Voriconazole tablets

Pharmacological action mechanism Voriconazole's mechanism of action 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. Voriconazole 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 Aspergillus fungi tested. 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. Microbiological clinical studies have shown that voriconazole has clinical efficacy (defined as improvement or cure) against Aspergillus, including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, and Aspergillus nidulans; Candida, including Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, and some Candida dubliniensis, Candida vulgaris, and Candida guilliermondii; Actinomyces, including Scedosporium apiospermum and Scedosporium prolificum, and Fusarium. Other fungal infections that respond to voriconazole (usually cured or improved) include Alternaria, Blastomyces dermatitidis, Blastomyces capitateus, Cladosporium, Coccidioides immitis, Otocorona, Cryptococcus neoformans, Conychosporon beaked, Exophiala spinulosa, Chromosporium persei, Madura mycetoma, and Paecilomyces lilacinus; Penicillium, including Blue-shaped fungi of Marneffei, Phiala rotundifolia, and Scopulariopsis brevis; and Trichosporon, including Trichosporon albus. In vitro studies have observed that voriconazole has antibacterial effects on the following clinically isolated fungi, including Acremonium, Alternaria, Diplodia, Phiala cladosporioides, and Histoplasma capsulatum. Voriconazole can inhibit most strains in the concentration range of 0.05 to 2 μg/ml. In vitro studies have shown that voriconazole has antibacterial effects 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-infective treatment must be started before the results of culture and other laboratory tests are obtained, but once the results are obtained, the medication regimen should be adjusted accordingly. Drug sensitivity test methods Aspergillus and other filamentous fungi Aspergillus and other filamentous fungi breakpoint standards have not yet been established. Candida The breakpoint standards for voriconazole against Candida are only applicable to the 24-hour MIC reading results of the American Clinical and Laboratory Standards Institute (CLSI) M27 microbroth dilution method, or the 24-hour inhibition zone diameter reading results of the M44 disk diffusion method. Dilution technique: This method is used to quantitatively determine the minimum inhibitory concentration (MIC) of antifungal drugs. The MIC can be used to estimate the sensitivity of Candida to antifungal drugs. The MIC should be determined at 24 hours using a standardized measurement method (broth dilution method), and the MIC value should be interpreted according to the breakpoint standards in the table below. Diffusion technique: This qualitative method involves measuring the diameter of the zone of inhibition and can reproducibly assess the susceptibility of Candida species to antifungal drugs. This standardized method requires the use of a standardized inoculum concentration and a paper disk soaked with 1 microgram of voriconazole to test the susceptibility of yeast to voriconazole at 24 hours. The table below provides the breakpoint criteria for the disk diffusion method. Voriconazole susceptibility standard broth microdilution method 24 hours (MIC, in g/ml) disk diffusion method 24 hours (inhibition zone diameter, in mm) sensitive (S) intermediate (I) resistant (R) sensitive (S) intermediate (I) resistant (R) Candida albicans 0.12 0.25-0.5 1.0 17 15-16 14 Candida krusei ≤ 0.5 1 ≥ 2 15 13-14 12 Candida parapsilosis ≤ 0.12 0.25-0.5 ≥ 11 7 15-16 14 Candida tropicalis ≤ 0.12 0.25-0.5 ≥ 11 7 15-16 14 Note: Current data are insufficient to demonstrate a correlation between in vitro susceptibility testing of Candida glabrata and voriconazole and clinical outcomes. When the result is reported as sensitive (S), it means that the antimicrobial drug is likely to inhibit microbial growth at concentrations normally achieved at the site of infection. A report of Intermediate (I) indicates that the result is questionable and should be repeated if the organism is not sufficiently sensitive to alternative, clinically available agents. This classification implies that the drug is clinically appropriate when used in areas of the body where the drug is physiologically concentrated or at high doses. This classification also provides a buffer against large biases in interpretation due to minor, uncontrolled technical factors. A report of Resistant (R) indicates that the antimicrobial drug may not inhibit pathogen growth even at concentrations normally achieved at the site of infection; alternative treatment should be selected. Quality Control Standardized susceptibility testing methods require the use of laboratory controls to monitor and ensure the accuracy and precision of test supplies and reagents and test operator technique. The range values noted in the table below are determined using standard voriconazole powder. The dilution technique using a 1 μg disk requires compliance with the criteria in the table below. Note: Quality control microorganisms are specific microbial strains with biological characteristics associated with resistance mechanisms and fungal genetic expression characteristics that have no clinical significance. Acceptable QC range for voriconazole verified by susceptibility testing results QC strains Broth microdilution 24 hours (MIC, g/ml) Disk diffusion 24 hours (inhibition zone diameter, mm) Candida parapsilosis ATCC22019 0.016-0.12 28-37 Candida krusei ATCC6258 0.06-0.5 16-25 Candida albicans ATCC900 28* 31-42 * Due to wide inter-laboratory variability in initial QC studies, the QC range for this strain/antifungal combination has not been established. ATCC is a registered trademark of the American Type Culture Collection. Activity in Animal Models Voriconazole is active in immunocompetent and/or immunosuppressed guinea pigs against systemic and/or pulmonary infections caused by Aspergillus fumigatus (including a strain with reduced susceptibility to itraconazole) or Candida species (Candida albicans (including a strain with reduced susceptibility to fluconazole), Candida krusei, and Candida glabrata), with endpoints of prolonged survival and/or reduced fungal burden in target organs. In one trial, voriconazole was active against Scedosporium apiospermum infection in immunocompetent guinea pigs. Resistance The potential for the development of voriconazole resistance is known. Resistance mechanisms may include mutations in the ERG11 gene (which encodes the target enzyme, lanosterol 14α-demethylase), upregulation of gene expression of ATP-binding cassette efflux transporters (i.e., Candida resistance CDR pumps), reduced drug target binding, or a combination of these mechanisms. The development of resistance to fungi in the spectrum of voriconazole is not known. 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 replaced for treatment. Toxicological studies Genotoxicity When voriconazole was added during in vitro human lymphocyte culture, voriconazole's teratogenic effect (mainly chromosome breakage) was observed. No genotoxicity of voriconazole was found in the Ames test, CHO test, mouse micronucleus test or DNA repair test (unscheduled DNA synthesis test). Reproductive toxicity At exposures similar to human therapeutic doses, voriconazole did not impair the reproductive capacity of male and female rats. When the systemic exposure of voriconazole was equivalent to the exposure achieved by human therapeutic doses, it was teratogenic to rats and embryotoxic to rabbits. In perinatal studies, rats given exposures below those achieved with human therapeutic doses had prolonged gestation, prolonged parturition, dystocia leading to maternal death, and decreased perinatal pup survival. Similar to other azole antifungal drugs, the mechanism by which voriconazole affects parturition is likely species-specific, including reduced estradiol levels. Carcinogenicity A 2-year carcinogenicity study of voriconazole was conducted in rats and mice. Rats were orally administered voriconazole at 6, 18, or 50 mg/kg (0.2, 0.6, or 1.6 times the usual maintenance dose, calculated on a mg/m2 basis). Hepatocellular adenomas were detected in female rats given 50 mg/kg of voriconazole, and hepatocellular carcinomas were detected in male rats given 6 and 50 mg/kg doses. Mice were orally given 10, 30 or 100 mg/kg voriconazole (calculated as 0.1, 0.4 or 1.4 times the usual maintenance dose, respectively, in mg/m2). Hepatocellular adenomas were detected in mice of both sexes, and hepatocellular carcinomas were also detected in male mice given 1.4 times the usual maintenance dose of voriconazole. Other repeated-dose toxicity studies suggest that the target organ of voriconazole is the liver. Similar to other antifungal drugs, the plasma exposure of experimental animals when hepatotoxicity occurs 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.

The main ingredient of this product is voriconazole. Chemical name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-l-(1H-1,2,4-triazol-1-yl)-2-butanol Chemical structure: Molecular formula: C16H14F3N5O Molecular weight: 349.31

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

This product is a broad-spectrum triazole antifungal drug that is suitable for the treatment of the following fungal infections in adults and children aged 2 years and above: (1) Invasive aspergillosis. (2) Candidemia in non-neutropenic patients. (3) Severe invasive infections caused by Candida species resistant to fluconazole (including Candida krusei). (4) Severe infections caused by Actinomyces and Fusarium. This product is mainly used to treat patients with progressive, potentially life-threatening fungal infections. Prevention of invasive fungal infections in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

1. General considerations for dosage Voriconazole film-coated tablets should be taken at least 1 hour before or after meals. Blood electrolytes should be monitored before or during treatment with voriconazole, and electrolyte disorders such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected. For oral administration in adults, the first loading dose should be given on the first day to bring the blood drug concentration close to the steady-state concentration. Due to the high bioavailability of oral preparations (96%), oral and intravenous administration methods can be interchanged when clinically indicated. 2. Recommended dose, adjustment and duration of treatment Recommended dose for adults and adolescents (12-14 years old and weighing ≥50kg; 15-17 years old): Oral Patients weighing ≥40kg* Patients weighing 40kg* Loading dose (applicable to the first 24 hours) Administered once every 12 hours, 400mg each time Administered once every 12 hours, 200mg each time Maintenance dose (24 hours after the start of medication) Administered twice a day, 200mg each time Administered twice a day, 100mg each time* Applicable to patients aged 15 years or above Duration of treatment The duration of treatment depends on the clinical efficacy and microbiological test results of the patient after medication. Carefully choose a reasonable treatment time. See [Precautions]. Dose adjustment (adults) During the treatment with this product, the doctor should closely monitor its potential adverse reactions and adjust the drug dosage in time according to the specific situation of the patient. See [Adverse Reactions] and [Precautions]. If the patient's treatment response is poor, the oral maintenance dose can be increased to 300mg twice a day; for patients weighing 40kg, the dose is adjusted to 150mg twice a day. If the patient cannot tolerate the higher doses, the oral maintenance dose can be reduced by 50 mg each time, gradually reducing to 200 mg twice a day (100 mg twice a day for patients weighing 40 kg). If used for prevention, see below. Children aged 2 to less than 12 years and light-weight adolescents (12 to 14 years and weighing 50 kg) should take voriconazole at the pediatric dose because these adolescents metabolize voriconazole more similarly to children than to adults. The recommended dosing regimen is as follows: Oral loading dose (applicable to the first 24 hours) Maintenance therapy is not recommended (after 24 hours of starting medication) Twice daily, 9 mg/kg each time (maximum single dose 350 mg, twice a day) Remarks: Based on the results of a population pharmacokinetic analysis of 112 immunocompromised children aged 2 to 12 years and 26 immunocompromised adolescents aged 12 to 17 years. It is recommended to start treatment with intravenous infusion therapy and consider oral therapy only when significant clinical improvement is achieved. Note that voriconazole exposure at 8 mg/kg IV is approximately twice that at 9 mg/kg oral. The recommended pediatric dose is based on studies with the dry suspension. Bioequivalence studies of the oral suspension and tablets have not been performed in children. Given that pediatric patients may have shorter gastrointestinal transit times, tablet absorption in children may differ from that in adults. Therefore, the oral dry suspension formulation is recommended for pediatric patients aged 2 to 12 years. For all other adolescents (12 to 14 years and weighing ≥50 kg; 15 to 17 years of any weight), voriconazole should be administered at the adult dose. Dose Adjustment (Children [2 to 12 years] and Lightweight Adolescents [12 to 14 years and 50 kg]) If the patient does not respond well, increase the dose by 1 mg/kg (by 50 mg if the maximum oral dose used initially was 350 mg). If the patient cannot tolerate treatment, reduce the dose by 1 mg/kg (by 50 mg if the maximum oral dose used initially was 350 mg). This product has not been studied in pediatric patients aged 2 to 12 years with impaired hepatic or renal function. Prophylaxis in adults and children should be started on the day of transplantation and the duration of prophylaxis may be up to 100 days. The duration of prophylaxis should be minimized (based on neutropenia or immunosuppression) based on the risk of invasive fungal infection (IFI). The maximum duration of prophylaxis after transplantation may be continued to 180 days only if immunosuppression or graft-versus-host disease (GvHD) persists. Dosage The recommended prophylactic dosing schedule in each age group is the same as the therapeutic dosing schedule. Please refer to the therapeutic dosing schedule table above. Duration of prophylaxis The safety and efficacy of voriconazole for use for more than 180 days have not been adequately studied in clinical trials. For prophylactic use of voriconazole for more than 180 days (6 months), the benefit-risk balance needs to be carefully evaluated. The following applies to both therapeutic and prophylactic dose adjustments For prophylactic use, no dose adjustment is recommended in the absence of efficacy or treatment-related adverse events. If treatment-related adverse events occur, discontinuation of voriconazole and use of alternative antifungal agents must be considered. Dose adjustment for combined use When used with phenytoin, it is recommended that the oral maintenance dose of voriconazole be increased from 200 mg twice daily to 400 mg twice daily (for patients weighing 40 kg, the dose is increased from 100 mg twice daily to 200 mg twice daily). Voriconazole should be avoided in combination with rifabutin. If combined use is necessary, it is recommended that the oral maintenance dose of voriconazole be increased from 200 mg twice daily to 350 mg twice daily (for patients weighing 40 kg, the dose is increased from 100 mg twice daily to 200 mg twice daily). When used in combination with efavirenz: If the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the dose of efavirenz is reduced by 50%, that is, reduced to 300 mg once daily, voriconazole can be used in combination with efavirenz. When voriconazole treatment is discontinued, efavirenz should be restored to the original dose. 3. Elderly people No dose adjustment is required for the use of this product in the elderly. 4. Renal impairment Renal impairment has no effect on the pharmacokinetics of oral administration of this product. Therefore, patients with mild to severe renal impairment do not need to adjust the dose of this product. Voriconazole can be removed by hemodialysis with a clearance rate of 121 ml/min. Four hours of hemodialysis can only remove a small amount of the drug, and no dose adjustment is required. 5. Liver impairment The loading dose of voriconazole remains unchanged in patients with mild to moderate cirrhosis (Child-Pugh A and B), but the maintenance dose is halved. There are currently no studies on the use of voriconazole in patients with severe cirrhosis (Child-Pugh C). The safety data of voriconazole in the treatment of patients with abnormal liver function tests (abnormal aspartate aminotransferase (AST), glutamate aminotransferase (ALT), alkaline phosphatase (AP) or total bilirubin more than 5 times the upper limit of normal) are very limited. There are reports that voriconazole is associated with abnormal liver function test increases and clinical signs of liver damage, such as jaundice. Therefore, patients with severe liver damage must weigh the pros and cons when using this product. Patients with liver damage must closely monitor drug toxicity when using this product. 6. Children's use The safety and effectiveness of this product have not been evaluated in children under 2 years old.

1. Safety Summary The safety data of voriconazole in adults come from a safety database including more than 2,000 subjects (including 1,603 adult patients receiving treatment and 270 adult patients in additional prevention studies). It represents different populations, including patients with hematological malignancies, HIV-infected patients with esophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidemia and aspergillosis, and healthy volunteers. The most commonly reported adverse reactions are visual impairment, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abnormal liver function tests, respiratory distress, and abdominal pain. The severity of adverse reactions is generally mild to moderate. No significant clinical differences were found when analyzing safety data by age, race, and gender. 2. List of adverse reactions In the table below, because most studies are open, all causally related adverse reactions and their frequency categories in 1,873 adults in combined treatment (1,603 cases) and prevention (270 cases) studies are listed by system organ classification. Frequency: Very common: (≥1/10); Common (≥1/100 but 1/10); Uncommon (≥1/1000 but 1/10); Rare (≥1/10000 but 1/1000); Very rare (1/10000); Unknown (cannot be inferred from known data). In each frequency group, the adverse reaction types are arranged in descending order of severity. Table Adverse reactions reported in patients receiving voriconazole System organ class Very common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1000 to <1/100 Rare ≥1/10000 to <1/1000 Frequency unknown (cannot be extrapolated from known data) Infections and infestations Sinusitis Pseudomembranous colitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Squamous cell carcinoma* Blood and lymphatic system abnormalities Agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anemia Bone marrow failure, lymphadenopathy, eosinophilia Disseminated intravascular coagulation Immune system abnormalities Hypersensitivity Allergic reactions Endocrine abnormalities Adrenal insufficiency, hypothyroidism Hyperthyroidism Metabolic and nutritional abnormalities External Peripheral edema Hypoglycemia, hypokalemia, hyponatremia Mental abnormalities Depression, hallucinations, anxiety, insomnia, agitation, confusion Nervous system abnormalities Headache Convulsions, syncope, tremor, increased muscle tension 3. Paresthesia, somnolence, dizziness Cerebral edema, encephalopathy 4. Extrapyramidal disease 5. Peripheral neuropathy, ataxia, hypoesthesia, dysgeusia Hepatic encephalopathy, Guillain-Barré syndrome, nystagmus Eye abnormalities Visual damage 6 Retinal hemorrhage Optic nerve abnormalities 7. Optic disc edema 8. Oculomotor crisis, diplopia, scleritis, blepharitis Optic nerve atrophy, corneal opacity Ear and labyrinth abnormalities Hearing loss, vertigo, tinnitus Cardiac abnormalities Supraventricular arrhythmia, tachycardia, bradycardia Ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, ECG QT prolongation, supraventricular tachycardia Torsades de pointes, complete atrioventricular block, bundle branch block, nodal heart rhythm Vascular abnormalities Hypotension, phlebitis Thrombophlebitis, lymphangitis Respiratory, thoracic and mediastinal abnormalities Respiratory distress 9 Acute respiratory distress syndrome, pulmonary edema Gastrointestinal abnormalities Diarrhea, vomiting, abdominal pain, nausea Cheilitis, indigestion, constipation, gingivitis peritonitis, pancreatitis, tongue enlargement, duodenitis, gastroenteritis, glossitis Hepatobiliary abnormalities Abnormal liver function tests Jaundice, cholestatic jaundice, hepatitis 10 Liver failure, hepatomegaly, cholecystitis, cholelithiasis Skin and subcutaneous tissue abnormalities Rash Exfoliative dermatitis, alopecia, maculopapular rash, pruritus, erythema Stevens-Johnson syndrome (Stevens-Johnson syndrome [SJS]) 8, phototoxicity, Purpura, urticaria, allergic dermatitis, papular rash, macular rash, eczema Toxic epidermal necrolysis 8, drug reaction with eosinophilia and systemic symptoms (DRESS) 8, angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug eruption Cutaneous lupus erythematosus*, freckles*, lentigo* Musculoskeletal and connective tissue disorders Back pain Arthritis Periostitis* Kidney and urinary system disorders Acute renal failure, hematuria Tubular necrosis, proteinuria, nephritis General disorders and administration site conditions Fever Chest pain, facial edema 11, fatigue, chills Injection site reactions, influenza-like illness Examinations Increased serum creatinine Increased blood urea, increased blood cholesterol* Adverse reactions discovered after marketing 1 Includes neutropenia with or without fever. 2 Includes immune thrombocytopenic purpura. 3 Includes stiff neck and tetany. 4Includes hypoxic-ischemic encephalopathy and metabolic encephalopathy. 5Includes akathisia and Parkinson's disease. 6See "Visual impairment" in [Adverse Reactions]. 7Persistent optic neuritis has been reported postmarketing. See [Precautions]. 8See [Precautions]. 9Includes dyspnea and exertional dyspnea. 10Includes drug-induced liver injury, toxic hepatitis, hepatocellular injury, and liver toxicity. 11Includes periorbital edema, lip edema, and oral edema. Description of selected adverse reactions Visual impairment: Visual impairment associated with voriconazole (including blurred vision, photophobia, green vision, color vision, color blindness, blue vision, eye disease, halos, night blindness, oscillopsia, photopsia, flashing scotomas, decreased visual acuity, visual brightness, visual field defects, vitreous floaters, and xanthoopia) is common. Visual impairment is transient and can be fully recovered. Most resolve spontaneously within 60 minutes, and no clinically significant long-term visual reactions have been observed. There is evidence that this condition is alleviated after repeated administration of voriconazole. Visual impairment is generally mild, rarely leads to discontinuation of the drug, and has no long-term sequelae. Visual impairment may be related to higher blood concentrations and/or doses. Although the site of action of voriconazole seems to be mainly limited to the retina, its mechanism of action remains unclear. In a study, the effects of voriconazole on retinal function were studied in healthy volunteers, and it was found that this product could reduce the amplitude of the retinal electrographic waveform, which returned to normal after discontinuation of the drug. Electroretinogram (ERG) is usually used to detect the current in the retina. ERG changes did not progress during the 29-day treatment period and recovered completely after discontinuation of voriconazole. Long-term visual adverse events have been reported after marketing. Skin reactions: Skin reactions were common in patients treated with voriconazole in clinical trials. However, these patients had serious underlying diseases and used multiple concomitant drug products. Most rashes were mild to moderate. Severe cutaneous adverse reactions (SCARs) have occurred in patients during voriconazole treatment. These severe reactions include Stevens-Johnson syndrome (SJS, rare), toxic epidermal necrolysis (TEN, rare), drug reaction with eosinophilia and systemic symptoms (DRESS, rare), and erythema multiforme (rare) (see [Precautions]). If a patient develops a rash, they should be closely observed, and if the lesions progress, voriconazole should be discontinued. Photosensitivity reactions (such as freckles, lentigo, and actinic keratosis) have been reported, especially during long-term treatment. Cutaneous squamous cell carcinoma has been reported in patients treated with voriconazole for a long time. The mechanism of its formation remains unclear. Liver function tests: In the voriconazole clinical research program, the overall incidence of elevated transaminases 3xULN (not necessarily an adverse event) in adult and pediatric subjects receiving voriconazole for concomitant treatment and prevention was 18.0% (319/1768) and 25.8% (73/283), respectively. Abnormal liver function tests may be related to higher blood drug concentrations and/or higher doses. Most abnormal liver function tests recover without dose adjustment or after dose adjustment, or after drug discontinuation. Severe hepatotoxic reactions, including jaundice, hepatitis, and liver failure leading to death, have occurred with voriconazole in patients with other serious underlying diseases. Prevention An open-label, controlled, multicenter study comparing voriconazole with itraconazole for primary prevention in adults and adolescents undergoing allogeneic HSCT without previously confirmed or clinically diagnosed IFI reported that 39.3% of subjects in the voriconazole group and 39.6% of subjects in the itraconazole group permanently discontinued the study drug due to adverse events. Fifty subjects (21.4%) in the voriconazole group and 18 (7.1%) in the itraconazole group permanently discontinued the study drug due to treatment-emergent hepatic adverse events. Pediatric patients: The safety of voriconazole was studied in 288 pediatric patients aged 2 to 12 years (169 patients) and 12 to 18 years (119 patients) who received voriconazole for prevention (183 patients) and treatment (105 patients) in clinical trials. The safety of voriconazole was also studied in an additional 158 pediatric patients aged 2 to 12 years in a compassionate use program. Overall, the safety of voriconazole in the pediatric population was similar to that in adults. However, a trend toward a higher frequency of liver enzyme elevations (reported as adverse events in clinical trials) was observed in pediatric patients than in adults (14.2% of children had elevated transaminases compared with 5.3% of adults). Postmarketing data suggest that the incidence of skin reactions (particularly erythema) may be higher in pediatric patients compared with adults. Twenty-two patients under the age of 2 years were treated with voriconazole in the compassionate use program and reported the following adverse reactions (related to voriconazole cannot be ruled out): photosensitivity reaction (1 case), arrhythmia (1 case), pancreatitis (1 case), increased blood bilirubin (1 case), increased liver enzymes (1 case), rash (1 case), and papilledema (1 case). Pancreatitis has been reported in pediatric patients in post-marketing reports. 3. Clinical studies in adults in China In an open, prospective, uncontrolled, multicenter study, the safety of voriconazole treatment in Chinese patients with confirmed or clinically diagnosed severe invasive fungal infections was evaluated. A total of 77 Chinese patients with confirmed or clinically diagnosed severe invasive fungal infections were enrolled and treated with voriconazole. A total of 62 subjects (80.5%) reported 182 all-cause adverse events during treatment, of which 90 were considered to be related to treatment. The most common all-cause treatment-emergent adverse events were hypokalemia (13.0%; 5.2% treatment-related) and visual disturbances (13.0%; all treatment-related). Most adverse events were mild or moderate. Adverse events reported by 18 subjects (23.4%) were severe. Fourteen subjects (18.2%) experienced one or more serious adverse events during the study, none of which were related to treatment. An additional five subjects (6.5%) experienced one or more serious adverse events after treatment ended; only one of these was considered treatment-related. Seven subjects (9.1%) died during the study, and another seven subjects (9.1%) died after permanent discontinuation of treatment or after the study ended (but within the reporting period). Laboratory abnormalities and changes in vital signs were generally unremarkable. Reporting suspected adverse reactions It is important to report suspected adverse reactions after a drug has been approved for marketing in order to continuously monitor the balance between the drug's benefits and risks.

1. This product is contraindicated for patients who are allergic to its active ingredients or excipients. 2. This product is contraindicated for use in combination with CYP3A4 substrates, including terfenadine, astemizole, cisapride, pimozide and quinidine. This is because this product can increase the blood concentration of the above drugs, leading to QT interval prolongation and occasional torsade de pointes ventricular tachycardia. 3. This product is contraindicated for use in combination with sirolimus. Voriconazole can significantly increase the blood concentration of sirolimus. Therefore, these two drugs are contraindicated for use in combination. 4. This product is contraindicated for use in combination with rifampicin, carbamazepine and phenobarbital. These drugs may significantly reduce the blood concentration of this product. Therefore, this product is contraindicated for use in combination with these drugs. 5. This product is contraindicated for use in combination with efavirenz at a standard dose of 400 mg (once a day) or higher, because when healthy subjects use this dose of efavirenz and voriconazole at the same time, the blood concentration of voriconazole is significantly reduced. Voriconazole can also significantly reduce the blood concentration of efavirenz. 6. This product is prohibited from being used in combination with high doses of ritonavir (400 mg or more each time, twice a day). When healthy subjects used this dose of ritonavir and voriconazole at the same time, the blood concentration of voriconazole was significantly reduced. 7. This product is prohibited from being used in combination with ergot alkaloids, including ergotamine, dihydroergotamine, etc. Ergot alkaloids are substrates of CYP3A4. After the two are used together, the blood concentration of ergot drugs may increase and cause ergot poisoning. 8. This product is prohibited from being used in combination with St. John's wort.

Precautions for children: The safety and effectiveness of children aged 2 to 12 years and light-weight adolescents (12 to 14 years old and weighing 50 kg) and adolescents (12 to 14 years old and weighing ≥50 kg; 15 to 17 years old) have been established, and the recommended dosage should be strictly followed. For details, please refer to the content under [Usage and Dosage]. The safety and effectiveness of this product in children under 2 years old have not been established. Precautions for pregnancy and lactation: There is currently insufficient data to evaluate the safety of voriconazole in pregnant women. Animal experiments have shown that this product has reproductive toxicity, 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 in lactating women. Breastfeeding must be stopped when voriconazole is started. Fertility In animal studies, male and female rats did not show impaired reproductive ability. Elderly precautions: In a multiple-dose oral administration study, the Cmax and AUCτ of healthy elderly men (≥65 years old) were 61% and 86% higher than those of healthy young men (18-45 years old), respectively. However, there was no significant difference between the Cmax and AUCτ of healthy elderly women (≥65 years old) and healthy young women (18-45 years old). The dosage was not adjusted according to age in the treatment study. The relationship between blood drug concentration and age was observed in the study. The safety of voriconazole in young and elderly patients is similar, so there is no need to adjust the dosage of this product for elderly patients.

The following are the interactions between voriconazole and other drugs and other types of interactions. Voriconazole is metabolized by cytochrome P450 isoenzymes and inhibits the activity of cytochrome P450 isoenzymes, including CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease the blood concentration of voriconazole, respectively. Therefore, this product may increase the blood concentration of substances metabolized by CYP450 isoenzymes. Unless otherwise specified, drug interaction studies were conducted in healthy adult male volunteers. Multiple doses were administered orally, 200 mg 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. Voriconazole should be used with caution in patients who are using other drugs that can prolong the QTc interval. When used in combination with voriconazole, the blood concentration of drugs metabolized by CYP3A4 isoenzymes (such as some antihistamines, quinidine, cisapride, pimozide) may increase, so the combination of these two drugs is prohibited. Table of drug interactions The interactions between voriconazole and other drugs are detailed in the table below ("QD" indicates once daily, "BID" indicates twice daily, "TID" indicates three times daily, and "ND" indicates undetermined). The direction of the arrow for each pharmacokinetic parameter is determined based on the 90% confidence interval of the ratio of the geometric means of each parameter, and is within (↔), below (↓), or above (↑) the range of 80-125%. The asterisk (*) indicates that there is an interaction between the two. AUCt, AUCt and AUC0-¥ represent the dosing interval, the time from zero to detectable drug in the blood, and the area under the drug-time curve from zero to infinity, respectively. The interactions in this table are described in the following order: prohibited for co-use; dose adjustment and close clinical and/or biological monitoring are required when co-use is used; and finally, there is no obvious pharmacokinetic interaction, but it may be of concern in clinical treatment. Drug Name [Mechanism of Interaction] Geometric Mean Change in Interaction (%) Recommendations for Coadministration Astemizole, cisapride, pimozide, quinidine, and terfenadine [CYP3A4 substrates] Although not studied, increased plasma concentrations of these drugs may lead to QT prolongation and, occasionally, torsade de pointes. Concomitant use of carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital) [Strong CYP450 inducers] Although not studied, carbamazepine and long-acting barbiturates may significantly reduce voriconazole plasma concentrations. Concomitant use of efavirenz (a non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; CYP3A4 inhibitor and substrate] Efavirenz 400 mg once daily and voriconazole 200 mg twice daily** Efavirenz 300 mg once daily and voriconazole 400 mg twice daily* Efavirenz Cmax 38% Efavirenz AUCt 44% Voriconazole Cmax¯ 61% Voriconazole AUCt¯ 77% Efavirenz Cmax ↔ Efavirenz AUCt 17% compared with efavirenz alone (600 mg once daily) Voriconazole Cmax 23% Voriconazole AUCt¯ 7% compared with voriconazole alone (200 mg twice daily) Concomitant use of this drug at standard doses with efavirenz at standard doses (400 mg once daily or higher) is contraindicated. Voriconazole may be co-administered with efavirenz if the following conditions are met: The maintenance dose of voriconazole is increased to 400 mg twice daily and the dose of efavirenz is reduced to 300 mg once daily. When voriconazole treatment is discontinued, efavirenz should be restored to its original dose. Ergot alkaloids (e.g., ergotamine and dihydroergotamine) [CYP3A4 substrates] Although not studied, voriconazole may increase the plasma concentration of ergot alkaloids, leading to ergot toxicity. Concomitant use of rifabutin [a strong CYP450 inducer] 300 mg once daily. 300 mg once daily. (When used in combination with voriconazole, the dose of voriconazole is 350 mg twice daily)* 300 mg once daily. (Combined with voriconazole, the dose of voriconazole is 400 mg twice a day)*Voriconazole Cmax¯69%Voriconazole AUCt¯78%Compared with voriconazole alone (200 mg twice a day), voriconazole Cmax¯4%Voriconazole AUCt¯32%Rifabutin Cmax195%Rifabutin AUCt331%Compared with voriconazole alone (200 mg twice a day), voriconazole Cmax104%Voriconazole AUCt87%Concomitant use of voriconazole and rifabutin should be avoided unless the benefits outweigh the risks after weighing them. The maintenance dose of voriconazole can be increased to 5 mg/kg (administered intravenously twice daily) or from 200 mg orally twice daily to 350 mg orally twice daily (from 100 mg orally twice daily to 200 mg orally twice daily for patients weighing less than 40 kg). When rifabutin is used in combination with voriconazole, close monitoring of the patient's complete blood count and rifabutin-related adverse reactions (such as uveitis) is recommended. Rifampin (600 mg once daily) [strong CYP450 inducer] Voriconazole Cmax¯93% Voriconazole AUCt¯96% Concomitant use of ritonavir (protease inhibitor) [strong CYP450 inducer; CYP3A4 inhibitor and substrate] is prohibited. High dose (400 mg twice daily) Low dose (100 mg twice daily)* Ritonavir Cmax and AUCt ↔ Voriconazole Cmax¯66% Voriconazole AUCt¯82% Ritonavir Cmax¯25% Ritonavir AUCt¯13% Voriconazole Cmax¯24% Voriconazole AUCt¯39% Concomitant use of voriconazole with high-dose ritonavir (400 mg or higher twice daily) is prohibited. Co-administration of voriconazole with low-dose ritonavir (100 mg twice daily) should be avoided unless the benefit/risk assessment for the patient supports the use of voriconazole. St. John's wort [CYP450 inducer; P-gp inducer] 300 mg three times a day. (Combined with a single dose of voriconazole 400 mg) A published independent study showed that after co-administration of the two: voriconazole AUC0-¥¯59% Contraindicated for co-administration of everolimus [CYP3A4 substrate, PgP substrate] Although not studied, voriconazole may significantly increase the plasma concentration of everolimus. Co-administration of voriconazole and everolimus is not recommended because voriconazole may significantly increase the plasma concentration of everolimus. Phenytoin [CYP2C9 substrate and strong CYP450 inducer] 300 mg once a day. 300 mg once a day. (with voriconazole, voriconazole dose is 400 mg twice daily) * Voriconazole Cmax¯49% Voriconazole AUCt¯69% Phenytoin Cmax67% Phenytoin AUCt81% Compared with voriconazole (200 mg twice daily), voriconazole Cmax34% Voriconazole AUCt39% Co-administration of voriconazole and phenytoin should be avoided unless the benefits outweigh the risks. Close monitoring of phenytoin blood concentrations is recommended. Phenytoin can be used with voriconazole in the following circumstances: the maintenance dose of voriconazole is increased to 5 mg/kg (intravenous drip, twice daily) or increased from 200 mg orally twice daily to 400 mg orally twice daily (for patients weighing less than 40 kg, the dose is increased from 100 mg orally twice daily to 200 mg orally twice daily). The co-administration of the anticoagulant warfarin (single dose 30 mg, co-administered with voriconazole, voriconazole dose is 300 mg twice daily) [CYP2C9 substrate] and other oral coumarins (e.g., phenylprocoumon, acenocoumarol) [CYP2C9 and CYP3A4 substrates] prolongs the prothrombin time to a maximum of approximately twice the normal time. Although not studied, voriconazole may increase the plasma concentration of coumarins, which may lead to a prolongation of the prothrombin time. When an anticoagulant is co-administered with voriconazole, it is recommended that the patient's prothrombin time or other appropriate anticoagulant test be closely monitored and the dose of the anticoagulant adjusted accordingly. Benzodiazepines (e.g., midazolam, triazolam, alprazolam) [CYP3A4 substrates] Although not clinically studied, voriconazole may increase the plasma concentration of benzodiazepines metabolized by CYP3A4, resulting in a prolonged sedative effect of these drugs. When the two are used together, a reduction in the dose of the benzodiazepine should be considered. Immunosuppressants [CYP3A4 substrates] Sirolimus (single dose 2 mg) Cyclosporine (long-term cyclosporine treatment for stable renal transplant patients) Tacrolimus (0.1 mg/kg once a day) A published independent study showed that after the two are used together: Sirolimus Cmax 6.6 times Sirolimus AUC0-¥ 11 times Cyclosporine Cmax 13% Cyclosporine AUCt 70% Tacrolimus Cmax 117% Tacrolimus AUCt2 21% Voriconazole and sirolimus are prohibited from being used together. When patients who have been treated with cyclosporine start using voriconazole, it is recommended to halve the dose of cyclosporine and closely monitor the blood concentration of cyclosporine. Increased blood concentrations of cyclosporine can cause nephrotoxicity. After discontinuation of this product, the blood concentration of cyclosporine still needs to be closely monitored, and the dose of cyclosporine can be increased if necessary. When patients who have been treated with tacrolimus start using voriconazole, it is recommended to reduce the dose of tacrolimus to 1/3 of the original dose and closely monitor the blood concentration of tacrolimus. Increased blood concentrations of tacrolimus can cause nephrotoxicity. After discontinuation of this product, the blood concentration of tacrolimus still needs to be closely monitored, and the dose of tacrolimus can be increased if necessary. Long-acting opioids [CYP3A4 substrates] Oxycodone (single dose 10 mg) A published independent study showed that after the two were co-administered: Oxycodone Cmax 1.7 times Oxycodone AUC0-¥ 3.6 times When co-administered with voriconazole, the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (such as hydrocodone) should be reduced, and frequent monitoring of some adverse reactions related to opioids should be performed if necessary. Methadone (32-100 mg each time, once a day) [CYP3A4 substrate] R-methadone (active configuration) Cmax 31% R-methadone (active configuration) AUCt 47% S-methadone Cmax 65% S-methadone AUCt 103% When co-administered with voriconazole, close and frequent monitoring of adverse reactions and toxicity related to methadone, including QTc interval prolongation, is recommended. If necessary, reduce the dose of methadone. Nonsteroidal anti-inflammatory drugs (NSAIDs) [CYP2C9 substrates] Ibuprofen (single dose 400 mg) Diclofenac (single dose 50 mg) S-ibuprofen Cmax 20% S-ibuprofen AUC0-¥100% Diclofenac Cmax 114% Diclofenac AUC0-¥78% Close monitoring for adverse reactions and toxicity related to NSAIDs is recommended when co-administered with voriconazole. Dose reduction of NSAIDs may be necessary if necessary. Omeprazole (40 mg once daily)* [CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate] Omeprazole Cmax 116% Omeprazole AUCt 280% Voriconazole Cmax 15% Voriconazole AUCt 41% Voriconazole may also inhibit proton pump inhibitors that are other CYP2C19 substrates, resulting in increased plasma concentrations of these drugs. No dose adjustment of voriconazole is required. When voriconazole is initiated in patients who are taking omeprazole at a daily dose of 40 mg or more, it is recommended that the omeprazole dose be halved. Oral contraceptives* [CYP3A4 substrate; CYP2C19 inhibitor] Norethindrone/ethinyl estradiol (1 mg/0.035 mg once daily) Ethinyl estradiol Cmax 36% Ethinyl estradiol AUCt 61% Norethindrone Cmax 15% Norethindrone AUCt 53% Voriconazole Cmax 14% Voriconazole AUCt 46% It is recommended that you monitor for adverse reactions related to oral contraceptives in addition to those related to voriconazole. Short-acting opioids [CYP3A4 substrates] Alfentanil (20 mg/kg once daily, concurrently with naloxone) Fentanyl (5 mg/kg once daily) A published independent study showed that after the two were co-administered: alfentanil AUC0-¥6 times A published independent study showed that after the two were co-administered: fentanyl AUC0-¥1.34 times When co-administered with voriconazole, the dose reduction of alfentanil, fentanyl and other short-acting opioids with similar structures and metabolized by CYP3A4 (such as sufentanil) should be considered. Close and frequent monitoring of respiratory depression and other opioid-related adverse reactions is recommended, and the monitoring period should be extended appropriately. Statins (such as lovastatin) [CYP3A4 substrates] Although not clinically studied, the co-administration of voriconazole and statins may increase the blood concentration of statins metabolized by CYP3A4, which may lead to rhabdomyolysis. Consider reducing the dose of statins when the two are used together. Sulfonylureas (e.g., tolbutamide, glipizide, glyburide) [CYP2C9 substrates] Although not studied, voriconazole may increase the plasma concentration of sulfonylureas, thereby causing hypoglycemia. Close monitoring of blood glucose is recommended. Consider reducing the dose of sulfonylureas. Vinca alkaloids (e.g., vincristine and vinblastine) [CYP3A4 substrates] Although not studied, voriconazole may increase the plasma concentration of vinca alkaloids, thereby causing neurotoxicity. Consider reducing the dose of vinca alkaloids. Other HIV protease inhibitors (e.g., saquinavir, amprenavir, and nefinavir)* [CYP3A4 substrates and inhibitors] No relevant clinical studies have been conducted. In vitro studies have shown that voriconazole may inhibit the metabolism of HIV protease inhibitors, and HIV protease inhibitors may also inhibit the metabolism of voriconazole. Close monitoring for any potential drug toxicity and/or drug failure may be warranted, and dose adjustments of both drugs may be necessary. Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, nevirapine)* [CYP3A4 substrates, inhibitors, or CYP450 inducers] have not been clinically studied. In vitro studies have shown that NNRTIs inhibit the metabolism of voriconazole, and voriconazole may also inhibit the metabolism of NNRTIs. The effect of efavirenz on the in vivo metabolism of voriconazole suggests that non-nucleoside reverse transcriptase inhibitors may induce voriconazole metabolism. Close monitoring for any potential drug toxicity and/or drug failure may be warranted, and dose adjustments of both drugs may be necessary. Cimetidine (400 mg each time, twice daily) [nonspecific CYP450 inhibitor and increases gastric pH] Voriconazole Cmax 18% Voriconazole AUCt 23% No dose adjustment required Digoxin (0.25 mg each time, once daily) [P-gp substrate] Digoxin Cmax ↔ Digoxin AUCt ↔ No dose adjustment required Indinavir (800 mg each time, 3 times daily) [CYP3A4 inhibitor] and substrates] Indinavir Cmax ↔ Indinavir AUCt ↔ Voriconazole Cmax ↔ Voriconazole AUCt ↔ No dose adjustment required Macrolide antibiotics Erythromycin (1 g twice daily) [CYP3A4 inhibitor] Azithromycin (500 mg once daily) Voriconazole Cmax and AUCt ↔ Voriconazole Cmax and AUCt ↔ It is not known what effect voriconazole has on erythromycin or azithromycin. No dose adjustment required Mycophenolic acid (single dose 1g) [UDP-glucuronosyltransferase substrate] Mycophenolic acid Cmax ↔ Mycophenolic acid AUCt ↔ No dose adjustment required Prednisone (single dose 60mg) [CYP3A4 substrate] Prednisone Cmax 11% Prednisone AUC 0-¥34% No dose adjustment required Ranitidine (150mg twice daily) [Increases gastric pH] Voriconazole Cmax and AUCt ↔ Not required No dose adjustment required

Store tightly closed at room temperature.

0.2 g

12 months

Changchun HaiYue Pharmaceutical Limited By Share Ltd.

• Founded in:

  1992-09-12

• Address:

  No. 5555, Shuangying Road, Shuangyang Economic Development Zone, Shuangyang District, Changchun City

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  912201016059030427

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  226.1666 million yuan

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