Date of approval.
Date of revision.
Voriconazole Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Voriconazole Tablets
English name: Voriconazole Tablets
Hanyu Pinyin: Fulikangzuo Pian
Ingredients
The main ingredient of this product is voriconazole.
Chemical name: (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
Chemical structure formula.
Molecular formula: C16H14F3N5O
Molecular weight: 349.31
【Properties】.
50mg specification: white or off-white round biconvex film-coated tablets, engraved with “283” on one side and “S” on the other side.
0.2g specification: white or off-white capsule-shaped biconvex film-coated tablets with “285” engraved on one side and “S” on the other side.
Indications
This product is a broad-spectrum triazole antifungal drug indicated for the treatment of the following fungal infections in adults and pediatric patients aged 2 years and older.
(1) Invasive Aspergillosis.
(2) Candidaemia in non-neutropenic patients.
(3) Severe invasive infections caused by fluconazole-resistant Candida (including Candida klebsiella).
(4) Severe infections caused by Foot Actinomyces spp. and Fusarium spp.
This product is mainly used for the treatment of patients with progressive, potentially life-threatening fungal infections.
Prevention of invasive fungal infections in high-risk patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
【Specifications】.
(1) 50mg (2) 0.2g
Dosage and Administration
1.General considerations of dosage
Voriconazole film-coated tablets should be taken at least 1 hour before or 1 hour after a meal.
Blood electrolytes should be monitored before or during treatment with voriconazole, and electrolyte disorders such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected.
Adults
For oral administration, the first loading dose should be given on the first day to bring the blood concentration close to the steady-state concentration. Due to the high bioavailability of the oral formulation (96%), the two methods of administration, oral and intravenous, can be interchanged when clinically indicated.
2. Recommended dose and its adjustment and duration of treatment
Recommended dose for adults and adolescents (12-14 years old and weighing ≥50 kg; 15-17 years old).
Oral patient weight ≥40kg* Patient weight <40kg* Loading dose (applicable to the first 24 hours) 400mg once every 12 hours 200mg once every 12 hours Maintenance dose (after 24 hours of initiation) 200mg twice daily 100mg twice daily* Applicable to patients aged 15 years or above
Duration of treatment
Duration of treatment depends on the clinical efficacy of the patient after dosing and the results of microbiological testing, and a reasonable duration of treatment should be carefully selected. See [Precautions].
Dose adjustment (adults)
During treatment with this product, physicians should closely monitor its potential adverse effects and promptly adjust the drug regimen according to the patient’s specific situation, see [Adverse Reactions] and [Precautions].
If the patient responds poorly to treatment, the maintenance dose for oral administration may be increased to 300 mg twice daily; for patients weighing <40 kg, the dose is adjusted to 150 mg twice daily.
If the patient cannot tolerate the higher doses described above, the maintenance dose for oral administration may be reduced by 50 mg per dose, tapering to 200 mg twice daily (for patients weighing <40 kg, reduce to 100 mg twice daily).
If used for prophylaxis, please see below.
Children 2 years to <12 years of age or younger and light weight adolescents (those 12 to 14 years of age and weighing <50 kg)
Voriconazole should be administered at pediatric doses because these adolescents metabolize voriconazole in a manner more similar to that of children than adults.
The recommended dosing regimen is as follows.
Oral loading dose
(for the first 24 hours) Maintenance therapy is not recommended
(after 24 hours of initiation) administered twice daily at 9 mg/kg (maximum single dose 350 mg twice daily) Remarks: Based on the results of a population pharmacokinetic analysis of 112 immunodeficient pediatric patients aged 2 to <12 years and 26 immunodeficient adolescent patients aged 12 to <17 years.
It is recommended that treatment be initiated by intravenous drip therapy and that oral therapy be considered only when significant clinical improvement is achieved. Note that voriconazole exposure at 8 mg/kg IV drip is approximately twice as high as voriconazole exposure at 9 mg/kg orally.
The recommended dose for children is based on studies with dry mixes. Bioequivalence studies of oral suspensions and tablets have not been conducted in children. Considering that the gastrointestinal passage time may be shorter in pediatric patients, the absorption of tablets may be different in children than in adult patients. Therefore, an oral dry suspension formulation is recommended for pediatric patients aged 2 to <12 years.
For all other adolescents (12 to 14 years and ≥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 Light Weight Adolescents [12 to 14 years and <50 kg])
If the patient does not respond adequately, the dose may be increased by 1 mg/kg (50 mg if the maximum oral dose of 350 mg was initially used). If the patient is unable to tolerate treatment, decrease the dose by 1 mg/kg (increase by 50 mg if the maximum oral dose initially used was 350 mg).
The application of this product has not been studied in pediatric patients 2 to <12 years of age with hepatic or renal insufficiency.
Prophylaxis in adults and children
Prophylaxis should begin on the day of transplantation and may be administered for up to 100 days. The number of days of prophylaxis should be shortened as much as possible based on the risk of invasive fungal infection (IFI) (as determined by neutropenia or immunosuppression). The maximum number of days of prophylaxis after transplantation may be up to 180 days only if immunosuppression or graft-versus-host disease (GvHD) persists.
Dosage
The recommended prophylactic dosing regimen in each age group is the same as the therapeutic dosing regimen. Please see the therapeutic dosing regimen table above.
Duration of Prophylaxis
The safety and efficacy of voriconazole use beyond 180 days has not been adequately studied in clinical trials.
For prophylactic use of voriconazole beyond 180 days (6 months), the balance of benefit and risk needs to be carefully evaluated.
The following applies to both treatment and prophylaxis
Dose Adjustment
For prophylactic use, dose adjustment is not recommended in the absence of efficacy or in the event of treatment-related adverse events. If treatment-related adverse events occur, discontinuation of voriconazole and use of an alternative antifungal agent must be considered.
Dose Adjustment in Combination
In combination 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 combination 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).
In combination with efavirenz: voriconazole may be 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%, i.e., to 300 mg once daily. Efavirenz should be restored to its initial dose when voriconazole treatment is discontinued.
3. Elderly
No dose adjustment is required when applying this product in the elderly.
4. Renal impairment
Renal impairment has no effect on the pharmacokinetics of this product when administered orally. Therefore, no dose adjustment is required for mild to severe renal impairment.
Voriconazole can be cleared by hemodialysis with a clearance rate of 121 ml/min. 4 hours of hemodialysis can only clear a small amount of the drug and no dose adjustment is required.
5. Liver function impairment
In patients with mild to moderate cirrhosis (Child-Pugh A and B), the loading dose of voriconazole remains unchanged, but the maintenance dose is reduced by half.
There are no studies on the use of voriconazole in patients with severe cirrhosis (Child-Pugh C).
Safety data for voriconazole in patients with abnormal liver function tests (abnormal aspartate aminotransferase (AST), glutamate aminotransferase (ALT), alkaline phosphatase (AP), or total bilirubin more than 5 times above the upper limit of normal) are very limited.
Voriconazole has been reported to be associated with abnormal increases in liver function tests and clinical signs of liver injury, such as jaundice, and therefore its use in patients with severe hepatic impairment must be weighed against the advantages and disadvantages.
The toxic effects of voriconazole must be closely monitored in patients with hepatic impairment.
6. Pediatric use
The safety and efficacy of this product have not been evaluated in pediatric patients under 2 years of age.
Adverse reactions]
The following adverse reaction data are from the literature.
1.Safety summary
Safety data for voriconazole in adults were obtained from a safety database including more than 2000 subjects (including 1603 adult patients receiving treatment and 270 adult patients in additional prophylactic studies). It represents a diverse population, including patients with hematologic malignancies, HIV-infected patients with esophageal candidiasis and refractory fungal infections, non-granulocytopenic patients with candidemia and aspergillosis, and healthy volunteers.
The most commonly reported adverse reactions were visual impairment, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abnormal liver function tests, respiratory distress, and abdominal pain.
The severity of adverse reactions was generally mild to moderate. Analysis of safety data by age, race and gender did not show significant clinical differences.
2. List of Adverse Reactions
In the table below, all causally related adverse reactions and their frequency categories occurring in 1873 adults in the combined treatment (1603 cases) and prophylaxis (270 cases) studies are listed by system organ because most of the studies were open-ended.
Frequency of occurrence: very common: (≥1/10); common (≥1/100 but <1/10); rare (≥1/1000 but <1/100); rare (≥1/10,000 but <1/1000); very rare (<1/10000); unknown (cannot be inferred from known data).
In each frequency group, the types of adverse reactions were listed in descending order of their nature and severity.
Table
Adverse reactions reported in patients applying voriconazole
Systemic organ classification Very common
≥1/10 Common
≥1/100 to <1/10 Rare
≥1/1,000 to <1/100 Rare
≥1/10,000 to <1/1,000 Frequency unknown
(cannot be extrapolated from known data) Infections and invasions Sinusitis Pseudomembranous colitis Benign, malignant, and tumors of unknown nature (including cysts and polyps) Squamous cell carcinoma* Hematologic and lymphatic system abnormalities Granulocyte deficiency 1, complete blood cytopenia, thrombocytopenia 2, leukopenia, anemia Bone marrow failure, lymphadenopathy, eosinophilia Disseminated intravascular coagulation Immune system abnormalities Hypersensitivity allergy Endocrine abnormalities Adrenal insufficiency, hypothyroidism Hyperthyroidism Metabolic and nutritional abnormalities Peripheral edema Hypoglycemia, hypokalemia, hyponatremia Psychiatric abnormalities Depression, hallucinations, anxiety, insomnia, agitation, confused state of consciousness Neurological abnormalities Headache Convulsions, syncope, tremor, increased muscle tone3, sensory abnormalities, drowsiness, dizziness Cerebral edema, encephalopathy4, extrapyramidal disorders5 , peripheral neuropathy, ataxia, hypesthesia, taste disturbance hepatic encephalopathy, Green-Barre syndrome, nystagmus ocular abnormalities visual damage 6 retinal hemorrhage optic nerve abnormalities 7, optic nerve papilledema 8, actinic nerve crisis, diplopia, sclerochoroiditis, blepharitis optic nerve atrophy, corneal clouding ear and vagus abnormalities hypoacusis, vertigo, tinnitus cardiac abnormalities
Supraventricular arrhythmia, tachycardia, bradycardia
Ventricular fibrillation, ventricular extrasystole, ventricular tachycardia, prolonged QT on ECG, supraventricular tachycardia tip-twist ventricular tachycardia, complete AV block, bundle branch block, junctional 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 labyrinthitis, dyspepsia, constipation, gingivitis peritonitis, pancreatitis, tongue enlargement, duodenitis, gastroenteritis, tongue inflammation 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, phototoxicity, purpura, urticaria, allergic dermatitis, papulopapular rash, macular rash, eczema toxic epidermal necrolysis relaxans, angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug rash cutaneous lupus erythematosus*, freckles*, freckle-like nevus* Musculoskeletal and connective tissue abnormalities
Back pain arthritis Osteochondritis* Kidney and urinary system abnormalities
Acute renal failure, hematuria tubular necrosis, proteinuria, nephritis Systemic abnormalities and drug administration site conditions
Fever Chest pain, facial edema11, malaise, chills Injection site reactions, flu-like illness Examination Elevated blood creatinine Elevated blood urea, elevated blood cholesterol *Adverse reactions identified after marketing
1 Including neutropenia with or without fever.
2
Including immune thrombocytopenic purpura.
3
Includes neck stiffness and twitching of the hands and feet.
4
Includes hypoxic-ischemic encephalopathy and metabolic encephalopathy.
5
Includes dyscalculia and Parkinson’s disease.
6
See “Visual impairment” in [Adverse Reactions].
7
Persistent optic neuritis has been reported post-marketing. See [Precautions].
8
See [Precautions].
9
Includes dyspnea and exertional dyspnea.
10
Includes drug-related liver injury, toxic hepatitis, hepatocellular injury, and hepatotoxicity.
11
Includes periorbital edema, lip edema, and oroedema.
Description of selected adverse reactions
Visual impairment.
Visual impairment associated with voriconazole (including blurred vision, photophobia, green vision, chromophobia, color blindness, blue vision, eye disease, dizziness, night blindness, vibrational hallucinations, flash hallucinations, flash dark spots, decreased visual acuity, visual brightness, visual field defects, vitreous floaters, and xanthopsia) is common. Visual impairment associated with voriconazole treatment is common in treatment studies. Visual impairment is transient and can be fully recovered. Most resolves spontaneously within 60 minutes, and no clinically significant long-term visual response has been seen. There is evidence that this is reduced with repeated voriconazole administration. Visual impairment is generally mild and leading to discontinuation is rare, with no long-term sequelae. Visual impairment may be associated with higher blood levels and/or doses.
Although the site of action of voriconazole appears to be primarily confined to the retina, its mechanism of action remains unclear. In one study, the effects of voriconazole on retinal function were studied in healthy volunteers and found that the product reduced the amplitude of the retinal electrical waveform and returned to normal after discontinuation of the drug. The electroretinogram (ERG) is commonly used to detect electrical currents in the retina. changes in the ERG did not progress over the 29-day treatment period and fully recovered after discontinuation of voriconazole.
Long-term visual adverse events have been reported post-marketing.
Skin Reactions.
Skin reactions were common in voriconazole-treated patients in clinical trials. However, these patients had severe underlying disease combined with the use of multiple concomitant drug products. Most rashes were mild to moderate. Severe skin reactions occurred in patients during voriconazole treatment. These severe reactions included Stevens-Johnson syndrome (rare), toxic epidermal necrolysis relaxans (rare), and erythema multiforme (rare).
If patients develop a rash, they should be closely monitored and voriconazole discontinued if the lesions progress. Photosensitivity reactions (e.g., freckles, freckle-like nevi, and actinic keratoses) have been reported, particularly during long-term treatment.
Squamous cell carcinoma of the skin has been reported in patients treated with long-term voriconazole. The mechanism of formation remains unclear.
Liver function tests.
The overall incidence of elevated transaminases>3xULN (not necessarily constituting an adverse event) in adult and pediatric subjects receiving voriconazole for combination therapy and prophylaxis in the voriconazole clinical research program was 18.0% (319/1768) and 25.8% (73/283), respectively. Abnormal liver function tests may be associated with higher blood levels and/or higher doses.
Most abnormal liver function tests recover without dose adjustment or recover after dose adjustment, or in some cases after discontinuation of the drug.
There have been serious hepatotoxic reactions with voriconazole in patients with other serious underlying conditions, including jaundice, hepatitis, and liver failure leading to death.
Prevention
An open, controlled, multicenter study conducted in adult and adolescent patients receiving allogeneic HSCT with no prior confirmed or clinically diagnosed IFI compared primary prevention with voriconazole versus itraconazole and reported that 39.3% of subjects in the voriconazole group were permanently discontinued due to adverse events, compared to 39.6% of subjects in the itraconazole group who were Itraconazole group. Fifty (21.4%) subjects in the voriconazole group permanently discontinued the study drug due to an on-treatment hepatic adverse event compared to 18 (7.1%) in the itraconazole group.
Pediatric patients.
The safety of voriconazole was studied in 288 pediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and treatment (105) 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 seen 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 transaminase elevations in children compared with 5.3% in adults). Post-marketing data suggest that the incidence of skin reactions (especially erythema) may be higher in pediatric patients compared to adults. 22 patients less than 2 years of age treated with voriconazole in the compassionate use program reported the following adverse reactions (which could not be excluded as voriconazole-related): photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), elevated blood bilirubin (1) , elevated liver enzymes (1 case), rash (1 case), and optic nerve papilledema (1 case). Pancreatitis in pediatric patients has been reported in post-marketing reports.
3. Clinical study in Chinese adults
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 treatment-emergent all-cause adverse events, 90 of which were considered treatment-related. The most common all-cause adverse events occurring on treatment were hypokalemia (13.0%; 5.2% treatment-related) and visual disturbances (13.0%; all treatment-related). The majority of adverse events were mild or moderate. 18 subjects (23.4%) reported severe adverse events. 14 subjects (18.2%) had one or more serious adverse events during the study period, but none were treatment-related. An additional 5 subjects (6.5%) experienced 1 or more serious adverse events after the end of treatment; only 1 of these was considered treatment-related. 7 subjects (9.1%) died during the study and another 7 subjects (9.1%) died after permanent discontinuation of treatment or after the end of the study (but during the reporting period). Abnormal laboratory tests and changes in vital signs were not significant overall.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions after a drug has received marketing approval in order to continuously monitor the balance between the benefits and risks of the drug.
Contraindications
1. This product is contraindicated in persons with hypersensitivity to its active ingredients or its excipients.
2. The combination of this product with CYP3A4 substrates, including terfenadine, astemizole, cisapride, pimozide and quinidine, is prohibited. Because this product can increase the blood concentration of the above drugs, resulting in QT interval prolongation, and occasionally seen tip-twisting ventricular tachycardia.
3.The combination of this product and sirolimus is prohibited. Voriconazole can significantly increase the blood concentration of sirolimus, therefore, the combination of these two drugs is prohibited.
4.The combination of this product with rifampin, carbamazepine and phenobarbital is prohibited. These drugs may significantly reduce the blood concentration of this product, therefore, the combination of this product with these drugs is prohibited.
5. The combination of efavirenz at the standard dose with efavirenz at 400 mg (once daily) and higher is prohibited because the blood concentration of voriconazole was significantly reduced in healthy subjects when efavirenz and voriconazole were applied simultaneously at this dose. Voriconazole also significantly reduced the blood concentration of efavirenz.
6. This product is contraindicated in combination with high doses of ritonavir (400 mg and above per dose, twice daily). In healthy subjects, the blood concentration of voriconazole was significantly reduced when this dose of ritonavir was applied simultaneously with voriconazole.
7. The combination of this product with ergot alkaloids, including ergotamine and dihydroergotamine, is prohibited. Ergot alkaloids are substrates of CYP3A4, and the blood concentration of ergot drugs may be increased after the combination of the two and lead to ergot toxicity.
8. The combined use of this product with St. John’s wort is prohibited.
Precautions】
1. Allergic reactions: Use with caution if you are known to be allergic to other azole drugs.
2.Cardiovascular system: Voriconazole is associated with prolonged QTc interval. A very small number of patients using this product have been reported to develop tip-twist ventricular tachycardia. These patients are usually associated with risk factors such as previous cardiotoxic chemotherapeutic agents, cardiomyopathy, hypokalemia, or concomitant use of other drugs that may induce tachyarrhythmias. Therefore, voriconazole needs to be used with caution in patients with risk factors for arrhythmias, such as
Congenital or acquired QTc interval prolongation.
Cardiomyopathy, especially in the presence of current heart failure.
Sinus bradycardia with symptomatic arrhythmias.
Concomitant use of drugs known to prolong the QTc interval.
Blood electrolytes should be monitored prior to or during treatment with voriconazole, and electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia should be corrected if present.
A study showed that a single administration of voriconazole equivalent to 4 times the conventional dose in healthy volunteers did not reveal subjects with QTc intervals exceeding 500 ms (note: threshold for possible clinical adverse events (e.g., tardive dyskinesia)).
3. Hepatotoxicity: In clinical studies, there were severe hepatic reactions (including hepatitis, biliary stasis and fatal fulminant liver failure) in the voriconazole-treated group. Cases of hepatic reactions occurred primarily in patients with severe underlying disease (primarily malignant hematologic disease). Transient hepatic reactions, including hepatitis and jaundice, can occur in patients with no other established risk factors. Liver function abnormalities usually improve upon discontinuation of the drug.
4. Monitor liver function: Patients must be carefully monitored for hepatotoxicity while receiving voriconazole therapy. Clinical monitoring should include laboratory tests of liver function (especially aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) at the start of voriconazole therapy and at least weekly for the first month. The shorter the duration of treatment, the better, but the frequency may be reduced to monthly if liver function tests are unchanged after continuation of treatment based on a benefit-risk assessment. Patients must be routinely monitored for liver function both at the beginning of treatment and when liver function abnormalities occur during treatment to prevent more severe liver damage. Monitoring should include laboratory evaluation of liver function (especially liver function tests and bilirubin).
If liver function tests reveal significant elevations, voriconazole should be discontinued unless the physician assesses the patient’s benefit-risk and concludes that the drug should be continued.
Liver function monitoring is required in both children and adults.
5. Visual impairment: The effect of voriconazole on visual function beyond 28 days of treatment is not known. Visual adverse reactions, including blurred vision, optic neuritis and optic nerve papillary edema, have been reported with the application of this product. If continuous treatment exceeds 28 days, visual function, including visual acuity, visual field, and color vision, needs to be monitored.
6. Renal adverse reactions: Acute renal failure has been reported to occur in critically ill patients when this product is applied. Patients treated with voriconazole may also be co-administered with nephrotoxic drugs or other conditions that cause renal decompensation. (See [Adverse Reactions]).
7. Monitor renal function: The use of this product requires monitoring of renal function, which includes laboratory tests, especially blood creatinine values.
8. Monitor pancreatic function: Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation), especially children, should be closely monitored for pancreatic function during treatment with voriconazole. Monitoring of serum amylase or lipase may be considered in this clinical situation.
9. Adverse skin reactions: Exfoliative skin reactions, such as Stevens-Johnson Syndrome, have occurred during treatment. If the patient develops a rash, it needs to be closely observed. If lesions worsen, the drug must be discontinued.
In addition, voriconazole has been associated with phototoxicity, including reactions such as freckles, freckle-like nevi, actinic keratoses, and pseudoporphyria. All patients, including children, are advised to avoid direct sunlight during voriconazole treatment and to use measures such as protective clothing and sunscreen with a high sun protection factor (SPF) as appropriate.
10. Long-term treatment
For long-term exposures (treatment or prophylaxis) beyond 180 days (6 months), the balance of benefit and risk needs to be carefully evaluated, and therefore, physicians should consider whether it is necessary to limit voriconazole exposure. The following serious adverse events have been reported with long-term voriconazole use.
Squamous cell carcinoma of the skin (SCC) has been reported in some patients with phototoxic reactions to long-term voriconazole therapy. If a patient experiences a phototoxic reaction, discontinuation of voriconazole and use of alternative antifungal medications should be considered after consultation with a multidisciplinary team and the patient should be referred to dermatology. For early diagnosis and management of precancerous lesions, systematic and periodic evaluation of skin lesions is required in cases where voriconazole is continued despite the development of phototoxicity-related lesions. If a diagnosis of precancerous lesions or squamous cell carcinoma of the skin is confirmed, voriconazole should be discontinued.
Combined fluorosis and elevated alkaline phosphatase have been reported in transplant patients with non-infectious osteochondritis. Voriconazole should be discontinued if the patient presents with skeletal pain and imaging consistent with the manifestations of fluorosis or periostitis.
11. Pediatric Use
The safety and efficacy of this product in children under 2 years of age have not been established (see [Adverse Reactions] and [Pharmacokinetics]). Voriconazole is indicated for pediatric patients ≥ 2 years of age. A higher frequency of elevated liver enzymes has been observed in the pediatric population (see [ADVERSE REACTIONS]). Liver function needs to be monitored in both children and adults. Oral bioavailability is limited in pediatric patients 2 to <12 years of age with malabsorption and particularly low body weight. In such cases, intravenous application of voriconazole is recommended.
The frequency of phototoxic reactions is higher in the pediatric population. Because of its reported progression to SCC, strict photoprotective measures must be taken in this patient population. For children who develop photoaging damage (e.g., freckle-like nevus or freckles), sunlight avoidance and dermatologic follow-up (even after discontinuation of treatment) are recommended.
12., Prevention
In case of treatment-related adverse events (hepatotoxicity, phototoxicity and severe skin reactions such as SCC, severe or prolonged visual disturbances and periostitis), discontinuation of voriconazole and use of alternative antifungal drugs must be considered.
13.Phenytoin (CYP2C9 substrate and strong CYP450 inducer): This product should be avoided in combination with phenytoin as far as possible, and when it must be applied simultaneously after weighing the advantages and disadvantages, it is recommended to closely monitor the concentration of phenytoin.
14.Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is combined with efavirenz, the dose of voriconazole should be increased by 400 mg every 12 hours, while the dose of efavirenz should be reduced by 300 mg every 24 hours.
15. Rifabutin (strong CYP450 inducer)
Close monitoring of complete blood counts and adverse effects of rifabutin is required when the two are combined. Simultaneous application of these two drugs should be avoided unless the benefits outweigh the disadvantages.
16, Ritonavir (strong CYP450 inducer; CYP3A4 inhibitor and substrate) Voriconazole should be avoided in combination with low-dose ritonavir (100 mg twice daily) unless the patient’s benefit/risk assessment justifies the use of voriconazole.
17. Everolimus (CYP3A4 substrate, P-gp substrate): The combination of voriconazole and everolimus is not recommended because voriconazole is expected to significantly increase the drug concentration of everolimus, and there are currently no dose recommendations for the combination situation due to insufficient data.
18. Methadone (CYP3A4 substrate): When used in combination with voriconazole, methadone needs to be closely monitored for adverse effects and toxicity, including prolonged QTc interval, because the blood concentration of methadone is increased when combined with voriconazole. Methadone dose may need to be reduced.
19. Short-acting opioids (substrates of CYP3A4): When combining with voriconazole, consider reducing the dose of alfentanil, fentanyl and other short-acting opioids that are structurally similar to alfentanil and metabolized by CYP3A4 (e.g., sufentanil). When alfentanil is combined with voriconazole, its half-life is prolonged 4-fold, and an independent study showed that combining with voriconazole increased the mean AUC 0-∞ of fentanyl, necessitating close monitoring for opioid-related adverse effects (including prolonging its respiratory monitoring period).
20.Long-acting opioids (CYP3A4 substrates): When combined with voriconazole, consider reducing the dose of oxycodone and other long-acting opioids metabolized by CYP3A4 (e.g., hydrocodone) and closely monitor opioid-related adverse reactions.
21, Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitors): Cmax and AUCτ of voriconazole were significantly increased when oral voriconazole was combined with oral fluconazole in healthy populations. Methods to reduce the dose or frequency of administration of voriconazole and fluconazole to eliminate this effect have not been identified. Monitoring for voriconazole-related adverse reactions is recommended when fluconazole is followed by voriconazole.
22. Voriconazole tablets contain a lactose component and should not be used in rare, congenital galactose intolerance, Lapp lactase deficiency, or impaired glucose-galactose absorption.
23. Effects on the ability to drive and operate machines: Voriconazole may have some effects on the ability to drive and operate machines. It may cause transient and reversible visual changes, including blurred vision, visual changes, visual enhancement and/or photophobia. Patients must avoid hazardous work, such as driving or operating machinery, when these symptoms occur.
24. Embryo-fetal toxicity
Voriconazole can cause fetal damage when applied to pregnant women.
In animal studies, voriconazole use has been associated with teratogenicity, embryotoxicity, prolonged gestation, obstructed labor, and embryonic death. If voriconazole is used during pregnancy, or if pregnancy occurs during administration, the patient should be informed of the potential risk of this product to the fetus.
25. Laboratory tests
Electrolyte disturbances, including hypokalemia, hypomagnesemia, and hypocalcemia, should be corrected prior to the use of voriconazole.
Patient management should include laboratory evaluation of renal function (especially serum creatinine) and liver function (especially liver function tests and bilirubin).
26.Drug-related effects
See [Drug Interactions].
Pregnant women and nursing mothers
Pregnant women
Women of childbearing age
Women of childbearing age should use effective contraception during the use of voriconazole.
Lactating women
There is no information on the secretion of voriconazole in breast milk. Breastfeeding must be discontinued when voriconazole is initiated.
Fertility
In animal studies, male and female rats did not show impaired fertility.
[Pediatric Use].
Safety and efficacy have been established in children 2 to <12 years of age and in light weight adolescents (12 to 14 years of age and weighing <50 kg) and adolescents (12 to 14 years of age and weighing ≥ 50 kg; 15 to 17 years of age) and should be applied strictly in accordance with the recommended doses as described under [DOSAGE AND ADMINISTRATION].
The safety and efficacy of this product in children under 2 years of age have not been established.
Geriatric Use]
In a multi-dose oral dosing study, Cmax and AUCτ were 61% and 86% higher, respectively, in healthy older men (≧65 years) compared to healthy younger men (18-45 years). However, Cmax and AUCτ were not significantly different in healthy older women (≧ 65 years) compared with healthy younger women (18 to 45 years).
Dosing was not adjusted for age in the treatment studies. The relationship between blood levels and age was observed in the study. The safety profile of voriconazole was similar in young and elderly patients, therefore no dose adjustment was required for elderly patients.
Drug Interactions]
The following are the interactions of voriconazole with other drugs and other types of interactions
Voriconazole is metabolized by cytochrome P450 isozymes and inhibits the activity of cytochrome P450 isozymes, including CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isozymes may increase or decrease the blood concentration of voriconazole, respectively, and therefore, this product may increase the blood concentration of substances metabolized by CYP450 isozymes.
Unless otherwise noted, drug interaction studies were conducted in healthy adult male volunteers. A multiple-dose dosing regimen of 200 mg per oral dose twice daily was used until steady-state concentrations were achieved. The results of these studies are also informative for other populations and other routes of administration.
Use voriconazole with caution if you are using other drugs that prolong the QTc interval. The combination of voriconazole with drugs metabolized by CYP3A4 isoenzymes (e.g., some antihistamines, quinidine, cisapride, permethrin) may result in increased blood concentrations; therefore, the combination of these two drugs is contraindicated.
Drug Interaction Table
The interactions between voriconazole and other drugs are detailed in the table below (“QD” for once daily, “BID” for twice daily, “TID” for three times daily, “ND” for undetermined). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the ratio of the geometric mean of each parameter, within (↔), below (↓), or above (↑) the 80-125% range. An asterisk (*) indicates an interaction between the two. auct, auct and auc0-¥ indicate 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: combination is prohibited; combination requires dose adjustment and close clinical and/or biological monitoring; and finally, there are no significant pharmacokinetic interactions, but may be of concern in clinical treatment.
Drug name [mechanism of interaction] Geometric mean change in interaction (%) Recommendations for co-administration
Astemizole, cisapride, pimozide, quinidine, and terfenadine
[Although not studied, increased blood levels of these drugs cause prolongation of the QT interval and occasionally lead to tip-twisting ventricular tachycardia.
Combination of carbamazepine and long-acting barbiturates (e.g., phenobarbital, meperidine) is prohibited
[Although not studied, carbamazepine and long-acting barbiturates may significantly reduce voriconazole blood levels.
Combination of efavirenz (a non-nucleoside reverse transcriptase inhibitor) is prohibited
[CYP450 inducer; CYP3A4 inhibitor and substrate]
Efavirenz 400 mg once daily in combination with voriconazole 200 mg twice daily**
Efavirenz 300 mg once daily in combination with voriconazole 400 mg twice daily
Low dose (300 mg once daily in combination with voriconazole, which is administered at 400 mg twice daily)*
Efavirenz Cmax
38% efavirenz AUCt
44% Efavirenz Cmax
Voriconazole Cmax
¯ 61% voriconazole AUCt
¯ 77%
Compared with efavirenz alone (600 mg once daily)
Efavirenz Cmax ↔ Efavirenz AUCt
17%
Compared with voriconazole alone (200 mg twice daily), the
Voriconazole Cmax
23% Voriconazole AUCt
¯ 7%
Concomitant administration of this product at standard doses (400 mg once daily or higher) with efavirenz is prohibited.
Voriconazole may be combined with efavirenz when 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 each time. When voriconazole treatment is discontinued, efavirenz should be returned to its initial dose.
Ergot alkaloids (e.g., ergotamine and dihydroergotamine)
[CYP3A4 substrates] Although not studied, voriconazole may increase blood levels of ergot alkaloids, leading to ergot toxicity.
Combination is prohibited
Rifabutin
[Potent CYP450 inducer].
300 mg per dose, once daily.
300 mg once daily.
(In combination with voriconazole, the dosage of voriconazole is 350 mg twice daily)*
300 mg once daily.
(In combination with voriconazole, voriconazole is administered at a dosage of 400 mg twice daily)*
Voriconazole Cmax
¯ 69% voriconazole AUCt
¯ 78%
Compared to voriconazole alone (200 mg per dose, twice daily)
Voriconazole Cmax
¯ 4% voriconazole AUCt
¯ 32%
Rifabutin Cmax
195% Rifabutin AUCt
331%
Compared with voriconazole alone (200 mg per dose, twice daily)
Voriconazole Cmax
104% Voriconazole AUCt
87% Concomitant use of voriconazole and rifabutin should be avoided unless the benefits outweigh the harms on balance.
The maintenance dose of voriconazole may be increased to 5 mg/kg (administered intravenously twice daily) or from 200 mg per oral dose twice daily to 350 mg per oral dose twice daily (or from 100 mg per oral dose twice daily to 200 mg per oral dose twice daily for patients weighing <40 kg).
When rifabutin is used in combination with voriconazole, close monitoring of patients for complete blood counts and adverse reactions associated with rifabutin (e.g., uveitis) is recommended. Rifampin (600 mg per dose, once daily)
[potent CYP450 inducer] voriconazole Cmax
¯ 93% voriconazole AUCt
¯ 96% Combination prohibited
Ritonavir (protease inhibitor)
[Potent CYP450 inducer; CYP3A4 inhibitor and substrate]
High dose (400 mg per dose, twice daily)
Low dose (100 mg per dose, 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.
Combination of voriconazole with low-dose ritonavir (100 mg twice daily) should be avoided unless the benefit/risk assessment of the patient supports the use of voriconazole.
St. John’s Wort.
[CYP450 inducer; P-gp inducer]
300 mg per dose, 3 times daily.
(in combination with a single dose of voriconazole 400 mg) The results of a published independent study showed that, when combined, the two
Voriconazole AUC0-∞
¯ 59%
Combination prohibited
everolimus
[CYP3A4 substrate, PgP substrate] Although not studied, voriconazole may significantly increase the blood concentration of everolimus.
The combination of voriconazole and everolimus is not recommended because voriconazole may significantly increase blood concentrations of everolimus.
Fluconazole (200 mg once daily) [CYP2C9, CYP2C19 and CYP3A4 inhibitor]
Voriconazole Cmax
57% voriconazole AUCt
79%
Fluconazole Cmax ND Fluconazole AUCt ND No method has been identified to reduce the dose or frequency of administration of voriconazole and fluconazole to eliminate this effect. Monitoring for voriconazole-related adverse reactions is recommended when fluconazole is followed by voriconazole. Phenytoin.
[CYP2C9 substrate and potent CYP450 inducer]
300 mg per dose, once daily.
300 mg per dose, once daily.
(In combination with voriconazole, the dosage of voriconazole is 400 mg per dose, twice daily)*
Voriconazole Cmax
¯ 49% voriconazole AUCt
¯ 69%
Phenytoin Cmax
67% Phenytoin AUCt
81%
Compared with voriconazole (200 mg per dose, twice daily)
Voriconazole Cmax
34% Voriconazole AUCt
39% Simultaneous voriconazole and phenytoin combination should be avoided unless the benefits outweigh the harms on balance. Close monitoring of phenytoin blood levels is recommended.
Phenytoin may be combined with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg (IV twice daily) or from 200 mg orally twice daily to 400 mg orally twice daily (or from 100 mg orally twice daily to 200 mg orally twice daily for patients <40 kg).
Anticoagulants
Warfarin (single dose of 30 mg in combination with voriconazole, which is administered at a dosage of 300 mg twice daily)
[CYP2C9 substrate]
Other oral coumarins (e.g., phenylpropylhydroxycoumarin, vinblastine coumarin)
[CYP2C9 and CYP3A4 substrates]
The combination of the two prolongs the prothrombin time by up to approximately two times the normal time.
Although not studied, voriconazole may increase the blood levels of coumarins, which in turn may lead to prolonged prothrombin time.
When anticoagulants are used in combination with voriconazole, it is recommended that the patient’s prothrombin time or other appropriate anticoagulation test be monitored closely and that the anticoagulant dose be adjusted accordingly.
Benzodiazepines (e.g., midazolam, triazolam, alprazolam)
[Although not clinically studied, voriconazole may increase the blood levels of benzodiazepines metabolized by CYP3A4, which in turn may lead to a prolonged sedative effect of these drugs.
A reduction in the dose of benzodiazepines should be considered when the two are used in combination. Immunosuppressants
[CYP3A4 substrate]
Sirolimus (single dose 2 mg)
Cyclosporine (long-term cyclosporine therapy in stable renal transplant patients)
Tacrolimus (0.1 mg/kg per dose, once daily)
The results of a published independent study showed that after combining the two.
Sirolimus Cmax
6.6-fold sirolimus AUC0-∞
11 times
Cyclosporine Cmax
13% cyclosporine AUCt
70%
Tacrolimus Cmax
117% Tacrolimus AUCt
221%
Combination of voriconazole with sirolimus is prohibited.
When starting voriconazole in patients already receiving cyclosporine therapy, it is recommended to reduce the dose of cyclosporine by half and to closely monitor the blood concentration of cyclosporine. Increased blood levels of cyclosporine can cause nephrotoxicity. Close monitoring of cyclosporine blood levels is still required after discontinuation of this product, and the dose of cyclosporine may be increased if necessary.
When starting voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to 1/3 of the original dose and that tacrolimus blood levels be monitored closely. Increases in tacrolimus blood levels can cause nephrotoxicity. Close monitoring of tacrolimus blood levels is required after discontinuation of the drug, and the dose of tacrolimus may be increased if necessary.
Long-acting opioids
[CYP3A4 substrate]
Oxycodone (single dose 10 mg)
The results of a published independent study have shown that, when combined, both
Oxycodone Cmax
1.7 times oxycodone AUC0-∞ 3.6 times When combined with voriconazole, lower doses of oxycodone and other long-acting opioids metabolized via CYP3A4 (e.g., hydrocodone) should be considered, and some adverse effects associated with opioids should be monitored frequently if necessary.
Methadone (32 to 100 mg per dose, once daily)
[CYP3A4 substrate] R-methadone (active conformation) Cmax
31% R-methadone (active conformation) AUCt
47% S-methadone Cmax
65% S-methadone AUCt
103% When combined with voriconazole, close and frequent monitoring for methadone-related adverse effects and toxicity, including prolonged QTc interval, is recommended. If necessary, reduce the dose of methadone.
Non-steroidal anti-inflammatory drugs (NSAIDs)
[CYP2C9 substrate]
Ibuprofen (single dose 400 mg)
Diclofenac (single dose 50mg)
S-ibuprofen Cmax
20% S-ibuprofen AUC0-∞
100%
Diclofenac Cmax
114% Diclofenac AUC0-∞ 78%
When combined with voriconazole, close monitoring for adverse reactions and toxicity associated with NSAIDs is recommended. Dose reduction of NSAIDs may be required 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 other proton pump inhibitors of CYP2C19 substrates, resulting in increased blood levels of these drugs.
No dose adjustment of voriconazole is required.
When starting concomitant voriconazole in patients who are taking 40 mg or more daily doses of omeprazole, it is recommended that the omeprazole dose be reduced by half.
Oral contraceptives*.
[CYP3A4 substrate; CYP2C19 inhibitor]
Ethinylestradiol / ethinylestradiol (1 mg per dose/0.035 mg once daily) Ethinylestradiol Cmax
36% Ethinylestradiol AUCt
61%
Ethinylestradiol Cmax
15% Ethinylestradiol AUCt
53%
Voriconazole Cmax
14% Voriconazole AUCt
46% It is recommended to monitor for adverse reactions related to oral contraceptives in addition to those related to voriconazole.
Short-acting opioids
[CYP3A4 substrate]
Alfentanil (20 mg/kg per dose, once daily with concomitant naloxone)
Fentanyl (5 mg/kg per dose, once daily) Results of a published independent study showed that, when combined, both
Alfentanil AUC0-∞
6 times
The results of one published independent study showed that after combining the two.
Fentanyl AUC0-∞
1.34 times
Dose reduction of alfentanil, fentanyl and other short-acting opioids similar in structure and metabolized by CYP3A4 (e.g., sufentanil) should be considered when combined with voriconazole. Close and frequent monitoring for respiratory depression and other opioid-related adverse reactions is recommended and should be extended as appropriate. Statins (e.g., lovastatin)
[CYP3A4 substrate] Although not clinically studied, voriconazole in combination with statins may increase blood levels of statins metabolized via CYP3A4, which may lead to rhabdomyolysis.
A reduction in the dose of statins should be considered when combining the two drugs. Sulfonylureas (e.g., toluenesulfonylurea, glipizide, glibenclamide)
[CYP2C9 substrate] Although not studied, voriconazole may increase the blood levels of sulfonylureas, thereby causing hypoglycemia.
Close monitoring of the patient’s blood glucose is recommended. Dose reduction of sulfonylureas should be considered. Vinca alkaloids (e.g., vincristine and pergolide)
[CYP3A4 substrates] Although not studied, voriconazole may increase blood concentrations of perphenazine alkaloids, resulting in neurotoxicity.
Dose reductions of vincristine alkaloids should be considered.
Other HIV protease inhibitors (e.g., saquinavir, amprenavir, and nelfinavir)* [CYP3A4 substrates and inhibitors] No relevant clinical studies have been conducted. In vitro studies suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors, and that HIV protease inhibitors may also inhibit the metabolism of voriconazole.
Any possible drug toxicity/or drug failure should be closely monitored, and dose adjustments may also be required for both.
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, nevirapine)* [CYP3A4 substrates, inhibitors or CYP450 inducers] have not been studied in clinical studies. In vitro studies have shown that NNRTIs may inhibit the metabolism of voriconazole, while voriconazole may also inhibit the metabolism of NNRTIs.
The effect of efavirenz on the metabolism of voriconazole in vivo suggests the possibility of induction of voriconazole metabolism by non-nucleoside reverse transcriptase inhibitors.
Any potential for drug toxicity/or drug failure should be closely monitored, and dose adjustments may also be required for both.
Cimetidine (400 mg twice daily) [non-specific CYP450 inhibitor and increased gastric acid pH] Voriconazole Cmax
18% Voriconazole AUCt
23% No dose adjustment required Digoxin (0.25 mg once daily) [P-gp substrate] Digoxin Cmax ↔ Digoxin AUCt ↔ No dose adjustment required Indinavir (800 mg once daily) [CYP3A4 inhibitor and substrate] Indinavir Cmax ↔ Indinavir AUCt ↔
Voriconazole Cmax ↔ Voriconazole AUCt ↔ No dose adjustment required Macrolide antibiotics
Erythromycin (1 g per dose, 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 is required
Mescaline (single dose 1 g)
[uridine diphosphate glucuronosyltransferase substrate]
mescaline Cmax ↔ mescaline AUCt ↔ No dose adjustment required prednisone (single dose 60 mg)
[CYP3A4 substrate]
Prednisone Cmax
11% Prednisone AUC0-∞
34% No dose adjustment required Ranitidine (150 mg twice daily) [Increased gastric acid pH] Voriconazole Cmax
and AUCt ↔ No dose adjustment required
[Drug overdose
There were three pediatric patients in the clinical study who experienced accidental drug overdose. These patients received five times the recommended intravenous dose of voriconazole, and one case of photophobia lasting 10 minutes occurred.
There is no known antidote for voriconazole.
The known clearance of voriconazole by hemodialysis is 121 ml/min,. Therefore, hemodialysis helps to remove voriconazole from the body in case of drug overdose.
Pharmacology and Toxicology
Pharmacological action
Mechanism of action
The mechanism of action of voriconazole is to inhibit the cytochrome P450-mediated 14α-sterol demethylation in the fungus, thus inhibiting the biosynthesis of ergosterol. In vitro tests have shown that voriconazole has broad-spectrum antifungal effects. Voriconazole was antibacterial against Candida spp. (including fluconazole-resistant Candida cladococcalis, Candida smoothis and Candida albicans resistant strains) and fungicidal against all Aspergillus spp. fungi tested. In addition, voriconazole is also fungicidal in vitro against other pathogenic fungi, including genera with low susceptibility to existing antifungals, such as Actinomyces foot and Fusarium spp.
Microbiology
Clinical studies have shown voriconazole to be clinically effective against Aspergillus spp. including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Aspergillus oryzae; Candida spp. including Candida albicans, Candida smoothus, Candida klebsiella, Candida subsmoothus, Candida tropicalis, and some Candida dublini, Candida ordinarius, and Candida gilimontaneus; and Actinomyces spp. including Aspergillus tip and Aspergillus polymorpha and Fusarium spp. Efficacy (defined as improvement or cure).
Other fungal infections for which voriconazole treatment is effective (usually cured or improved) include Streptomyces, Bacillus dermatitidis, Bacillus cephalosporus, Bacillus branchioides, Clostridium vulgaris, Corynebacterium corneum, Cryptococcus novicola, Cryptococcus rotundus, Echinococcus vulgaris, Peptostreptomyces, Podococcus madurensis, Penicillium spp., Penicillium spp. including Penicillium manifaciens, Rotten wood bottle mold, Short broom mold, and Trichosporon spp. Trichosporon albicans infections.
In vitro tests have observed antibacterial effects of voriconazole against the following clinically isolated fungi, including Penicillium spp, Streptomyces spp, Bipolaris spp, Bacillus spp, and Histoplasma capsulatum. Voriconazole can inhibit most strains in the concentration range of 0.05 to 2 μg/ml.
In vitro tests have shown that voriconazole has antibacterial effects on Aspergillus spp. and Sporotrichum spp. but its clinical significance is unclear.
Specimens should be collected for fungal culture and other relevant laboratory tests (serology and histopathology) should be performed prior to treatment in order to isolate and identify the pathogenic organism. Anti-infective therapy must be administered until culture results and other laboratory tests are available, but once results are obtained, the drug regimen should be adjusted accordingly.
Drug sensitivity test methods
Aspergillus spp. and other filamentous fungi
Fold point criteria for Aspergillus spp. and other filamentous fungi have not been established.
The fold point criteria for Candida spp. voriconazole against Candida spp. apply only to the American Clinical and Laboratory Standardization Institute (CLSI) M27 micro
Broth dilution method for 48-hour minimum inhibitory concentration (MIC) readings or M44 paper diffusion method for 24-hour inhibition circle diameter readings.
Micro broth dilution technique: This method is used to quantify the minimum inhibitory concentration (MIC) of antifungal drugs, by which the susceptibility of Candida spp. to antifungal drugs can be estimated.MIC should be determined at hour 48 using a standardized method that requires a standard inoculum concentration using the micro dilution method (broth) and a standard voriconazole powder concentration.MIC values should be interpreted according to the fold points in the following table The criteria are interpreted.
Diffusion method technique: This qualitative method requires the measurement of the diameter of the inhibition circle and is capable of reproducibly assessing the susceptibility of Candida spp. to antifungal drugs. The standardized method requires the use of standardized inoculum concentrations and the use of paper sheets saturated with 1 µg voriconazole at the 24th hour to test the susceptibility of yeasts to voriconazole. The table below provides the fold point criteria for the paper diffusion method.
Voriconazole Susceptibility Criteria
Microvolume broth dilution method at 48 hours
(MIC in mg/ml) Paper diffusion method for 24 hours
(Diameter of inhibition circle in mm) Sensitive (S) Intermediary (I) Resistant (R) Sensitive (S) Intermediary (I) Resistant (R) Voriconazole £1.02.0 ³4.0³1714 to 16 £13 Note: The above table provides the fold points (μg/ml) for voriconazole against Candida spp.
Sensitive means that when the recommended dose of antifungal drug is applied, the drug concentration usually achieved can inhibit the strain at the site of infection. Intermediate means that the infection caused by the causative strain can be effectively treated when the drug is administered at local physiological concentrations or when high doses of the drug are used. Resistant means that the drug concentration normally achievable when using a normal dosing regimen does not inhibit the causative strain and that the clinical effectiveness of the drug has not been reliably demonstrated in therapeutic studies for that strain of infection.
Quality Control
Standardized drug-sensitivity testing methods require the use of quality control microorganisms to ensure the accuracy of the technical approach to the test. The range values noted in the table below were determined using standard voriconazole powder and 1 μg paper.
Note: Quality control microorganisms are specific strains of microorganisms that have biological and fungal genetic expression characteristics associated with resistance mechanisms and have no clinical significance.
Acceptable quality control range for voriconazole as verified by drug sensitivity test results
Quality control strain micro broth dilution method for 48 hours
(MIC in mg/ml) Paper diffusion method for 24 hours
(Diameter of inhibition circle in mm) Near smooth Candida
ATCC 22019 0.03-0.2528-37 grams of Candida
ATCC 6258 0.12-1.0 16～25 Candida albicans
ATCC 90028 * 31 to 42* Due to extensive inter-laboratory variation in the initial QC studies, the QC range for this strain/antifungal combination has not been determined.
ATCC is a registered trademark of the American Standard Collection of Biological Products.
Activity in animal models
Voriconazole was effective 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 spp. [Candida albicans (including a strain with reduced susceptibility to fluconazole), Candida klebsiella and Candida smoothus] in a study with the following endpoints: prolonged survival of infected animals and/or target organ reduced fungal load. In one trial, voriconazole was effective in immunocompetent guinea pigs against C. tiposporium infection.
Drug resistance
In vitro resistance to voriconazole by Candida, Aspergillus, Actinomyces, and Fusarium spp. has not been adequately studied. The development of resistance in various types of fungi in the antimicrobial spectrum of voriconazole is not yet known.
It is possible that fungi with reduced susceptibility to fluconazole and itraconazole may also have reduced susceptibility to voriconazole, suggesting that cross-resistance may exist among these azoles. The relationship between cross-resistance and clinical efficacy has not been fully established. If a clinical case of an isolate exhibits cross-resistance, it may be necessary to change to another antifungal agent.
Toxicological studies
Repeated dosing toxicity
Repeated dosing toxicity studies suggest that the target organ of voriconazole is the liver. Similar to other antifungal agents, hepatotoxicity occurred in experimental animals at plasma exposures equivalent to those achieved with human therapeutic doses. Experiments in rats, mice and dogs have found that voriconazole also induces microscopic lesions in the adrenal glands.
Genotoxicity
Teratogenic effects of voriconazole (mainly chromosome breakage) were observed when voriconazole was added during in vitro human lymphocyte culture. No genotoxicity of voriconazole was observed in the Ames assay, CHO assay, mouse micronucleus assay or DNA repair assay (unconventional DNA synthesis assay).
Reproductive toxicity
At exposures similar to human therapeutic doses, voriconazole did not impair reproduction in either male or female rats. Voriconazole was teratogenic in rats and embryotoxic in rabbits at systemic exposures equivalent to those achieved with human therapeutic doses. In perinatal studies, rats given exposures lower than those achieved with human therapeutic doses had prolonged gestation and prolonged labor, causing obstructed labor leading to maternal death and reduced survival of perinatal pups. Similar to other azole antifungals, the mechanism by which voriconazole affects labor is likely to be species-specific, including a reduction in estradiol levels.
Carcinogenicity
A 2-year study of voriconazole carcinogenicity was conducted in rats and mice. Rats were given voriconazole 6, 18, or 50 mg/kg (0.2, 0.6, or 1.6 times the usual maintenance dose on a mg/m2 basis, respectively) orally. Hepatocellular adenomas were detected in female mice given 50 mg/kg voriconazole, and hepatocellular carcinomas were detected in male mice given 6 mg/kg and 50 mg/kg doses. Hepatocellular adenoma was detected in mice of both sexes given 10, 30 or 100 mg/kg voriconazole (0.1, 0.4 or 1.4 times the usual maintenance dose, respectively, on a mg/m2 basis) orally, and hepatocellular carcinoma was also detected in male mice given 1.4 times the usual maintenance dose of voriconazole.
[Pharmacokinetics].
The following data are from the literature.
1. General pharmacokinetic characteristics
Pharmacokinetic studies of voriconazole were conducted in healthy subjects, special populations and patients, respectively. The pharmacokinetic characteristics (including rapid absorption, stable absorption, in vivo accumulation and non-linear pharmacokinetics) of voriconazole administered orally twice daily at 200 mg or 300 mg for 14 days in patients with risk factors for trichinosis (mainly malignancies of the lymphatic system or hematopoietic tissues) were found to be consistent with those of healthy subjects.
Because voriconazole is saturated in metabolism, its pharmacokinetics are nonlinear, with the proportional increase in exposure being much greater than the proportional increase in dose. Thus if the oral dose is increased from 200 mg twice daily to 300 mg twice daily, the estimated exposure (AUCτ) increases by a mean of 2.5-fold. A maintenance dose of 200 mg orally (or 100 mg for patients weighing less than 40 kg) achieves an approximate voriconazole exposure of 3 mg/kg IV. A maintenance dose of 300 mg orally (150 mg for patients weighing less than 40 kg) achieves an approximate exposure of 4 mg/kg intravenously. When given at the recommended loading dose (intravenous or oral), the subject’s blood levels approached steady-state concentrations within 24 hours. If no loading dose is given, most subjects reach steady-state concentrations by approximately day 6 after multiple doses administered twice daily.
Absorption
Oral absorption of this product is rapid and complete, with peak blood concentrations reached 1 to 2 hours after administration. The absolute bioavailability after oral administration is approximately 96%. When multiple doses are administered and taken together with a high-fat meal, the peak blood concentration (Cmax) and the area under the drug-time curve (AUCτ) between doses of voriconazole are reduced by 34% and 24%, respectively. Gastric fluid pH changes had no effect on the absorption of this product.
Distribution
The volume of distribution of voriconazole at steady-state concentrations was 4.6 l/kg, suggesting a wide distribution in tissues. The plasma protein binding rate was approximately 58%. In one study, cerebrospinal fluid from eight patients was examined and voriconazole was detected in the cerebrospinal fluid of all patients.
Biotransformation
In vitro assays have shown that voriconazole is metabolized by hepatic cytochrome P450 isozymes, CYP2C19, CYP2C9 and CYP3A4.
The pharmacokinetics of voriconazole varies widely between individuals.
In vivo studies suggest an important role for CYP2C19 in the metabolism of this product, an enzyme with genetic polymorphisms, e.g., 15-20% of Asians are weak metabolizers, compared to only 3%-5% of whites and blacks. Studies in healthy whites and healthy Japanese showed that drug exposure (AUCτ) was on average 4-fold higher in weak metabolizers and 2-fold higher in heterozygous strong metabolizers than in pure congenic strong metabolizers.
The major metabolite of voriconazole is N-oxide, which accounts for approximately 72% of the plasma. This metabolite has weak antibacterial activity and has no significant effect on the pharmacological action of voriconazole.
Clearance
Voriconazole is mainly metabolized by the liver, and less than 2% of the drug is excreted in its original form via urine.
After administration of radioisotope-labeled voriconazole, approximately 80% and 83% of the radioactivity was recovered in the urine in multiple intravenous and multiple oral dose administrators, respectively. The vast majority of the radioactivity (>94%) was excreted in the urine within 96 hours after administration (intravenous drip or oral).
The terminal half-life of voriconazole is dose dependent. The terminal half-life after oral administration of 200 mg is approximately 6 hours. Due to its non-linear pharmacokinetic characteristics, the terminal half-life value cannot be used to predict the accumulation or clearance of voriconazole.
2. Pharmacokinetic-pharmacodynamic relationship
In 10 treatment studies, the median mean and maximum plasma concentrations in subjects were 2425 ng/ml (interquartile range 1193 to 4380 ng/ml) and 3742 ng/ml (interquartile range 2027 to 6302 ng/ml), respectively. Mean, maximum and minimum blood concentrations were not found to be associated with treatment outcome in the study and this relationship was not explored in the prophylaxis study.
Analysis of the pharmacokinetics-pharmacodynamics of clinical study data revealed that voriconazole blood concentrations were associated with abnormal liver function tests and visual disturbances. Dose adjustment was not explored in the prevention study.
3. Pharmacokinetics in special populations
Gender
In a multi-dose oral dosing study, Cmax and AUCτ were 83% and 113% higher, respectively, in healthy young women compared to healthy young men (18-45 years of age). In the same study, Cmax and AUCτ were not significantly different in healthy older women compared with healthy older men (≧65 years).
No dose adjustment was required for patients of different genders in clinical applications. The safety and blood levels of voriconazole were similar in male and female patients; therefore, no dose adjustment by gender was required.
Older Adults
In a multi-dose oral dosing study, Cmax and AUCτ were 61% and 86% higher, respectively, in healthy older men (≧65 years) compared with healthy younger men (18-45 years). However, Cmax and AUCτ were not significantly different in healthy older women (≧ 65 years) compared with healthy younger women (18-45 years).
Dosing was not adjusted for age in the treatment studies. The relationship between blood levels and age was observed in the study. The safety profile of voriconazole was similar in younger and older patients; therefore, no dose adjustment was required for the application of this product in older patients.
Pediatric Population
The recommended dose for pediatric and adolescent patients is based on the results of a population pharmacokinetic analysis of 112 immunocompromised pediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. In three pediatric pharmacokinetic studies, multiple doses of 3, 4, 6, 7, and 8 mg/kg twice daily intravenously and multiple doses of 4 mg/kg, 6 mg/kg, and 200 mg twice daily orally (using an oral dry suspension) were evaluated. In an adolescent pharmacokinetic study, a loading dose of 6 mg/kg administered intravenously twice daily on day 1, followed by a maintenance dose of 4 mg/kg administered intravenously twice daily, and a maintenance dose of 300 mg tablets administered orally twice daily were evaluated. Greater inter-subject variability was observed in pediatric patients compared to adults.
Comparison of population pharmacokinetic data in children and adults showed that the total exposure (AUCt) following an intravenous 9 mg/kg loading dose in children is expected to be comparable to the total exposure following an intravenous 6 mg/kg loading dose in adults. The total exposure in children following intravenous 4 mg/kg and 8 mg/kg maintenance doses administered twice daily is expected to be comparable to the total exposure in adults following intravenous 3 mg/kg and 4 mg/kg administered twice daily, respectively. The expected total exposure after oral administration of a maintenance dose of 9 mg/kg twice daily (maximum dose of 350 mg) in children is comparable to the total exposure after oral administration of 200 mg twice daily in adults. The voriconazole drug exposure provided by an intravenous drip of 8 mg/kg was approximately 2-fold higher than that provided by an oral dose of 9 mg/kg.
Relative to adults, pediatric patients have higher elimination capacity with higher maintenance doses by IV drip due to larger liver to body weight ratios, but oral bioavailability in pediatric patients may be limited by malabsorption and low body weight at young ages. In such cases, intravenous voriconazole is recommended.
Most adolescent patients with voriconazole drug exposure are comparable to adults receiving the same dosing regimen. Lower voriconazole drug exposure was observed in some low weight adolescents, and it is likely that the metabolic profile of voriconazole use in these subjects is similar to that of children. Based on the results of the population pharmacokinetic analysis, it is recommended that adolescents 12 to 14 years of age weighing less than 50 kg receive pediatric doses (see [DOSAGE AND ADMINISTRATION]).
Renal Dysfunction
No significant changes in voriconazole pharmacokinetic parameters were observed in patients with normal renal function and in patients with mild (creatinine clearance of 41-60 ml/min) to severe (creatinine clearance of <20 ml/min) renal impairment who received a single oral dose of 200 mg of this product. The plasma protein binding rate was similar in those with different degrees of renal impairment. See the dosing and renal function monitoring recommendations in [Dosage] and [Precautions].
In Hepatic Impairment
After a single oral dose of voriconazole 200 mg, the AUCτ was 233% higher in patients with mild to moderate cirrhosis (Child-Pugh A and B) than in those with normal hepatic function. Protein binding was unaffected by hepatic impairment.
In a multi-dose oral dosing study, a maintenance dose of 100 mg twice daily in patients with moderate cirrhosis (Child-Pugh B) and 200 mg twice daily in those with normal liver function resulted in similar AUCτ in both. No pharmacokinetic information is available for patients with severe cirrhosis (Child-Pugh C). For recommended dose and monitoring in case of hepatic impairment, see [Dosage] and [Precautions].
Storage
Store airtight at room temperature (10~30℃).
Package
HDPE bottle; 30 tablets/bottle.
Expiration date
24 months
【Execution standard
Approval Number】
【Manufacturer】
Company Name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal Code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web
Address: www.huahaipharm.com