What Is Voriconazole?

The chemical name of voriconazole is (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1,2,4-tri Azol-1-yl) -2-butanol, white to off-white crystalline powder, molecular formula is C ₁₆ H ₁₄ F ₃ N ₅ O, molecular weight is 349.31000, density is 1.42 g / cm3, melting point is 127-130 ° C, boiling point It is 508.6ºC at 760 mmHg, flash point is 261.4ºC, refractive index is 1.616, and vapor pressure is 3.63E-11mmHg at 25 ° C.

Chinese name: Voriconazole
Foreign name: voriconazole

CAS number: 137234-62-9
Molecular formula: C16H14F3N5O

Introduction to voriconazole compounds

Voriconazole Basic Information

Chinese name: voriconazole

Chinese alias: (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol- 1-yl) -2-butanol

English name: voriconazole

English alias: (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan- 2-ol; (2R, 3S) -2- (2,4-Difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl)- 2-butanol; Voriconazole; Vorionazole;

CAS number: 137234-62-9

Molecular formula: C ₁₆ H14F ₃ N ₅ O

Molecular weight: 349.31000

Structural formula:

Exact mass: 349.11500

PSA: 76.72000

LogP: 2.17690 ^[1]

Physicochemical properties of voriconazole

Appearance and properties: white to off-white crystalline powder

Density: 1.42 g / cm3

Melting point: 127-130 ° C

Boiling point: 508.6ºC at 760 mmHg

Flash point: 261.4ºC

Refractive index: 1.616

Vapor pressure: 3.63E-11mmHg at 25 ° C ^[1]

Voriconazole molecular structure data

1. Molar refractive index: 85.62

2. Molar volume (cm / mol): 244.7

3. Isotonic specific volume (90.2K): 634.4

4. Surface tension (dyne / cm): 45.1

5. Polarizability (10-24cm3): 33.94 ^[2]

Voriconazole uses

A drug for treating fungal infections is a broad-spectrum antifungal drug, which has a therapeutic effect on fungal infections in humans and animals. ^[1]

Voriconazole Compound Related Drugs

Voriconazole drug name:

[General name] voriconazole tablets

[Product Name] Pinup

[English name] Voriconazole Tablets

[Chinese Pinyin] Fu Li Kang Zuo Pian ^[3]

Voriconazole Ingredients:

Main ingredients: Voriconazole Chemical name: (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1,2,4-tri Azol-1-yl) -2-butanol, molecular formula: C ₁₆ H ₁₄ F ₃ N ₅ O, molecular weight: 349.3 ^[3]

Voriconazole belongs to the category:

Chemical Drugs and Biological Products >> Antimicrobials >> Antifungals >> azoles ^[3]

Voriconazole properties:

This product is a film-coated tablet, which appears white to off-white after removing the coating. ^[3]

Indications for voriconazole :

This product is a broad-spectrum triazole antifungal drug, and its indications are as follows:
Treatment of invasive aspergillosis;
Treatment of severe invasive infections caused by fluconazole-resistant Candida (including Candida crocus)
Treatment of severe infections caused by Actinomyces and Fusarium;
This product should be used primarily to treat progressive, life-threatening infections in immunodeficiency patients. ^[3]

Voriconazole specifications:

50mg ^[3]

Voriconazole Usage and dosage:

Adult drugs are administered orally, and a loading dose should be given on the first day of the first administration, so that the blood drug concentration approaches the steady-state concentration on the first day of administration. Due to the high bioavailability of oral tablets (96%), the intravenous and oral routes of administration are interchangeable when clinically indicated.
The detailed dosage is shown in the table below:

Loading dose (for the first 24 hours) 6 mg / kg every 12 hours (for the first 24 hours)
Maintenance dose (24 hours after starting the drug) Intravenous infusion * 4mg / kg administered once every 12 hours 200mg administered once every 12 hours Note: * Oral maintenance dose: once every 12 hours for patients weighing 40kg, 200mg each time; adult patients weighing <40kg, once every 12 hours, 100mg each time.
Sequential therapy of intravenous drip and oral administration can still be used for sequential treatment. At this time, oral drug administration does not need to give a loading dose, because the intravenous drip administration has made the voriconazole plasma concentration steady state. The recommended doses are as follows:
Loaded dose is intravenously infused once every 12 hours, 6 mg / kg each time (for the first 24 hours)
Maintenance Dose for Intravenous Drip Oral *
4mg / kg once every 12 hours 200mg once every 12 hours Note: * oral maintenance dose: for patients weighing 40kg, once every 12 hours, 200mg each; adult patients weighing <40kg every 12 hours 100 mg once.
The course of treatment depends on the clinical and microbiological response of the patient after the medication.
Dose adjustment During the treatment with this product, the doctor should closely monitor its potential adverse reactions and adjust the drug plan in time according to the specific conditions of the patient, see [Adverse Reactions] and [Cautions].
Oral administration: If the patient's response to treatment is poor, the maintenance dose for oral administration can be increased to 300 mg twice daily; for patients weighing less than 40 kg, the dose can be adjusted to 150 mg twice daily.
If the patient cannot tolerate the above-mentioned higher dose, the maintenance dose for oral administration can be reduced by 50 mg each time, gradually reduced to twice daily, 200 mg each time (for patients weighing less than 40 kg, reduced to twice daily, 100 mg each time ).
Medication for the Elderly There is no need to adjust the dosage when using this product.
Renal impairment patients with moderate to severe renal dysfunction (creatinine clearance <50ml / min) in patients with this product, accumulation of excipient thiobutyl ether--cyclodextrin sodium (SBECD) can occur. Such patients should choose oral administration, unless the advantages of using intravenous preparations outweigh the disadvantages. In these patients, the serum creatinine level must be closely monitored during intravenous administration, and if abnormally increased, consideration should be given to oral administration.
Voriconazole can be cleared by hemodialysis with a clearance rate of 121 ml / min. Four hours of hemodialysis can remove only a small amount of medication without the need to adjust the dose.
The intravenous excipient thiobutyl ether--cyclodextrin sodium (SBECD) has a clearance rate of 55 ml / min in hemodialysis.
Patients with liver impairment who take acute liver damage (increased alanine aminotransferase ALT / GOT and aspartate aminotransferase AST / GST increase) do not need to adjust the dose, but liver function should continue to be monitored to see if it further increases.
It is recommended that the loading dose of voriconazole be unchanged in patients with mild to moderate cirrhosis (Child-Pugh A and B), but that the maintenance dose be halved.
There are no studies on the use of this product in children with severe cirrhosis (Child-Pugh C).
It has been reported that this product is associated with abnormally increased liver function tests and signs of liver damage (such as jaundice), so patients with severe liver function must weigh the advantages and disadvantages when applying this product. Patients with impaired liver function must closely monitor drug toxicity when using this product.
The safety and effectiveness of voriconazole in children under 12 years of age have not been established.
A total of 22 patients with invasive aspergillosis aged 12-18 years were selected in the therapeutic study, and the maintenance dose of voriconazole was given, that is, once every 12 hours, 4 mg / kg each time, and 12 patients (55%) were effective in treatment. .
Youth (12 to 16 years)
In therapeutic studies, little research has been done on the pharmacokinetic properties of voriconazole in adolescents. ^[3]

Voriconazole adverse reactions:

The most common adverse events in the treatment trials were visual impairment, 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 include increased liver function test values, rashes, and visual impairment.
Discussion of adverse reactions The data in the table below are derived from 1493 patients who participated in the voriconazole treatment study. It represents a different group of people, including patients with low immune function, such as patients with hematological malignancies, HIV patients, and patients with non-neutropenia. It does not include healthy volunteers, patients who were given treatment for compassion, but not patients who participated in treatment studies. Among these patients, 62% were male, with an average age of 45.1 years (12-90 years, of which 49 patients were 12-18 years), 81% were white, and 9% were black. 561 patients were treated with voriconazole for more than 12 weeks, and 136 patients were treated for more than 6 months. The following table summarizes adverse events that occurred at a rate of 1% and events that occurred at a rate of <1% in all treatment studies.

In study 307/602, 381 patients with acute invasive aspergillosis were first treated with voriconazole (196 cases) and amphotericin B (185 cases), and then sequentially with other licensed antifungal drugs. Study 305 evaluated the efficacy of voriconazole (200 patients) and fluconazole (191 patients) in the treatment of esophageal candidiasis. Laboratory laboratory abnormalities in these studies will be discussed in later clinical trial values.
Adverse events during treatment (including adverse events with an incidence of 1% in all treatment studies, and important events with an incidence of <1%, these adverse events may be drug-related or unknown to the drug):

Visual disorders and voriconazole-related visual disorders are more common. In clinical trials, about 30% of patients have experienced visual changes, visual enhancement, blurred vision, changes in color vision, and / or photophobia. Visual impairment is usually mild and rarely causes discontinuation. Visual impairment may be associated with higher blood concentrations and / or doses.
Although the site of action of voriconazole appears to be mainly confined to the retina, its mechanism of action remains unclear. In one study, the effect of voriconazole treatment on retinal function was studied in healthy volunteers for 28 days, and it was found that this product can reduce the amplitude of retinal wave waveform, narrow the visual field and change color vision. Electroretinograms are commonly used to detect current conditions in the retina. The electroretinogram, visual field, and color vision returned to normal 14 days after the drug was stopped. The effect of voriconazole on vision can occur early in the medication and persist throughout the duration of the medication. There is evidence that visual impairment is associated with multiple doses.
In skin clinical trials, skin reactions were more common in the voriconazole-treated group. The mechanism of these skin adverse events remains unclear. But usually these patients also have other serious underlying diseases and need to receive multiple treatments at the same time. In clinical trials, the incidence of voriconazole-related rash was 6% (86/1493). Most rashes are mild to moderate, including Stevens-Johnson syndrome, toxic epidermal melt necrosis, and erythema polymorpha. Once the patient has a rash, close observation must be performed, and if the skin lesion becomes worse, the drug must be discontinued. Photosensitivity has also been reported, and photosensitivity reactions are more common in patients with long-term treatment. Severe skin reactions are rare. It is recommended to avoid strong direct sunlight during voriconazole treatment.
Other less common adverse events The adverse events listed below occurred in all patients (including healthy volunteers, etc., N = 2090) who used voriconazole, and their incidence was <1%. These adverse events include those who cannot be associated with voriconazole or who help doctors manage the risk of patients taking medications, but do not include the adverse events listed in the table above or all adverse events reported in clinical trials.
Systemic reactions: abdominal enlargement, allergic reactions, allergic reactions, ascites, weakness, back pain, cellulitis, edema, facial edema, flank pain, flu-like symptoms, graft-versus-host reaction, granulomas, infection, bacterial infection, Fungal infection, injection site pain, injection site infection / inflammation, mucosal dysfunction, multiple organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.
Cardiovascular system: atrial arrhythmia, atrial fibrillation, complete atrioventricular block, dual law, bradycardia, bundle branch block, enlarged heart, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident , Congestive heart failure, deep thrombophlebitis, endocarditis, extrasystole, asystole, myocardial infarction, nodular arrhythmia, palpitations, phlebitis, orthostatic hypotension, pulmonary embolism, prolonged QT interval , Supraventricular tachycardia, syncope, thrombophlebitis, vasodilation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including apical torsional ventricular tachycardia).
Digestive system: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, duodenal ulcer perforation, duodenitis, indigestion, dysphagia, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal Bleeding, increased GGT / LDH, gingivitis, glossitis, bleeding gums, gingival hyperplasia, vomiting blood, liver coma, liver failure, hepatitis, bowel perforation, bowel ulcers, hepatomegaly, melena, oral ulcers, pancreatitis, parotid glands Swelling, periodontitis, proctitis, pseudomeningitis, rectal dysfunction, rectal bleeding, gastric ulcers, gastritis, and enlarged tongue.
Endocrine: Adrenal insufficiency, diabetes insipidus, hyperthyroidism, reduced thyroid function.
Blood and lymph: agranulocytosis, anemia (large cell anemia, megaloblastic anemia, small cell anemia, orthocytic anemia), aplastic anemia, hemolytic anemia, prolonged bleeding time, cyanosis, dissemination Intravascular coagulation, ecchymoses, eosinophilia, hypervolemia, lymphadenopathy, lymphangitis, bone marrow suppression, petechiae, purpura, splenomegaly, thrombotic thrombocytopenic purpura.
Nutrition and metabolism: proteinuria, increased urea nitrogen, increased creatinine phosphate kinase, edema, impaired glucose tolerance, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, high Uric acidemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, uremia.
Musculoskeletal: arthralgia, arthritis, osteonecrosis, bone pain, calf cramps, myalgia, muscle weakness, myopathy, osteomalacia, osteoporosis.
Nervous system: different dreams, acute brain syndrome, agitation, inability to sit still, forgetfulness, anxiety, ataxia, cerebral edema, coma, insanity, convulsions, delirium, dementia, disintegration of personality, depression, diplopia, encephalitis, encephalopathy , Euphoria, extrapyramidal syndrome, epileptic seizures, Guillain-Barre syndrome, hypertonia, hyposensory, insomnia, increased intracranial pressure, hyposexuality, neuralgia, neuropathy, nystagmus, eyeballs Twist crisis, paresthesia, psychosis, lethargy, suicidal tendency, tremor, dizziness.
Respiratory system: increased cough, dyspnea, epistaxis, hemoptysis, hypoxia, pulmonary edema, pharyngitis, pleural effusion, pneumonia, respiratory dysfunction, respiratory distress syndrome, respiratory infections, rhinitis, sinusitis, sound changes.
Skin and appendages: hair loss, angioedema, contact dermatitis, discoid lupus erythematosus, eczema, erythema polymorpha, exfoliative dermatitis, mixed drug rash, rickets, herpes simplex, melanosis, photosensitive skin reaction, silver Psoriasis, skin discoloration, dermatosis, dry skin, Stevens-Johnson syndrome, sweating, toxic epidermal melting and necrosis, urticaria.
Special sensations: abnormal regulation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, dry eyes, keratitis, keratoconjunctivitis, dilated pupils, night blindness, optic atrophy, optic neuritis, external ear inflammation , Optic nerve papillary edema, retinal hemorrhage, retinitis, scleritis, loss of taste, abnormal taste, tinnitus, uveitis, visual field defect.
Genitourinary system: anuria, atrophic eggs, decreased creatinine clearance, dysmenorrhea, dysuria, epididymitis, diabetes, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, tubular necrosis, irregular uterine bleeding, Nephritis, nephropathy, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine bleeding, vaginal bleeding.
Clinical laboratory test values In clinical trials, the overall incidence of clinically significant transaminase abnormalities in the voriconazole group was 13.4% (200/1493). Abnormal liver function tests may be associated with higher blood concentrations and / or doses. The vast majority of patients can continue to use the drug according to the original dosing schedule, or adjust the dose and continue to use the drug (including withdrawal).
In patients taking voriconazole, severe liver toxicity such as jaundice rarely occurs, and hepatitis and fatal liver failure are even more rare. Most of these adverse events were accompanied by other serious underlying diseases.
Liver function should be checked both at the beginning and during treatment with voriconazole. If abnormal liver function occurs during treatment, close monitoring should be performed to prevent more severe liver damage. Management should include laboratory evaluation of liver function (especially liver function tests and bilirubin). If clinical signs and symptoms are consistent with the development of liver disease and can be attributed to voriconazole, the drug must be discontinued.
It has been reported that acute renal failure can occur when applying this product in severe patients. This product can be used in combination with nephrotoxic drugs and when patients with other underlying diseases, renal dysfunction may occur. Therefore, renal function should be monitored when using this product, including laboratory tests, especially serum creatinine.
The following two tables list the number of patients with hypokalemia and the clinical significance of renal and liver function in two randomized, controlled, and multicenter studies of studies 305 and 307/602.
Scheme 305
Clinically significant laboratory abnormalities

Scheme 307/602
Clinically significant laboratory abnormalities ^[3]

Voriconazole contraindications:

This product is contraindicated in people with a known history of allergies to voriconazole or any of the excipients.
This product is forbidden to be combined with CYP3A4 substrate, terfenadine, astemizole, cisapride, pimozide or quinidine, because this product can increase the blood concentration of the above drugs, leading to prolonged QT interval And occasionally apical torsional ventricular tachycardia (see [Drug Interactions]).
This product is forbidden to be combined with rifampicin, carbamazepine and phenobarbital, the latter can significantly reduce the blood concentration of this product.
This product cannot be combined with ergot alkaloids (ergotamine, dihydroergotamine). Ergot alkaloids are substrates of CYP3A4. 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 the two drugs cannot be used simultaneously.
This product is forbidden to be combined with ritonavir (400mg each time, every 12 hours). Healthy subjects were given ritonavir (400 mg each time, every 12 hours) and voriconazole. The blood concentration of voriconazole was significantly reduced. Ritonavir 100 mg 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 voriconazole concentration has not been studied.
This product is not allowed to be used simultaneously with efavirenz. When both were applied at the same time, the blood concentration of voriconazole was significantly reduced, while the blood concentration of efavirenz was significantly increased.
This product is not allowed to be used at the same time as rifabutin. In combination, the blood concentration of voriconazole was significantly reduced, while the blood concentration of rifabutin was significantly increased. ^[3]

Voriconazole warning:

Visual impairment: The effect of voriconazole on visual function after treatment for more than 28 days is unclear. If the treatment is continued for more than 28 days, monitor visual function including visual acuity, vision range, and color vision.
Hepatotoxicity: In clinical trials, severe liver adverse reactions (including hepatitis, cholestasis, and fatal fulminant liver failure) were uncommon in the voriconazole-treated group. It has been reported that hepatotoxic reactions occur mainly in patients with severe underlying diseases (mainly hematological malignancies). Liver reactions, including hepatitis and jaundice, can occur in patients without other identified risk factors. Abnormal liver function usually improves after discontinuation.
Monitor liver function: Liver function needs to be checked at the beginning and during the treatment of voriconazole. Patients must routinely monitor liver function at the beginning of treatment and when abnormal liver function occurs during treatment to prevent more severe 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, drug withdrawal should be considered.
Galactose intolerance: Voriconazole tablets contain lactose. Rare, congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not be used. ^[3]

Voriconazole precautions:

WARNING VISUAL IMPACT: The effect of voriconazole on visual function beyond 28 days of treatment is unclear. If the treatment is continued for more than 28 days, monitor visual function including visual acuity, vision range, and color vision.
Hepatotoxicity: In clinical trials, severe liver adverse reactions (including hepatitis, cholestasis, and fatal fulminant liver failure) were not common in the voriconazole-treated group. It has been reported that hepatotoxic reactions occur mainly in patients with severe underlying diseases (mainly hematological malignancies). Liver reactions, including hepatitis and jaundice, can occur in patients without other identified risk factors. Abnormal liver function usually improves after discontinuation.
Monitor liver function: Liver function needs to be checked at the beginning and during the treatment of 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, drug withdrawal should be considered.
Pregnant women: Voriconazole can cause fetal harm when used in pregnant women.
Reproductive studies have shown that at a dose of 10 mg / kg (calculated as mg / m2, which is equivalent to 0.3 times the recommended maintenance dose), voriconazole has teratogenic effects on the rats (chapped, hydronephrosis / hydroureter). At a dose of 100 mg / kg (six times the recommended maintenance dose), voriconazole is embryotoxic to rabbits. Other effects on rats include weakened ossification of the coccyx, skull, pubic bone, hyoid bone, and most ribs, abnormal sternum, and ureteral / pyelonic dilatation. Any dose of voriconazole can reduce blood estradiol levels in pregnant rats. At a dose of 10 mg / kg, voriconazole can also prolong the pregnancy time of rats and make it difficult to give birth, leading to an increase in the mortality of young rats during the perinatal period. In addition, voriconazole can increase rabbit embryo mortality, reduce fetal rabbit weight, increase skeletal variability, and increase ossification points outside the neck ribs and sternum.
If voriconazole is used during pregnancy, or if you become pregnant during medication, the patient should be informed of the potential danger of this product to the fetus.
Galactose intolerance: Voriconazole tablets contain lactose. Rarely, people with congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this product.
General Precautions Some pyrrole drugs, including voriconazole, can cause prolongation of the QT interval of the electrocardiogram. In clinical studies and post-marketing monitoring of voriconazole, there have been few reports of apical torsional VT. In severe patients with multiple mixed risk factors, such as with cardiomyopathy, hypokalemia, previous cardiotoxic chemotherapy, and concurrent application of other drugs that may cause apical torsional VT, apical torsion occurs Report of ventricular tachycardia.
Voriconazole should be used with caution in these patients with a potential risk of arrhythmias.
Strict correction of potassium, magnesium, and calcium is required before voriconazole treatment.
Reactions related to intravenous drip Infusion-related allergic reactions that occur during intravenous drip in healthy subjects are mainly flushing, fever, sweating, tachycardia, chest tightness, dyspnea, syncope, nausea, and itching As well as rashes, the above reactions are uncommon and mostly immediate. Consider discontinuation of the above reactions.
Patient information should inform patients:
· Voriconazole tablets should be taken after or at least 1 hour before a meal.
· Voriconazole may cause visual changes, including blurred vision and photophobia, so you cannot drive at night while using voriconazole.
Avoid visually hazardous work, such as driving or operating machines, if visual changes occur during medication.
Avoid strong, direct sunlight during medication.
Laboratory tests should correct electrolyte disorders before using voriconazole, including hypokalemia, hypomagnesemia, and hypocalcemia.
Renal function (mainly blood creatinine) and liver function (mainly liver function tests and bilirubin) must be monitored during medication.
For drug interactions, see [Drug Interactions].
Patients with impaired liver function are advised to continue monitoring liver function to see if there is further elevation.
It is recommended that the loading dose of voriconazole be unchanged for patients with mild to moderate cirrhosis (Child-Pugh A and B), but that the maintenance dose be halved.
There are currently no studies of voriconazole in patients with severe cirrhosis (Child-Pugh C). Voriconazole has been reported to be associated with abnormal liver function tests and clinical signs of liver damage such as jaundice. Therefore, patients with severe liver dysfunction must weigh the advantages and disadvantages when using this product, and closely monitor the toxicity of the drug.
In patients with renal impairment, moderate to severe renal dysfunction (creatinine clearance <50ml / min) in patients with this product may cause the accumulation of co-solvent SBECD. Unless the advantages of using intravenous preparations outweigh the disadvantages, oral administration should be used. Patients with renal dysfunction must monitor blood creatinine levels closely when intravenously administered, and should be considered for oral administration if elevated.
Voriconazole can be cleared by hemodialysis with a clearance rate of 121 ml / min. Four hours of hemodialysis can remove only a small amount of medication, and no dose adjustment is required.
The clearance rate of co-solvent SBECD in hemodialysis was 55 ml / min.
Renal adverse events, renal function monitoring has reported that acute renal failure can occur in patients with this product. This product can be used in combination with nephrotoxic drugs and when patients with other underlying diseases, renal dysfunction may occur. Renal function needs to be monitored when using this product, including laboratory tests, especially serum creatinine values.
Skin reactions rarely occur during treatment, such as Stevens-Johnson syndrome. If the patient develops a skin rash, close observation is needed, and if the skin lesion becomes more serious, the drug should be discontinued. In addition, this product can cause photosensitivity, especially during long-term treatment. It is recommended to inform patients to avoid direct sunlight when applying this product.
Carcinogenicity, mutagenicity and reproductive damage A 2-year study of voriconazole carcinogenicity in rats and mice was performed. Rats were orally administered 6, 18 or 50 mg / kg of voriconazole, or 0.2, 0.6, or 1.6 times the usual maintenance dose of voriconazole calculated as mg / m2, respectively. Hepatocellular adenomas were detected in female rats given 50 mg / kg voriconazole, and hepatocellular carcinoma was detected in male rats given 6 and 50 mg / kg doses. Mice were orally administered voriconazole at 10, 30 or 100 mg / kg, or 0.1, 0.4 or 1.4 times the usual maintenance dose of voriconazole calculated as mg / m2, respectively. Hepatocyte glands were detected in mice of both sexes Hepatocellular carcinoma was also detected in male mice given 1.4 times the usual maintenance amount of voriconazole.
Adding voriconazole to human lymphocyte culture in vitro, we can observe the teratogenic effect of voriconazole (mainly chromosome breakage). No genotoxicity was found in voriconazole in the Ames test, CHO test, mouse micronucleus test, or DNA repair test (unconventional DNA synthesis test).
Preliminary research results show that 50 mg / kg, or 1.6 times the recommended maintenance amount of voriconazole, can significantly reduce the pregnancy rate of rats, but large-scale reproduction studies have not found these significant differences.
For teratogenic pregnant women, see [Warning].
Effects on the ability to drive and operate machines This product may cause transient, reversible visual changes, including blurred vision, visual changes, visual enhancement and / or photophobia. Patients with these symptoms must avoid hazardous work, such as driving or operating machinery. ^[3]

Voriconazole medication for pregnant and lactating women:

There is 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 danger to humans has not been determined.
Voriconazole should not be used in pregnant women unless the benefit to the mother is significantly greater than the potential toxicity to the fetus.
Women of childbearing age Women of childbearing age need to take effective contraception during the application of voriconazole.
Breastfeeding women have no data on the secretion of voriconazole in milk. Unless obvious advantages outweigh disadvantages, lactating women should not use voriconazole. ^[3]

Voriconazole medication for children:

The safety and effectiveness of voriconazole in children under 12 years have not been established.
A total of 22 patients with invasive aspergillosis aged 12-18 years were selected in the therapeutic study, and the maintenance dose of voriconazole was given, that is, once every 12 hours, 4 mg / kg each time, 12 patients (55%) were effective .
In therapeutic studies, little research has been done on the pharmacokinetic properties of voriconazole in adolescents. ^[3]

Voriconazole medication for the elderly:

In multidose therapy studies, patients 65 years of age accounted for 9.2% and patients 75 years of age accounted for 1.8%. A study in healthy volunteers showed that total exposure (AUC) and peak plasma concentration (Cmax) in older men were higher than in young men. Analysis of the pharmacokinetic data of 552 patients in 10 voriconazole treatment studies showed that after intravenous infusion or oral voriconazole, the plasma concentration of elderly patients was about 80% -90% higher than that of younger patients. However, the overall safety of older people is similar to that of young people, so no dose adjustment is necessary. ^[3]

Voriconazole drug interactions:

Unless otherwise noted, studies of drug interactions are performed in healthy male volunteers. A multi-dose administration method was used, each time 200 mg orally twice daily until a steady-state concentration was reached. The results of these studies have implications 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 interaction between the two drugs. The first and second parts of the interaction are described in the following order: combined use is prohibited; combined use requires dose adjustment and close clinical and / or biological monitoring; and finally there is no significant pharmacokinetic interaction, but it may be useful for clinical treatment Useful.
Effects of other drugs on voriconazole Voriconazole is metabolized by cytochrome P450 isoenzymes, including CYP2C19, CYP2C9, and CYP3A4. These isoenzyme inhibitors or inducers can increase or decrease the blood concentration of voriconazole, respectively.
Rifampicin (CYP450 inducer): In combination with rifampicin (600mg once daily), Cmax (peak concentration of blood drug) and AUC (area under the curve of the drug interval of the intervening period) of voriconazole are reduced by 93 % And 96%. Therefore, the combination of this product with rifampicin is prohibited (see [taboo]).
Carbamazepine and phenobarbital (potentially potent inducers of CYP450): Although not studied, carbamazepine and phenobarbital may significantly reduce the blood concentration of voriconazole, so this product and these two drugs are banned Combination (see [Contraindications]).
Cimetidine (non-specific CYP450 inhibitor and can increase the pH of gastric acid): When combined with Cimetidine (400 mg twice daily), Cmax and AUC of voriconazole increase by 18% and 23, respectively. %. The combination of the two does not need to adjust the dose of this product.
Ranitidine (increased gastric pH): Ranitidine (150 mg twice daily) has no significant effect on Cmax and AUC of voriconazole.
Macrolide antibiotics: erythromycin (CYP3A4 inhibitor, 1 g twice daily) and azithromycin (500 mg once daily) have no significant effect on 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 those drugs metabolized by CYP45O isoenzymes.
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrate): Although not studied, voriconazole is banned from terfenadine, astemizole, cisapride, pimidine Zit or quinidine. Because this product can increase the blood concentration of the above drugs, resulting in prolonged QT interval, and occasionally tip torsional ventricular tachycardia can occur (see [Contraindications]).
Sirolimus (CYP3A4 substrate): Cmax and AUC of sirolimus (single 2g) increased by 556% and 1014% when used in combination with voriconazole. Therefore, the combination of these two drugs is prohibited (see [Contraindications]).
Ergot alkaloids (CYP3A4 substrate): Although not studied, ergot alkaloids (ergotamine and dihydroergotamine) in combination with voriconazole may increase plasma concentrations, resulting in ergot poisoning. Therefore, the combination of voriconazole and ergot alkaloids is prohibited (see [Contraindications]).
Cyclosporine (CYP3A4 substrate): In stable kidney transplant patients, voriconazole increases the Cmax and AUC of cyclosporine by at least 13% and 70%, respectively. When patients who have been treated with cyclosporine begin to use this product, it is recommended that their cyclosporine dose be halved and that the plasma concentration of cyclosporine be closely monitored. Increased cyclosporine concentration can cause renal toxicity. After discontinuing this product, the cyclosporine concentration needs to be closely monitored, and the cyclosporine dose can be increased if necessary.
Tacrolimus (CYP3A4 substrate): Cmax and AUCt of tacrolimus (a single dose of 0.1 mg / kg) increased by 117% and 221% when used in combination with voriconazole. When patients who have been treated with tacrolimus begin to use this product, it is recommended that the dose of tacrolimus be reduced to one-third of the original dose, and blood concentration should be closely monitored. Increased tacrolimus concentration can cause renal toxicity. After discontinuation of this product, the concentration of tacrolimus needs to be closely monitored, and the tacrolimus dose can be increased if necessary.
Oral anticoagulant warfarin (CYP2C9 substrate): voriconazole (300 mg twice daily) and warfarin (30 mg single dose), prothrombin time can be prolonged by up to 93%. Therefore, when the two are combined, it is recommended to closely monitor the prothrombin time.
Other oral anticoagulants, such as phenprohydroxycoumarin and acetocoumarol (CYP2C9 and CYP3A4 substrates): Although not studied, coumarin levels may increase when coumarins are used in combination with voriconazole, thus Prolong prothrombin time. If patients are taking both voriconazole and coumarin preparations, the prothrombin time needs to be closely monitored and the dose of anticoagulant adjusted accordingly.
Sulfonylureas (substrates of CYP2C9): Although not studied, voriconazole may still increase the blood concentration of sulfonylureas (such as tolbutamide, glipizide, and glibenclamide) when applied simultaneously, which can Hypoglycemia. Therefore, it is recommended to closely monitor blood glucose when the two are combined.
Statins (substrates of CYP3A4): Although not clinically studied, in vitro tests (human liver microsomes) have demonstrated that voriconazole has an inhibitory effect on the metabolism of lovastatin. Therefore, the combination of voriconazole and statins may increase the blood concentration of statins metabolized by CYP3A4. Increased blood concentration of statins may cause rhabdomyolysis, it is recommended that the dose of statins should be adjusted when the two are combined.
Benzodiazepines (CYP3A4 substrate): 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 (such as midazolam and triazolam) metabolized by CYP3A4 and prolong the sedation time. It is recommended to adjust the dose of benzodiazepines when the two drugs are combined.
Vinca alkaloids (CYP3A4 substrate): Although not studied, combined with voriconazole, vinca alkaloids (vincristine and vinblastine) may have increased plasma concentrations, which may cause neurotoxicity.
Prednisone (CYP3A4 substrate): Cmax and AUC of prednisone (single dose of 60 mg) increased by 11% and 34% respectively when used in combination with voriconazole. There is no need to adjust the dose when the two are combined.
Digoxin (P-glycoprotein-mediated transport): Voriconazole had no significant effect on the Cmax and AUC of digoxin (0.25 mg once daily).
Mycophenolic acid (UDP-glucuronyl acyltransferase substrate): Voriconazole has no significant effect on the Cmax and AUC of mycophenolic acid (1g single dose).
Two drugs interact with phenytoin (a strong inducer of CYP2C9 substrate and CYP450): The simultaneous application of phenytoin and voriconazole should be avoided unless the benefits outweigh the disadvantages after weighing.
Phenytoin 300mg once daily can reduce Cmax and AUC of voriconazole by 49% and 69%, respectively; voriconazole 400mg twice daily (see [Dosage and Administration]), can make phenytoin (1 time a day (300mg each time), Cmax and AUC increased by 67% and 81%, respectively. Therefore, when the two are combined, it is recommended to closely monitor the blood concentration of phenytoin.
2200mg2400mg 40kg 2100mg 2200mg25mg/kg See [Dosage and Administration].
CYP450
1300mg2200mgCmaxAUC69%78%2350mgCmaxAUC2200mg96%68%2400mg CmaxAUC2200mg104%87%CmaxAUC195%331%
2200mg2350mg 40kg 2100mg 2200mg25mg/kg
CYP2C19CYP2C19 CYP3A4 40mgCmaxAUC15%41%
CmaxAUC116%280%
CYP2C19
CYP3A4(3800mg)CmaxCmin()AUCCmaxAUC
HIVCYP3A4HIV/
NNRTICYP3A4CYP3A4CYP450delavirdNNRTI / ^[3]

35110

121ml/min SBECD55ml/minSBECD ^[3]

Mechanism of action Voriconazole's mechanism of action is to inhibit 14-sterol demethylation mediated by cytochrome P450 in fungi, thereby inhibiting ergosterol biosynthesis. In vitro tests have shown that voriconazole has a broad-spectrum antifungal effect. This product has antibacterial effect on Candida genus (including fluconazole-resistant Candida krusei, Candida glabrata and Candida albicans resistant strains), and has bactericidal effect on all Aspergillus fungi detected. In addition, voriconazole also has bactericidal effects on other pathogenic fungi in vitro, including those that are less sensitive to existing antifungal drugs, such as Apodactinomyces and Fusarium.
Animal experiments have found that the lowest bacteriostatic concentration 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 pyrrole antifungals.
Microbiology clinical trials have shown that voriconazole controls Aspergillus, including Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus nidulans; Candida species, including Candida albicans, and some Candida, Candida, C. inconspicua, Candida krusei, Candida subtilis, Candida tropicalis, and Candida gilimonium; genus Actinomyces, including Mycobacterium apophyllum and Mycobacterium avium and Fusarium, have clinical effects (improved or cured, see below) Clinical experience section).
Other fungal infections for which voriconazole is effective (usually cured or improved) include Alternaria, dermatitis, cephalosporins, Mycosporium, Coccidioides, Coriolus coronatus, New Cryptococcus Umbilicella, E. acanthoides, P. erythrocyticum, Pedicularis madura, Paecilomyces spp., Penicillium spp., Including Penicillium manifoldi, P. rotundii, Pleurotus spp. And hairy spores Infection with Trichoderma, including Trichosporum albus.
In vitro tests have observed that voriconazole has antibacterial effects on the following clinically isolated fungi, including Acremonium, Alternaria, Bipolaris, Mycobacterium, Cladophialophora spp., And capsular histoplasma. Voriconazole of 0.05-2 g / ml can inhibit most strains.
In vitro tests have shown that voriconazole has antibacterial effects on Curvularia and Sporothrix, but its clinical significance is unclear.
Before treatment, specimens should be collected for fungal culture, and other related laboratory tests (serology and histopathology) should be performed to isolate and identify pathogenic bacteria. Anti-infective treatment must be performed before obtaining culture results and other laboratory test results, 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 failure of clinical treatment. Infections caused by other pyrrole drug-resistant strains are also clinically effective. Due to the complexity of selected patients in clinical trials, it is difficult to determine the relationship between in vitro antibacterial activity and clinical outcomes. The critical concentration of voriconazole in drug sensitivity tests has not been established.
Drug resistance There are not enough studies on the in vitro resistance of Candida, Aspergillus, Apodactinomyces and Fusarium to voriconazole. The development of resistance to various fungi in the antibacterial spectrum of voriconazole is currently unknown.
Fungi with reduced sensitivity to fluconazole and itraconazole may also have reduced sensitivity to voriconazole, suggesting that cross-resistance may exist in these azoles. The relationship between cross-resistance and clinical efficacy has not been fully established. If isolates from clinical cases are cross-resistant, other antifungal medications may be needed.
Preclinical safety data Toxicity studies of repeated administration suggest that the target organ of voriconazole is the liver. Similar to other antifungal drugs, the plasma exposure in experimental animals when hepatotoxicity occurs is equivalent to that achieved with human therapeutic doses. Experiments in rats, mice, and dogs have found that voriconazole can also induce small lesions in the adrenal glands. Other routine studies of safety pharmacology, reproductive toxicity, and potential carcinogenicity have not found voriconazole to be particularly harmful to humans.
Reproductive studies have shown that when the systemic exposure of voriconazole is equivalent to that achieved by human therapeutic doses, it has teratogenic effects on rats and embryonic toxicity to rabbits. In the studies before and after childbirth, after rats were given lower than the human human therapeutic dose of exposure, the pregnancy time of the rats was prolonged, the childbirth time was prolonged, causing dystocia and causing maternal death, and the perinatal survival rate of young rats reduce. Similar to other pyrrole antifungals, the mechanism by which voriconazole affects labor is likely to be specific, including reducing estradiol levels.
In the preclinical data of the excipient thiobutyl ether--cyclodextrin sodium (SBECD), repeated toxicity studies have shown that SBECD mainly affects vesicular formation of urethral epithelial cells and activates liver and lung macrophages cell. Now that positive results have been obtained in the guinea pig maximization test (GMPT), prescribers should be aware of the potential for intravenous allergy to cause allergies. Genotoxicity and reproductive toxicity studies have shown that the excipient SBECD is not particularly harmful to humans. Carcinogenicity studies of SBECD have not been conducted. An impurity in SBECD is an alkylating mutagen. There is evidence that it is carcinogenic to rodents, so this impurity should be considered to be carcinogenic to humans. According to the results of the above studies, the course of intravenous preparations should not exceed 6 months.
Clinical experience In this section, patients who have been evaluated for clinical efficacy as both cured and improved are statistically valid.
Aspergillus Infection-The efficacy of voriconazole in patients with poor prognosis aspergillosis In vitro voriconazole has a bactericidal effect on Aspergillus. An open, randomized, multicenter study comparing the efficacy and survival benefits of voriconazole and amphotericin B in 277 patients with immunocompromised acute invasive aspergillosis for 12 weeks. The global effective rates for the treatment group and control group were 53% and 31%, respectively (the abnormal symptoms and signs at baseline and the imaging / bronchoscopy returned fully or partially to normal). The 84-day survival rate was significantly higher in the treatment group than in the control group. In addition, voriconazole has significant advantages in terms of the time of death and the time of discontinuation due to toxicity, and this advantage has significant clinical and statistical significance.
This study confirms the results of an earlier prospective study. The latter study was performed in patients with risk factors for poor prognosis, including graft-versus-host disease, especially in patients with intracranial infection (usually 100% mortality), and achieved good results after treatment with this product.
The study included brain, sinus, pulmonary aspergillosis, and disseminated aspergillosis in patients with underlying diseases such as bone marrow transplantation, solid organ transplantation, hematological malignancies, cancer, or AIDS.
Severe refractory candida infections This study included 55 patients with severe refractory candida infections (including candidiasis, disseminated, and other invasive candidiasis) who had previously been antifungal Treatment, especially fluconazole, was ineffective. After voriconazole treatment, 24 cases were effective (15 cases were cured and 9 cases were improved). Among patients infected with fluconazole-resistant non-Candida albicans strains, 3/3 of Candida krusei (cured) and 6/8 of Candida glabrata (5 cured and 1 improved) were effective in the treatment. Limited efficacy data also support clinical efficacy.
Infection with Foot Actinomyces and Fusarium is effective against the following rare fungal infections:
Actinomyces genus: In the voriconazole treatment group, 16 of 28 patients with Mycobacterium apex infection of the pointed foot were effective in treatment (6 cases were cured and 10 cases were improved); 7 of 7 patients with Mycobacterium infection with multi-foot development were effective (Both improved). In addition, one of the three patients with mixed (more than one pathogenic bacteria, including the genus Actinomyces) infection was effective in treatment.
Fusarium: 17 patients in the voriconazole treatment group were effective in 7 cases (3 cases were cured and 4 cases were improved). Of these 7 patients, 3 were eye infections, 1 was sinus infection, and 3 was disseminated infection. Another 4 patients had mixed infections including Fusarium spp., 2 of which were effective.
Most of the above-mentioned rare pathogenic infections are ineffective or intolerable to the original antifungal treatment.
In clinical trials, 561 patients were treated with voriconazole for more than 12 weeks and 136 patients for more than 6 months.
Pediatric experience 61 cases of pediatric patients with confirmed or highly suspected invasive fungal infection were treated with voriconazole, aged 9 months to 15 years, of which 34 were 2-12 years old and 20 were 12-15 years old.
Most (57/61) patients had previously used other antifungal drugs, but all failed. Five children aged 12-15 years were included in the therapeutic study, and the rest were treated with voriconazole in placebo. The underlying diseases of these children include hematological malignancies, aplastic anemia (27 cases), and chronic granulomatous disease (14 cases). Aspergillosis is most common among fungal infections (43/61; 70%). ^[3]

Voriconazole pharmacokinetics:

General pharmacokinetic characteristics The pharmacokinetics of voriconazole were studied in healthy subjects, special populations and patients, respectively. A study of patients with risk factors for aspergillosis (mainly malignant tumors of the lymphatic system or hematopoietic tissue) found that voriconazole was administered orally 200 mg or 300 mg twice daily for 14 days. Fast, stable absorption, in vivo accumulation and non-linear pharmacokinetics) consistent with healthy subjects.
Because the metabolism of voriconazole is saturable, its pharmacokinetics is non-linear, and the proportion of increase in exposure is far greater than the proportion of increase in dose. Therefore, if the oral dose is increased from 200 mg twice daily to 300 mg twice daily, the estimated exposure (AUC) increases by an average of 2.5 times. When the subject is given the recommended loading dose (intravenous or oral), his plasma concentration approaches the steady state concentration within 24 hours. If no loading dose is given, it is only twice a day, and the plasma concentration of most subjects reaches a steady state at about 6 days after multiple dose administration.
Absorption Oral absorption of this product is rapid and complete, peak blood concentration reached 1-2 hours after administration. The absolute bioavailability after oral administration is approximately 96%. When administered in multiple doses and taken at the same time as a high-fat meal, the peak plasma concentration of voriconazole and the area under the curve at the time of administration were reduced by 34% and 24%, respectively. Changes in gastric juice pH have no effect on the absorption of this product.
The distribution volume of voriconazole at the steady-state concentration of distribution was 4.6 l / kg, suggesting that this product is widely distributed in tissues. The plasma protein binding rate is about 58%. In one study, cerebrospinal fluid was measured in eight patients, and voriconazole was detected in all patients.
Metabolic in vitro experiments show that voriconazole is metabolized by liver cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4.
The pharmacokinetics of voriconazole vary widely among individuals.
In vivo studies show that CYP2C19 has an important role in the metabolism of this product. This enzyme has genetic polymorphisms, for example: 15-20% of Asians are weak metabolizers, while white and black weak metabolizers only account for 3- 5%. Studies in healthy whites and healthy Japanese indicate that the drug exposure (AUC) of weak metabolizers is on average 4 times higher than that of homozygous strong metabolizers, and that of strong heterozygous metabolizers is stronger than that of homozygotes 2 times higher.
The main metabolite of voriconazole is N-oxide, which accounts for about 72% in plasma. The metabolite has weak antibacterial activity and has no significant effect on the pharmacological effects of voriconazole.
Excretion of voriconazole is mainly metabolized by the liver, with less than 2% of the drug excreted in its original form through the urine.
After administering voriconazole labeled with a radioactive isotope, approximately 80% and 83% of the radioactivity of those who received multiple intravenous infusions and multiple doses of oral administration were recovered in urine. The vast majority of radioactivity (> 94%) was excreted in the urine within 96 hours after administration (intravenous and oral).
The terminal half-life of voriconazole is dose-dependent. The terminal half-life is about 6 hours after 200 mg orally. Due to its non-linear pharmacokinetic characteristics, the terminal half-life value cannot be used to predict the accumulation or elimination of voriconazole.
Pharmacokinetic-pharmacodynamic relationship. In 10 treatment studies, the median and mean median plasma concentrations of the subjects were 2425ng / ml (quartile range 1193-4380ng / ml) and 3742ng / ml (interquartile range 2027-6302ng / ml). No average, maximum, or minimum plasma concentrations were found to be related to treatment outcome in the study.
Analysis of pharmacokinetics-pharmacodynamics in clinical trial data found that the blood concentration of voriconazole was associated with abnormal liver function tests and visual impairment.
Pharmacokinetic Gender in Specific Populations In a multi-dose oral trial, Cmax and AUC in healthy young women were 83% and 113% higher than those in healthy young men (18-45 years), respectively. In the same trial, Cmax and AUC of healthy older women were not significantly different from healthy older men (65 years).
In clinical applications, dose adjustment is not required for patients of different sexes. Voriconazole has similar safety and plasma concentrations in both male and female patients, so there is no need to adjust the dose by sex.
Elderly In a multi-dose oral study, Cmax and AUC in healthy older men (65 years) were 61% and 86% higher than those in healthy young men (18-45 years), respectively. However, Cmax and AUC in healthy older women (65 years) were not significantly different from healthy young women (18-45 years).
The treatment dose was not adjusted according to age in the treatment study. The relationship between blood concentration and age was observed in the test. Voriconazole is similarly safe in young and elderly patients, so elderly patients do not need to adjust the dose.
Children underwent a population pharmacokinetic study in 35 immunocompromised children, aged 2 to 12 years old, given single or multiple intravenous doses, of which 24 were given in multiple doses. Children who received a maintenance dose of 4 mg / kg intravenously every 12 hours had median steady-state plasma concentrations similar to those of adults administered 3 mg / kg every 12 hours, which were 1186 ng / ml and 1155 ng / ml, respectively. Therefore, the recommended maintenance dose of voriconazole in children 2 to 12 years is: 4 mg / kg every 12 hours.
Renal impairment patients with moderate to severe renal impairment (blood creatinine value> 2.5mg / dl) when this product is used, accumulation of excipient thiobutyl ether--cyclodextrin sodium (SBECD) can occur. The recommended dosage and renal function monitoring can be found in [Usage and Dosage] and [Precautions].
After a single oral dose of voriconazole 200 mg in patients with liver impairment, the AUC of patients with mild to moderate cirrhosis (Child-pugh A and B) was 233% higher than those with normal liver function. The protein binding rate is not affected by liver damage.
In a multi-dose oral study, the maintenance dose for patients with moderate liver cirrhosis (Child-pugh B) was twice daily at 100 mg each; those with normal liver function were twice daily at 200 mg each. The results were two The AUC is similar. There are no pharmacokinetic data for patients with severe cirrhosis (Child-pugh C). For the recommended dosage and monitoring of liver function impairment, see [Usage and Dosage] and [Precautions]. ^[3]

Voriconazole expert review

This product is mainly used to treat life-threatening progressive infections in immunodeficiency patients. According to foreign reports, a group of double-blind, multi-dose treatment of oropharyngeal candidiasis for AIDS patients showed that 200 mg each time, 1 or 2 times a day, the clinical effective rate was 97% to 100%, no significant side effects were seen, only 32 cases Adverse reactions that may be related to the medication occurred, 6 of whom discontinued treatment for this reason, and 17 cases of dose-related visual impairment have been seen (3 cases were 50 mg per day, 4 cases were 200 mg per day, 10 cases were 200 mg per day, 2 times a day), of which only 2 patients discontinued the treatment. Generally, they were more sensitive to light and had a light stimulus or blurred vision. They were transient and completely recoverable, and some even continued to use the drug. Can also be restored. In another set of open trials, this product was used in patients with acquired immunodeficiency to treat acute invasive aspergillosis (many of them had a history of treatment with amphotericin B or itraconazole, and their clinical symptoms did not improve). The dose was 6mg / kg, intravenously every 12 hours, twice daily for 5 days. Followed by 3mg / kg for 6 to 27 consecutive days, then 200mg once again, intravenously every 12 hours, 2 times a day for 4 to 24 consecutive days. Of the 71 patients treated, 53 were available for analysis, of which 74% (39/53) had good results (8 patients recovered, 17 partially improved, and 14 patients were stable), 26% (14/53) failed treatment, and 8% Of patients (6/71) had mild to moderate visual impairment, and 4 (6%) patients discontinued treatment due to adverse reactions, including 1 with rash and 3 with elevated liver enzymes. In an open, uncontrolled clinical study, we observed that this product is used to treat chronic invasive aspergillosis without neutropenia. Many of these patients have used amphotericin B and itraconazole without receiving efficacy. Symptoms There was no improvement. Instead, this product was taken orally, 200 mg each time, twice a day for 4 to 24 weeks. According to its clinical symptoms and laboratory tests, 13 of 25 cases can be analyzed, 69% (9/13 ) The effect is significant, 31% (4/13) of treatment failure, 44% (11/25) of patients discontinued due to elevated liver enzymes. A large multicenter clinical study involving 800 patients was designed to compare the use of this product with amphotericin in patients with persistent fever and neutropenia. The results were similar, but this product The proportion of severe fungal infections in the group was significantly reduced. And the latter has more obvious damage to renal function. ^[4]