 12 hours (applicable to the first 24 hours). Then give the maintenance dose (24 hours after starting the drug) - patients weighing ≥40 kg: 200 mg twice a day; patients weighing <40 kg: 100 mg twice a day.

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

Contraindications:
This product is contraindicated in persons with a known history of allergy to voriconazole or any excipient.

Note:
1. Visual impairment: The effect of voriconazole on visual function when the treatment course exceeds 28 days is unclear. If treatment continues for more than 28 days, visual function, including visual acuity, range of vision, and color vision, needs to be monitored. 2. Hepatotoxicity: In clinical trials, serious liver adverse reactions (including hepatitis, cholestasis, and fatal fulminant liver failure) were uncommon in the voriconazole treatment group. It has been reported that hepatotoxic reactions mainly occur in patients with serious underlying diseases (mainly hematological malignancies). 3. Liver reactions, including hepatitis and jaundice, can occur in patients without other established risk factors. Abnormal liver function usually improves after stopping the drug. 4. Monitor liver function: Liver function needs to be checked at the beginning and during treatment with voriconazole. Patients must routinely monitor liver function at the beginning of treatment and when abnormal liver function occurs during treatment to prevent more serious liver damage. Monitoring should include laboratory tests of liver function (especially liver function tests and bilirubin). If clinical signs and symptoms are consistent with the development of liver disease, discontinuation of the drug should be considered. 5. Pregnant women: Voriconazole can cause fetal damage when used in pregnant women. Reproductive studies have shown that voriconazole has teratogenic effects (cleft palate, hydronephrosis/hydroureter) in rats at a dose of 10 mg/kg (equivalent to 0.3 times the recommended maintenance dose based on mg/m2). Voriconazole is embryotoxic in rabbits at a dose of 100 mg/kg (6 times the recommended maintenance dose). Other effects in rats include reduced ossification of the sacrococcygeal bone, skull, pubis, hyoid bone, and most ribs, sternal segment abnormalities, and ureteral/renal pelvic dilatation. Voriconazole reduces blood estradiol levels in pregnant rats at any dose. At a dose of 10 mg/kg, voriconazole can also prolong pregnancy in rats, cause dystocia, and increase perinatal mortality in young rats. In addition, voriconazole can increase embryonic mortality in rabbits, reduce fetal rabbit weight, increase skeletal mutation rate, and increase the number of ossification points outside the cervical ribs and sternum. If voriconazole is used during pregnancy, or if pregnancy occurs while taking voriconazole, the patient should be informed of the potential risk to the fetus. 6. Galactose intolerance: Voriconazole tablets contain lactose. People with rare congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this product. General Precautions: Some azoles, including voriconazole, can cause prolongation of the QT interval on the electrocardiogram. Torsades de pointes have been rarely reported during voriconazole clinical studies and postmarketing surveillance. 7. Torsade de pointes has been reported in critically ill patients with multiple mixed risk factors, such as cardiomyopathy, hypokalemia, previous cardiotoxic chemotherapy, and concurrent use of other drugs that may cause torsade de pointes. Voriconazole should be used with caution in patients with potential arrhythmias as described above.
Please read the instructions carefully and use it according to your doctor's advice.

Storage:
Sealed.

Mechanism of action:
1. 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 indicate that voriconazole has broad-spectrum antifungal effects. This product has an antibacterial effect against Candida species (including fluconazole-resistant Candida krusei, Candida glabrata and Candida albicans) and has a bactericidal effect against all Aspergillus fungi tested. In addition, voriconazole is bactericidal in vitro against other pathogenic fungi, including species that are less susceptible to existing antifungals, 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 clinical efficacy. This is a characteristic of azole antifungals. 2. Microbiology: Clinical trials have shown that voriconazole is effective against Aspergillus, including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, and Aspergillus nidulans; Candida, including Candida albicans, and some Candida dubliniensis, Candida glabrata, and C.incop icua, Candida krusei, Candida parapsilosis, Candida tropicalis, and Candida guillimondii; Actinomyces species, including Mycopodia acuminata and Mycopodia multisporum, and Fusarium species have clinical effects (improvement or cure, see the clinical experience section below). 3. Other fungal infections that are effective (usually cured or improved) with voriconazole include Alternaria, Blastomyces dermatitidis, Blastomyces capitis, Cladosporium, Coccidioides immitis, Otozoa coronalis, Cryptococcus neoformans, Beak Ophiophyllum genus, Exophyllum acanthoides, Chromomyces pereglorii, Madura mycetoma, Paecilomyces spp., Penicillium spp., including Penicillium manifesti, Phiala rotteni, Scopus brevis and Trichosporon spp., including Trichosporon albicans infection. 4. In vitro tests have observed that voriconazole has antibacterial effects on the following clinically isolated fungi, including Acremonium, Alternaria, Bipolarium, Cladophialophora spp., and Histoplasma capsulatum. Voriconazole at 0.05-2μg/ml can inhibit most bacterial strains. In vitro tests have shown that voriconazole has antibacterial effects against Curvularia and Sporothrix species, but its clinical significance is unclear. Before treatment, specimens should be collected for fungal culture and other relevant laboratory tests (serology and histopathology) should be performed to isolate and identify the pathogenic bacteria. Anti-infective therapy must precede culture and other laboratory test results, but once the results are available, the medication regimen should be adjusted accordingly. Clinical strains with reduced susceptibility to voriconazole have been identified. However, an increase in the minimum inhibitory concentration value does not necessarily lead to clinical treatment failure. Among infections caused by strains resistant to other azole drugs, there are also people who are clinically effective in treatment. Due to the complexity of enrolling patients in clinical trials, it is difficult to determine the relationship between in vitro antimicrobial activity and clinical treatment outcomes. The critical concentration of voriconazole in susceptibility testing has not yet been established. Resistance: There are insufficient studies on in vitro resistance to voriconazole in Candida, Aspergillus, Actinobacteria, and Fusarium species. 5. The development of resistance to various fungi in the antibacterial spectrum of voriconazole is currently unknown. Fungi with reduced susceptibility to fluconazole and itraconazole may also have reduced susceptibility 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, alternative antifungal treatment may be needed.

Efficacy and safety:
1. General pharmacokinetic characteristics Voriconazole pharmacokinetic studies were conducted in healthy subjects, special populations and patients. Studies on patients with risk factors for aspergillosis (mainly malignant tumors of the lymphatic system or hematopoietic tissue) found that voriconazole was taken orally twice a day, 200 mg or 300 mg each time for 14 days, and its pharmacokinetic characteristics (including rapid absorption, stable absorption, accumulation in the body and non-linear pharmacokinetics) were consistent with healthy subjects. Because the metabolism of voriconazole is saturable, its pharmacokinetics are nonlinear, and the proportion of increase in exposure dose is much greater than the proportion of dose increase. Therefore, if the oral dose is increased from 200 mg twice daily to 300 mg twice daily, the estimated exposure (AUCτ) increases by an average of 2.5-fold. When subjects are given the recommended loading dose (intravenous infusion or oral administration), the plasma concentration is close to the steady-state concentration within 24 hours. If no loading dose is given, only twice a day, the plasma concentration of most subjects reaches steady state on about the 6th day after multiple doses of administration. 2. Absorption: This product is absorbed rapidly and completely after oral administration, and peak plasma concentration is reached 1-2 hours after administration. The absolute bioavailability after oral administration is approximately 96%. When multiple doses were administered and taken simultaneously with a high-fat meal, the peak plasma concentration of voriconazole and the area under the drug-time curve between doses were reduced by 34% and 24%, respectively. Changes in gastric juice pH have no effect on the absorption of this product. Distribution: The volume of distribution of voriconazole at steady-state concentration is 4.6l/kg, indicating that this product is widely distributed in tissues. Plasma protein binding rate is approximately 58%. In one study, voriconazole was detectable in the cerebrospinal fluid of eight patients. 3. Metabolism: In vitro experiments show that voriconazole is metabolized by liver cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The pharmacokinetics of voriconazole vary widely between individuals. In vivo studies have shown that CYP2C19 plays an important role in the metabolism of this product. This enzyme has genetic polymorphisms. For example, 15-2% of Asians are poor metabolizers, while only 3-5% of whites and blacks are poor metabolizers. 4. Studies in healthy whites and healthy Japanese have shown that the drug exposure (AUCτ) of poor metabolizers is on average 4 times higher than the exposure of homozygous strong metabolizers, and the drug exposure of heterozygous strong metabolizers is 2 times higher than that of homozygous strong metabolizers. The main metabolite of voriconazole is N-oxide, which accounts for approximately 72% in plasma. This metabolite has weak antibacterial activity and has no significant impact on the pharmacological effects of voriconazole. Excretion: Voriconazole is primarily metabolized by the liver, with less than 2% of the drug excreted unchanged in the urine. After administration of voriconazole labeled with a radioisotope, approximately 80% and 83% of the radioactivity was recovered in the urine in patients receiving multiple intravenous infusions and multiple oral doses, respectively. The vast majority of the radioactivity (>94%) is excreted in the urine within 96 hours of administration (intravenous infusion or oral administration). The terminal half-period of voriconazole is dose-related. The terminal half-life after oral administration of 200 mg is approximately 6 hours. Due to its nonlinear pharmacokinetic characteristics, terminal half-life values ​​cannot be used to predict voriconazole accumulation or clearance.