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Vfend is antifungal.
Voriconazole is a broad-spectrum antifungal medication that belongs to the group of antibiotics with a triazole structure.
The mechanism of action of voriconazole is associated with inhibition of demethylation of 14α-sterol mediated by fungal cytochrome P450; This reaction is a key step in ergosterol biosynthesis.In vitro voriconazole has a broad spectrum of antifungal activity againstCandida spp. (including strainsS. krusei, resistant to fluconazole and resistant strainsC. glabrata andC. albicans), and also shows a fungicidal effect on all studied strainsAspergillus spp. and pathogenic fungi that have become relevant recently, including Scedosporium orFusarium which are limited in sensitivity to existing antifungal agents. Clinical efficacy has been demonstrated in infections caused by Aspergillus spp., includingA. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., includingC. albicans, C. glabrata, S. krusei, C. parapsilosis, and C. tropicalis, as well as for a limited number of strainsS. dubliniensis, S. inconspicua andS. guilliermondii, Scedosporium spp., includingS. apiospermum, S. prolificans andFusarium spp.
Other fungal infections in which the drug was used (often with a partial or complete response) included isolated cases of infections caused byAlternaria spp., Blastomyces dermatitidi includingR. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis andTrichosporon spp., includingT. beigelii.
In vitro demonstrated voriconazole activity against clinical strainsAcremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 to 2 μg / ml.
In vitro voriconazole activity was detected in relation toCurvularia spp. andSporothrix spp., however, its clinical significance is unknown.
The pharmacokinetics of voriconazole were studied in healthy people, members of special groups and patients. The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism. As the dose is increased, a disproportionate (more pronounced) increase in AUC (area under the concentration-time curve) is observed. According to calculations, an increase in the oral dose from 200 mg 2 times a day to 300 mg 2 times a day leads to an increase in AUCτ on average 2.5 times. With oral injection of shock doses, plasma concentrations approach equilibrium within the first 24 hours. If the patient does not receive a loading dose, then with repeated use of voriconazole 2 times a day, the drug cumulates, and equilibrium plasma concentrations are reached by the 6th most patients. Voriconazole is rapidly and almost completely absorbed after ingestion; Cmax Achieved 1–2 hours after administration. Bioavailability of voriconazole when administered is 96%. Repeated voriconazole intake with fatty foods Cmax and AUCτ reduced by 34 and 24% respectively. The absorption of voriconazole does not depend on the pH of the gastric juice. The estimated volume of voriconazole distribution in the equilibrium state is 4.6 l / kg, which indicates a wide distribution of the drug in the tissue. Plasma protein binding is 58%. Voriconazole is determined in the cerebrospinal fluid.
The pharmacokinetics of voriconazole is characterized by high interindividual variability. Researchin vitro have shown that voriconazole is metabolized by the action of the hepatic isoenzymes of cytochrome P450 - CYP2C19, CYP2C9 and CYP3A4. Researchin vivo also suggest that CYP2C19 plays an important role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, a reduced metabolism of voriconazole can be expected in representatives of 15–20% of the Asiatic and 3-5% of the Caucasoid and Negroid races. Studies in Caucasians and Japanese have shown that in patients with low AUC metabolismτ voriconazole is on average 4 times higher than in homozygous patients with active metabolism. In heterozygous patients with active AUC metabolismτvoriconazole is on average 2 times higher than that of homozygous. The main metabolite of voriconazole is N-oxide, which accounts for 72% of the circulating labeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall effect of voriconazole.Voriconazole is excreted by metabolism in the liver, less than 2% of the drug dose is excreted unchanged in the urine. After repeated IV and oral administration of labeled voriconazole, approximately 80% and 83% of the radioactive dose are detected in the urine, respectively. Most (> 94%) of the total dose is eliminated during the first 96 hours after oral administration and / in use. Terminal T1/2 voriconazole depends on the dose and is approximately 6 hours when taking the drug orally at a dose of 200 mg. Due to the nonlinearity of pharmacokinetics terminal T1/2 does not allow to predict cumulation or elimination of voriconazole.
Pharmacokinetics in Special Groups
Floor.By oral reapplication Cmax and AUCτ in healthy young women were 83 and 113%, respectively, higher than in young healthy men (18–45 years). Significant DifferencesCmax and AUCτ in healthy elderly men and healthy elderly women (≥65 years old) not. The need for dose adjustment depending on gender was not noted. Plasma concentrations in men and women are similar.
Age. Repeated oral administration Cmax and AUCτ in healthy older men (≥65 years), 61 and 86%, respectively, higher than in healthy young men (18–45 years). Significant Differences Cmax and AUCτhealthy elderly women (≥65 years) and healthy young women (18–45 years old) do not. The safety of voriconazole in young and elderly patients is the same, and therefore dose adjustment in the elderly is not required. The average equilibrium plasma concentrations of the drug in children receiving the drug at a dose of 4 mg / kg every 12 hours are comparable to those in adults receiving voriconazole at a dose of 3 mg / kg every 12 hours. The average concentration was 1186 ng / ml in children and 1155 ng / ml in adults. In this regard, the recommended maintenance dose for children aged 2 to 12 years is 4 mg / kg every 12 hours.
Impaired renal function.With a single dose of voriconazole orally at a dose of 200 mg, the pharmacokinetics of voriconazole in patients with normal renal function and patients from mild (Clcreatinin 41–60 ml / min) to severe (Cl creatinine -
Liver dysfunction.After a single oral dose of voriconazole at a dose of 200 mg AUC of evoriconazole in patients with mild or moderately severe liver cirrhosis (Child-Pugh A and B) is 233% higher than in patients with normal liver function. Impaired liver function does not affect the connection of voriconazole with plasma proteins. Repeated oral administration of AUC τvoriconazole is comparable in patients with moderately severe liver cirrhosis (Child-Pugh B) who received the drug at a maintenance dose of 100 mg 2 times a day, and in patients with normal liver function who received voriconazole at a dose of 200 mg 2 times a day. There are no data on pharmacokinetics in patients with severe liver cirrhosis (Child-Pugh C).
- Invasive aspergillosis.
- Severe invasive forms of candidal infections (including C. krusei).
- Candida esophagus.
- Severe fungal infections caused by Scedosporium spp and Fusarium spp.
- Other severe fungal infections with intolerance or refractoriness to other drugs.
- Prevention of “breakthrough” fungal infections in febrile patients at high risk (allogeneic bone marrow recipients in patients with relapsed leukemia).
1 tablet contains:
Active substance: voriconazole 200 mg;
Excipients: lactose monohydrate, pregelatinized starch, croscarmelose sodium, povidone, magnesium stearate;
Shell:Opadry white (hypromellose, titanium dioxide, lactose monohydrate, glycerol triacetate
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Dosage and Administration
Applied orally or parenterally in the form of infusion.
The dose is set individually, depending on the evidence, the age and body weight of the patient, the treatment regimen.
On the part of the organism as a whole: very often - fever, peripheral edema; often - chills, asthenia, chest pain, reactions and inflammation at the injection site, flu-like syndrome.
Since the cardiovascular system: often - lower blood pressure, thrombophlebitis, phlebitis; rarely - atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias; very seldom - supraventricular tachycardia, complete AV block, bundle of the bundle of His, nodular arrhythmias, ventricular tachycardia (including ventricular flutter), prolongation of the QT interval, ventricular fibrillation.
On the part of the digestive system: very often - nausea, vomiting, diarrhea, abdominal pain; often - increased activity of ALT, AST, alkaline phosphatase, LDH, GGT and plasma bilirubin levels, jaundice, cheilitis, cholestasis; rarely - cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, edema of the tongue, peritonitis; very rarely - pseudomembranous colitis, hepatic coma. In patients with serious underlying diseases (malignant hematological diseases) with the use of voriconazole, cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular insufficiency, leading to death) were rarely observed.
On the part of the endocrine system: rarely - adrenal insufficiency; very rarely - hyperthyroidism, hypothyroidism.
Allergic reactions: rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria; very rarely - angioedema, erythema multiforme. With intravenous infusion described anaphylactoid reactions, including hot flashes, fever, sweating, tachycardia, chest tightness, shortness of breath, fainting, itching, rash.
On the part of the hematopoietic system: often - thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia; rarely - lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, inhibition of bone marrow hematopoiesis; very rarely - lymphangitis.
Metabolism: often - hypokalemia, hypoglycemia; rarely - cholesterol.
On the part of the musculoskeletal system: often - back pain; rarely - arthritis.
From the side of the central nervous system and peripheral nervous system: very often - headache; often - dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesias; rarely - ataxia, cerebral edema, intracranial hypertension, hypoesthesia, nystagmus, dizziness, fainting; very rarely - Guillain-Barre syndrome, oculomotor crisis, escrapiramide syndrome.
On the part of the respiratory system: often - respiratory distress syndrome, pulmonary edema, sinusitis.
Dermatological reactions: very often - a rash; often - itching, maculo-papular rash, photosensitivity, alopecia, exfoliative dermatitis, swelling of the face, purpura; rarely psoriasis; very rarely - discoid lupus erythematosus.
On the part of the senses: often - visual disturbances (including violation / enhancement of visual perception, fog before the eyes, change in color perception, photophobia); rarely - blepharitis, optic neuritis, swelling of the nipple of the optic nerve, scleritis, taste disturbance, diplopia; very rarely - retinal hemorrhage, corneal clouding, optic nerve atrophy.
On the part of the urinary system: often - increased serum creatinine, acute renal failure, hematuria; rarely - an increase in residual nitrogen of urea, albuminuria, nephrite; very rarely - necrosis of the renal tubules.
Simultaneous medication - substrates of CYP3A4 - terfenadine, astemizole, cisapride, pimozide and quinidine; simultaneous administration of sirolimus; concomitant use of rifampicin, carbamazepine and long-acting barbiturates; simultaneous administration of ritonavir; simultaneous administration of efavirenz; simultaneous administration of ergot alkaloids (ergotamine, dihydroergotamine); hypersensitivity to voriconazole.
Vorikonazol is metabolized with the participation of CYP2C19, CYP2C9 and CYP3A4 isoenzymes. Inhibitors or inductors of these isoenzymes can, respectively, cause an increase or decrease in plasma concentrations of voriconazole.
With simultaneous use of rifampicin (inducer of CYP isoenzymes) at a dose of 600 mg / day, Cmax and AUC of voriconazole are reduced by 93% and 96%, respectively (the combination is contraindicated).
With simultaneous use with voriconazole, ritonavir (inducer of CYP isoenzymes, inhibitor and substrate CYP3A4) at a dose of 400 mg every 12 hours reduced Cmax in equilibrium and the AUC of voriconazole ingested, on average, by 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. It has been established that repeated oral administration of voriconazole does not have a pronounced effect on Cmax in the equilibrium state and AUC of ritonavir, which is also taken repeatedly (simultaneous use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).
When combined with powerful inducers of CYP isoenzymes with carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in plasma Cmax of voriconazole is possible, although their interaction has not been studied. This combination is contraindicated.
When combined with cimetidine (non-specific inhibitor of isoenzymes of CYP isoenzymes) in a dose of 400 mg 2 times / day, Cmax and AUC of voriconazole increase by 18% and 23%, respectively (dose adjustment of voriconazole is not required).
Vorikonazol inhibits the activity of CYP2C19, CYP2C9, CYP3A4, therefore it is possible to increase the plasma concentrations of drugs that are metabolized by these isoenzymes.
With simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide and quinidine, a significant increase in their plasma concentration is possible, which can lead to a prolongation of the QT interval and in rare cases to the development of ventricular fibrillation / flutter (the combination is contraindicated).
When combined, voriconazole increases Cmax and AUC of sirolimus (2 mg once) by 556% and 1014%, respectively (the combination is contraindicated).
With simultaneous use of voriconazole can cause an increase in the concentration of ergot alkaloids (ergotamine and dihydroergotamine) in plasma and the development of ergotism (this combination is contraindicated).
When used together in patients who have undergone kidney transplantation and are in a stable condition, voriconazole increases the Cmax and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of nephrotoxic reactions. When using voriconazole in patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine in 2 times and monitor its plasma levels. After the abolition of voriconazole, it is necessary to control the levels of cyclosporine and, if necessary, to increase its dose.
When combined, voriconazole increases Cmax and AUC of tacrolimus (used at a dose of 0.1 mg / kg once) by 117% and 221%, respectively, which may be accompanied by nephrotoxic reactions. When using voriconazole in patients receiving tacrolimus, it is recommended to reduce the dose of the latter to 1/3 and monitor its plasma levels. After the abolition of voriconazole, it is necessary to control the concentration of tacrolimus and, if necessary, to increase its dose.
The simultaneous use of voriconazole (at a dose of 300 mg 2 times / day) and warfarin (30 mg 1 time / day) was accompanied by an increase in the maximum prothrombin time to 93%.With the simultaneous appointment of warfarin and voriconazole, it is recommended to control the prothrombin time.
Vorikonazol when used together may cause an increase in plasma concentration of fenprocumone, acenocoumarol (substrates CYP2C9, CYP3A4) and prothrombin time. When using voriconazole in patients receiving coumarin preparations, it is necessary to monitor the prothrombin time at short intervals and adjust the dose of anticoagulants accordingly.
When used together, voriconazole may cause an increase in the concentration of sulfonylurea derivatives (CYP2C9 substrates) - tolbutamide, glipizide and glibenclamide in plasma and cause hypoglycemia. When applied simultaneously, it is necessary to carefully monitor blood glucose levels.
In vitro, voriconazole inhibits the metabolism of lovastatin (CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of statins metabolized by CYP3A4, which may increase the risk of developing rhabdomyolysis. With their simultaneous use, it is recommended to evaluate the feasibility of statin dose adjustment.
In vitro, voriconazole inhibits the metabolism of midazolam (CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and the development of a prolonged sedative effect. With the simultaneous use of these drugs is recommended to discuss the appropriateness of dose adjustment of benzodiazepine.
When used together, voriconazole can increase the content of vinca alkaloids (CYP3A4 substrates) - vincristine, vinblastine in plasma and lead to the development of neurotoxic reactions. It is recommended to discuss the feasibility of dose adjustment of vinca alkaloids.
Voriconazole increases Cmax and AUC of prednisolone (substrate CYP3A4), used at a dose of 60 mg once for 11% and 34%, respectively. Dose adjustment is not recommended.
With simultaneous use with voriconazole, efavirenz (CYP3A4 substrate, according to a number of studies, depending on the dose, is an inhibitor or inducer CYP3A4) used at a dose of 400 mg 1 time / day in an equilibrium state reduces Cmax and AUC of voriconazole on average by 61% and 77 % respectively. Voriconazole in equilibrium (400 mg orally every 12 hours on the first day, then 200 mg orally every 12 hours for 8 days) increases the equilibrium Cmax and AUC of efavirenz by an average of 38% and 44%, respectively (this combination is contraindicated).
When combined, phenytoin (CYP2С9 substrate and a powerful inducer of cytochrome P450 isoenzymes), used at a dose of 300 mg 1 time / day, reduces voriconazole Cmax and AUC by 49% and 69%, respectively; and voriconazole (400 mg 2 times / day) increases Cmax and AUC of phenytoin by 67% and 81%, respectively (if necessary, co-administration should carefully evaluate the ratio of the expected benefit and potential risk of combination therapy, as well as carefully monitor plasma phenytoin levels).
When used together, rifabutin (a cytochrome P450 inducer), used at a dose of 300 mg 1 time / day, reduces Cmax and AUC of voriconazole (200 mg 1 time / day) by 69% and 78%, respectively. When combined with rifabutin Cmax and AUC, voriconazole (350 mg 2 times / day) is 96% and 68%, respectively, of the indicators for voriconazole monotherapy (200 mg 2 times / day). When using voriconazole at a dose of 400 mg 2 times / day, Cmax and AUC, respectively, are 104% and 87% higher than with monotherapy with voriconazole at a dose of 200 mg 2 times / day. Voriconazole in a dose of 400 mg 2 times / day increases Cmax and AUC of rifabutin by 195% and 331%, respectively. With simultaneous treatment with rifabutin and voriconazole, it is recommended to regularly carry out a detailed analysis of the pattern of peripheral blood and monitor the undesirable effects of rifabutin (for example, uveitis).
When used together in a dose of 40 mg 1 time / day, omeprazole (inhibitor CYP2C19; substrate CYP2C19 and CYP3A4) increases the Cmax and AUC of voriconazole by 15% and 41%, respectively, and voriconazole increases the Cmax and AUC of omeprazole by 116% and 280%, respectively (hence , dose adjustment voriconazole is not required, and the dose of omeprazole should be reduced by 2 times). Consideration should be given to the possibility of drug interaction of voriconazole with other H + -K + -ATP-ase inhibitors, which are substrates of CYP2C19.
When used simultaneously with other HIV protease inhibitors (substrates and CYP3A4 inhibitors), the patient’s condition should be carefully monitored for possible toxic effects, since In vitro studies have shown that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) can mutually inhibit each other's metabolism.
Pregnancy and Lactation
Adequate and strictly controlled studies on the safety of voriconazole during pregnancy have not been conducted. In experimental studies on animals, it was found that voriconazole in high doses has a toxic effect on reproductive function. The possible risk to the person is not known.
Excretion of voriconazole in breast milk has not been studied.
Voriconazole should not be used during pregnancy and lactation, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus or infant.
During the period of treatment, women of reproductive age should use reliable methods of contraception.
To be used with caution in patients with severe hepatic insufficiency, with severe renal insufficiency (when administered parenterally), as well as in case of hypersensitivity to other drugs - azoles derivative.
Before treatment, correction of electrolyte disorders (hypokalemia, hypomagnesaemia and hypocalcemia) is required.
Sampling for culture and other laboratory tests (serological, histopathological) for the purpose of isolating and identifying pathogens should be carried out before the start of treatment. Therapy can be started before obtaining the results of laboratory tests, and then, if necessary, adjusted.
The use of voriconazole can lead to prolongation of the QT interval on the ECG, which is accompanied by rare cases of ventricular fibrillation-flutter in patients with multiple risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant therapy that could contribute to the development of adverse cardiovascular events). In patients with these potentially proarrhythmic conditions, voriconazole should be used with caution.
During treatment, liver function should be regularly monitored (if clinical signs of liver disease appear, the appropriateness of stopping therapy), kidney function (including serum creatinine level) should be discussed.
With the progression of dermatological reactions, the drug should be canceled.
During treatment, patients receiving voriconazole should avoid exposure to the sun and UV radiation.
With simultaneous use of voriconazole in patients receiving cyclosporine and tacrolimus, the dose of the latter should be adjusted and their plasma concentration should be monitored. After discontinuation of voriconazole, plasma concentrations of cyclosporine and tacrolimus should be estimated and, if necessary, increased their dose.
If necessary, the combined use of voriconazole and phenytoin should carefully evaluate the perceived benefits and potential risk of combination therapy and constantly monitor the level of phenytoin.
If necessary, the combined use of voriconazole and rifabutin should carefully evaluate the intended benefits and potential risks of combination therapy and carry it out under the control of the peripheral blood picture, as well as other possible undesirable effects of rifabutin.
The safety and efficacy of voriconazole in children under 2 years of age have not been established.
Influence on ability to drive motor transport and control mechanisms
Since voriconazole can cause transient visual impairment, including blurred vision, impaired / enhanced visual perception and / or photophobia, when such reactions occur, patients should not engage in potentially hazardous activities, such as driving or using complex equipment. Against the background of the use of voriconazole, patients should not drive a car in the dark.
- Brand name: Vfend
- Active ingredient: Voriconazole
- Dosage form: Pills
- Manufacturer: Pfizer
- Country of Origin: USA
- Direct injection HPLC micro method for the determination of voriconazole in plasma using an internal surface reversed-phase column
- ChemInform Abstract: Advances in the Development of Methods for the Synthesis of Triazole Antifungal Agents (Itraconazole (Sporanox), Fluconazole (Diflucan), Voriconazole (Vfend), Fosfluconazole (Prodif)]
- Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients
- Anti-infectious activity of intravitreal injectable voriconazole microspheres on experimental rabbit fungal endophthalmitis caused by aspergillus fumigatus
- Immune reconstitution syndrome after voriconazole treatment for cryptococcal meningitis in a liver transplant recipient
- Successful treatment of Scedosporium pneumonia with voriconazole during AML therapy and bone marrow transplantation
- Voriconazole into PLGA nanoparticles: Improving agglomeration and antifungal efficacy
- Dose tolerability of chronically inhaled voriconazole solution in rodents
- Measurement of voriconazole in serum and plasma
- Pharmacokinetics of voriconazole and cytochrome p450 2C19 genetic status
- Pharmacokinetic interaction between voriconazole and methadone at steady state in methadone patients
- Pharmacokinetic interaction between voriconazole and ritonavir at steady state in healthy subjects
- Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy subjects
- Opposite effects of short-term and long-term St John’s wort intake on voriconazole pharmacokinetics
- Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam
- Potent cytochrome P450 2C19 genotype–related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir
- Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life
- Fast, fully automated analysis of voriconazole from serum by LC–LC–ESI-MS–MS with parallel column-switching technique
- Fast and reliable determination of the antifungal drug voriconazole in plasma using monolithic silica rod liquid chromatography
- Simultaneous quantification of voriconazole and posaconazole in human plasma by high-performance liquid chromatography with ultra-violet detection
- Determination of voriconazole in human plasma and saliva using high-performance liquid chromatography with fluorescence detection
- Emergence of Candida albicans fungemia during voriconazole therapy
- Voriconazole-resistant disseminated Paecilomyces variotii infection in a neutropenic patient with leukaemia on voriconazole prophylaxis
- The efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis