Voriconazole – is an antifungal medication broad spectrum, which belongs to the structure of the triazole group of antibiotics.
The mechanism of action of voriconazole associated with inhibition of sterol 14α-demethylation mediated fungal cytochrome P450; This reaction is a key step in ergosterol biosynthesis.
In vitro voriconazole has a broad spectrum of antifungal activity and is active against Candida spp. (Including strains of C. krusei, fluconazole-resistant and resistant strains of C. glabrata and C. albicans), and has a fungicidal effect against all studied strains Aspergillus sp. as well as pathogenic fungi that have become relevant in recent years, including Scedosporium or of Fusarium, which limited sensitivity to existing antifungal agents.
Clinical efficacy was demonstrated in infections caused by Aspergillus spp., Including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., Including C. albicans, C. dubliniensis, C. glabrata, S. inconspicua, C. krusei, C. parapsilosis, C. tropicalis, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.
Other fungal infections which employ a formulation (often with a partial or complete response) included isolated cases of infections caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum , Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp., including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including T. beigelii.
In vitro activity demonstrated voriconazole against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was inhibited at concentrations of voriconazole from 0.05 to 2 mg / ml.
In vitro activity of voriconazole revealed against Curvularia spp. and Sporothrix spp., but its clinical significance is unknown.
voriconazole pharmacokinetics were studied in healthy people, and representatives of special groups of patients.
The pharmacokinetics of voriconazole is non-linear due to saturation of its metabolism. With increasing doses there is a disproportionate (more pronounced) increase AUC (area under the curve “concentration-time”). According to calculations, increase oral dose of 200 mg 2 times a day up to 300 mg 2 times a day AUCτ leads to an increase in average 2.5 times. When intravenous or oral administration of bolus plasma concentration close to the equilibrium within 24 hours. If the patient does not receive a loading dose, when repeated application voriconazole 2 times per day occurs accumulation of the drug, and the equilibrium concentration in plasma is achieved by the 6th day the majority of patients.
Voriconazole is rapidly and almost completely absorbed after oral administration; maximum plasma concentration (Cmax) is achieved after 1-2 h after administration. Bioavailability of voriconazole when administered is 96%. Repeated dose of voriconazole with fatty food Cmax and AUCτ is reduced by 34% and 24% respectively.
Suction voriconazole is independent of the pH of gastric juice.
The calculated volume of distribution at steady state voriconazole is 4.6 l / kg, which indicates the distribution of the active drug in the tissue. Plasma protein binding is 58%.
Voriconazole is determined in cerebrospinal fluid.
The pharmacokinetics of voriconazole characterized by high interindividual variability.
Studies in vitro have shown that voriconazole is metabolized by the action of hepatic cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4.
The in vivo studies also suggest that CYP2C19 plays an important role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, the reduced metabolism of voriconazole may be expected in 15-20% of Asians and 3-5% of white and black. Studies in Caucasians and Japanese people have shown that patients with reduced metabolism AUCτ of voriconazole by an average of 4 times higher than in homozygous patients with a high metabolism. In heterozygous patients with active metabolism AUCτ of voriconazole by an average 2-fold higher than in homozygous.
It is a major metabolite of voriconazole N-oxide, which accounts for 72% of circulating labeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.
In unaltered with urine output of less than 2% of the dose.
After repeated intravenous and oral administration of voriconazole labeled about 80% and 83% of the radioactive dose, respectively, is found in urine. Most (> 94%) of the total dose was excreted within the first 96 hours after oral and intravenous administration.
The terminal half-life of voriconazole is dependent on the dose and is approximately 6 hours while taking the drug orally at a dose of 200 mg. Due to the nonlinearity of the pharmacokinetics of the terminal elimination half-life does not allow to predict the cumulation or elimination of voriconazole.
Pharmacokinetics in special groups
In oral repeated administration Cmax and AUCτ in healthy young women were 83% and 113% respectively higher than in healthy young males (18-45 years). Significant differences in Cmax and AUCτ in healthy elderly males and healthy elderly women (> 65 years), no.
The need for dose adjustment based on gender is not marked. plasma concentration of both men and women are similar.
Repeated oral administration Cmax and AUCτ in healthy elderly men (> 65) 61%) and about 86% respectively, higher than in healthy young men (18-45 years). Significant differences in Cmax and AUCτ in healthy elderly women (> 65 years) and healthy young females (18-45 years) there. Safety of voriconazole in young and elderly patients is the same, therefore the dosage adjustment in the elderly is not required.
The average equilibrium concentration of drug in plasma in infants receiving the drug at a dose of 4 mg / kg every 12 hours, comparable with those of the adults receiving voriconazole at 3 mg / kg every 12 h Mean concentration was -. 1,186 ng / ml in children and 1155 ng / mL in adults. In this regard, the recommended maintenance dose in children aged 2 to
In single dose oral dose of voriconazole of 200 mg in patients with normal renal function, and from patients with lung (creatinine clearance of 41-60 ml / min) to severe (creatinine clearance in patients with moderate or severe renal impairment (serum creatinine levels of > 220 mol / l or 2.5 mg / dL) observed accumulation auxiliary substances constituting the lyophilisate for solution for injection – SBECD.
Abnormal liver function
After a single oral administration (200 mg) AUC voriconazole in patients with mild to moderately severe cirrhosis (Child-Pugh A and B) is 233% higher than in patients with normal liver function. Abnormal liver function does not affect the relationship with voriconazole plasma proteins.
Repeated oral administration AUCX voriconazole comparable in patients with moderate hepatic cirrhosis (Child-Pugh B) receiving the drug at a maintenance dose of 100 mg 2 times a day, and patients with normal liver function receiving voriconazole 200 mg 2 times a day . Information about the pharmacokinetics in patients with severe hepatic cirrhosis (Child-Pugh C) no.
1 film-coated tablet contains:
200 mg of voriconazole,
Opadry white (hypromellose, titanium dioxide, lactose monohydrate, glycerol triacetate)
- invasive aspergillosis
- severe forms of invasive Candida infections (including C. krusei), resistant to fluconazole.
- esophageal candidiasis caused by C. albicans, in immunocompromised patients.
- severe fungal infections caused by Scedosporium spp and Fusarium spp.
- severe fungal infections intolerant or refractory to other drugs.
- Prevention “breakthrough” of fungal infections in febrile patients with high-risk groups (recipients of allogeneic bone marrow, patients with relapsed leukemia).
- Vfend is contraindicated in patients with hypersensitivity to voriconazole or to any component of the product;
- the simultaneous use of Vfend and substrates of CYP3A4 – terfenadine, astemizole, cisapride, pimozide, or quinidine is contraindicated, since increase in the last plasma concentrations can lead to QT prolongation, and in rare cases to the development of atrial / ventricular fibrillation;
- the simultaneous use of Vfend and sirolimus is contraindicated, since voriconazole significantly increased sirolimus concentration in the plasma of healthy people;
- simultaneous use Vfend with rifampicin, carbamazepine and long-acting barbiturates (e.g. phenobarbital) contraindicated because these drugs significantly reduced plasma concentrations of voriconazole (see “Interaction».);
- simultaneous use Vfend with ritonavir (400 mg every 12 hours) is contraindicated since the latter significantly reduces the concentration of voriconazole in healthy subjects plasma;
- the simultaneous use of Vfend with efavirenz is contraindicated because the latter significantly reduces the concentration of voriconazole in plasma, and voriconazole, in turn, increases the plasma concentrations of efavirenz;
- the simultaneous use of ergot alkaloids (ergotamine, dihydroergotamine), which are substrates of CYP3A4, is contraindicated since increasing the concentration of these substances in plasma may lead to ergotism.
Precautions – severe hepatic failure, severe renal failure (for parenteral administration). Safety and efficacy in children under the age of 2 years have not been established. Increased sensitivity to other drugs – derivatives of azoles.
The table lists the undesirable effects were observed when using the drug, and possibly related to treatment. The most common adverse reactions were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. Adverse reactions were usually lightly or moderately expressed. Clinically significant depending on the age of the drug safety, race or gender is not identified
system of the body
Frequency * Adverse drug reactions ObschieOchen chastyeLihoradka, otekiChastyeOznoby peripheral, asthenia, chest pain, reaction / inflammation at the injection site, flu-sindromSerdechno sosudistayaChastyeSnizhenie blood pressure, thrombosis, flebitRedkiePredserdnye fibrillation, bradycardia, tachycardia, ventricular tachycardia aritmiya.Ochen redkieNadzheludochkovaya, complete atrio-ventricular block, bundle branch block, nodal arrhythmia, ventricular tachycardia (including ventricular fibrillation), lengthening the interval QT, fibrillation des udochkov.PischevareniyaOchen chastyeToshnota, vomiting, diarrhea, pain zhivoteChastyePovyshenie liver function tests (including ACT, AJIT, alkaline phosphatase, gamma-GT, LDH, bilirubin), jaundice, cheilitis, holestaz.RedkieHoletsistit, cholelithiasis, constipation, duodenitis, dyspepsia, increased liver, gingivitis, glossitis, hepatitis, hepatic insufficiency, pancreatitis, edema language peritonitOchen redkiePsevdomembranozny colitis, hepatic komaEndokrinnayaRedkieNedostatochnost cortex nadpochechnikovOchen redkoGipertireoz, gipotireozImmunnayaRedkieAllergicheskie rea ii, anaphylactoid reaktsiiKrov and lymphatic ChastyeTrombotsitopeniya, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pantsitopeniyaRedkieLimfadenopatiya, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, inhibition of bone krovetvoreniyaOchen redkieLimfangitMetabolizm and pitanieChastyeGipokaliemiya, gipoglikemiyaRedkieGiperholesterinemiyaSkeletno-myshechnayaChastoBol in spineRedkieArtritNervnayaOchen chastyeGolovnaya bolChastyeGo lovokruzhenie, hallucinations, confusion, depression, anxiety, tremor, agitation, paresteziiRedkieAtaksiya, edema of the brain, hypertension, gipostezii, nystagmus, dizziness, obmorokOchen redkieSindrom hyenas-Barre, oculomotor crisis, extrapyramidal sindromDyhatelnayaChastyeRespiratorny distress syndrome, pulmonary edema, sinusitKozha and subcutaneous tissue Very chastyeSypChastyeZud, maculopapular rash, photosensitivity skin reactions, alopecia, exfoliative dermatitis, swelling of the face, purpuraRedkieToksichesky epidermal Necrolyte from eczema, psoriasis, Steven-Johnson syndrome, krapivnitsaOchen redkieAngionevrotichesky edema, discoid lupus erythematosus, erythema multiforme, toxic epidermal nekrolizOrgany chuvstvOchen chastyeZritelnye disorders (including breach / enhancement of visual perception, the mist before his eyes, the change of color vision, photophobia) RedkieBlefarit, optic neuritis nerve swelling of the optic nerve papilla, scleritis, taste dysfunction, diplopiyaOchen redkieKrovoizliyanie retinal, corneal clouding, atrophy zritelnog nervaMochepolovayaChastyePovyshenie creatinine, acute renal failure, gematuriyaRedkiePovyshenie residual urea nitrogen, albuminuria, renal tubules nefritOchen redkieNekroz
* Criteria of evaluation were the following frequencies: very frequent > 10%; frequent – from > 1% to > 0.1% to
Voriconazole in the treatment of frequent visual impairment. Approximately 30% of patients there is a violation of visual perception: blurred vision, color vision change or photophobia. Visual disturbances are transient and fully reversible; in most cases they disappear spontaneously within 60 min. With repeated use of voriconazole there is a weakening of their expression. Visual impairment usually easily expressed, rarely require discontinuation of treatment and do not lead to any consequences in the long term. Visual impairment may be associated with higher plasma concentrations and / or doses of the drug.
their development mechanism is not known, although the drug is likely to act on the retina. In studying the effect of voriconazole on retinal function in healthy volunteers showed a reduction wave amplitude electroretinogram (ERG). With this method, the electrical current measured at the retina. ERG changes do not grow with continued treatment for 29 days and completely disappeared after discontinuation of voriconazole. The effect of a long-term treatment with voriconazole (more than 29 days) on visual function is not known.
Skin reactions occur in 19% of patients receiving voriconazole. In most cases, the rash is easy to moderate. In rare cases, the treatment of voriconazole develop severe skin reactions including Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rarely) and erythema multiforme (rare).
When the rash appears the patient should be carefully monitored, and if the progression of skin changes voriconazole advisable to cancel. In patients receiving long-term voriconazole therapy may develop photosensitivity skin reactions.
Indicators of liver function
The overall incidence of clinically significant increase of transaminases in patients receiving voriconazole, is 13.4%. Liver function abnormalities can be associated with higher plasma concentrations and / or doses of the drug. In most cases, liver function abnormalities disappear with continued treatment (no change in dose or after correction) or a termination.
In the application of voriconazole in cases of severe hepatotoxicity rarely observed in patients with serious underlying medical conditions. These cases may include cases of jaundice, hepatitis and hepatocellular failure, leading to death.
Reactions associated with infusion
Intravenous infusion of voriconazole may experience anaphylactoid reactions, including flushing, fever, sweating, tachycardia, chest tightness, shortness of breath, faintness, nausea, pruritus and rash. These symptoms appear immediately after the start of infusion.
How to accept, acceptance rate and dosage
Voriconazole tablets, coated tablets, taken orally for at least 1 hour before or 1 hour after a meal.
Use in Adults
Appointment of voriconazole intravenous or oral should start with the recommended loading dose, to the first day to achieve a serum concentration close to the equilibrium.
Given the high oral bioavailability (96%, see. Pharmacokinetics section), if clinically indicated possible move from intravenous to oral administration of the drug.
The following table provides detailed information on the dosage of the drug:
the body of 40 kg and with a mass boleePatsienty
body less than 40 kgNasyschayuschaya dose
– All indications
(First 24 hours) 6 mg / kg every 12 hours
(During the first 24 h) 400 mg every 12 hours
(During the first 24 h) 200 mg every 12 hours
(During the first 24 hours) Maintenance dose
(After the first 24 h)
breakthrough infektsiy3 mg / kg every 12 ch200 mg every 12 ch100 mg every 12 chTyazhelye invasive candida infection resistant to fluconazole / invasive aspergillosis / infection caused Scedosporiumi Fusarium / Other serious mold infektsii4 mg / kg every 12 ch200 mg every 12 ch100 mg every 12 chKandidoz esophagus caused by C. albicans, in immunocompromised patients
No rekomendatsiy200 ch100 mg every 12 mg every 12 hours
In case of insufficient effectiveness of treatment maintenance dose may be increased to 300 mg every 12 hours inside. In patients weighing less than 40 kg the dose may be increased to 150 mg every 12 hours inside.
If the patient does not tolerate the drug in high dose, it is reduced in steps of 50 mg to 200 mg every 12 hours inside (or 100 mg every 12 hours in patients weighing less than 40 kg).
Phenytoin may be used with voriconazole if the maintenance dose of the latter is increased from 200 to 400 mg every 12 hours inside (from 100 to 200 mg every 12 hours inwardly in patients weighing less than 40 kg).
Rifabutin may be used with voriconazole if the maintenance dose of the latter is increased from 200 to 350 mg every 12 hours inside (from 100 to 200 mg every 12 hours inwardly in patients weighing less than 40 kg).
The duration of treatment depends on the clinical effect and mycological analysis.
Use in the elderly
Dosage adjustment in the elderly is not required.
Use in patients with impaired renal function
Impaired renal function did not affect the pharmacokinetics of voriconazole when administered. Therefore, dose adjustment of voriconazole oral in patients with mild, moderate or severe renal impairment is not required.
Use in patients with impaired hepatic function
In acute liver damage, manifested by increased activity “liver” transaminases (AJIT, ACT), the dose correction is not required. In such cases it is advisable to continue monitoring the performance of the liver in order to detect them further increases.
In patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) is recommended to assign the standard loading dose of voriconazole, a lower maintenance dose of 2 times.
Patients with severe hepatic impairment voriconazole should be administered only in cases where the expected benefit outweighs the potential risk.
In patients with severe hepatic dysfunction treatment should be under constant supervision in order to detect signs of drug toxicity.
Use in children
The safety and efficacy of voriconazole in children aged less than 2 years have not been established. Therefore, voriconazole is not recommended for children younger than 2 years.
Experience of application in children is limited, making it difficult the choice of optimal dosages. However, pharmacokinetic studies in children voriconazole was used in the following schemes.
Children aged 2 to:
(First 24 hours) 6 mg / kg every 12 hours
(During the first 24 hours) 6 mg / kg every 12 hours
(During the first 24 hours) Maintenance dose
(After the first 24 hours) 4 mg / kg every 12 ch4 mg / kg every 12 hours
If the child can ingest the tablets, the dose is rounded to the nearest dose in mg / kg, 50 mg times, and administered in the form of whole tablets.
The pharmacokinetics and tolerability of higher doses have not been studied in children ..
Adolescents aged 12 to 16 years: the drug is dosed in the same way as in adults.
At a temperature of not higher than 30 ° C
The effect of other drugs on the pharmacokinetics of voriconazole
Voriconazole is metabolised by the action of cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may cause, respectively, increase or decrease voriconazole plasma concentrations.
voriconazole plasma levels are significantly reduced, while the use of the following drugs:
Rifampicin (inductor CYP450): Rifampicin (600 mg once a day) reduces C max (maximum plasma concentration) and AUCτ voriconazole by 93% and 96% respectively.
The simultaneous use of voriconazole and rifampicin is contraindicated (see. Contraindications section).
Carbamazepine and long-acting barbiturates (potent inducers of CYP450):
Carbamazepine and long-acting barbiturates (e.g., phenobarbital) are likely to significantly reduce plasma concentrations of voriconazole, while their interaction have not been investigated.
The simultaneous use of voriconazole with carbamazepine and long-acting barbiturates contraindicated (see. Contraindications section).
Given the small pharmacokinetic interaction or lack of significant interactions correction dose is not required following drugs:
Cimetidine (nonspecific inhibitor CYP450, while also increasing the pH of gastric juice): cimetidine (400 mg, 2 times a day) causes an increase in Cmax and voriconazole AUCX 18% and 23% respectively. No dose adjustment of voriconazole is not recommended.
Ranitidine (increases gastric pH): Ranitidine (150 mg, 2 times a day) has no significant influence on the Cmax and AUCτ voriconazole.
Antibiotics macrolides: Erythromycin (an inhibitor of CYP3A4; 1 g, 2 times a day) and azithromycin (500 mg once a day) has no significant effect on the Cmax and AUCτ voriconazole.
Effect of voriconazole on other drugs
Voriconazole inhibits the activity of cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4. In this regard, voriconazole may increase the plasma concentration of substances that are metabolized by these isoenzymes CYP450.
Concomitant use of voriconazole is contraindicated with the following agents:
Terfenadine, astemizole, cisapride, pimozide and quinidine (substrates CYP3A4): Although the interaction with these drugs has not been studied, however simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since an increase in their concentration in the plasma can lead to prolongation of the QT interval and in rare cases to the development of fibrillation / flutter.
Sirolimus (substrate CYP3A4): Voriconazole increases Cmax and AUCT sirolimus (2 mg single dose) at 556% and 1014%, respectively. The simultaneous use of voriconazole and sirolimus contraindicated.
Ergot alkaloids (substrates CYP3A4): Although the interaction with these treatments have not been investigated, however, voriconazole may cause an increase in the concentration of ergot alkaloids (ergotamine and dihydroergotamine) in plasma and ergotism development. The simultaneous use of ergot alkaloids with voriconazole contraindicated,
Interaction with voriconazole may lead to an increase in the blood concentration of the following drugs listed below. In this regard, when simultaneous application requires constant monitoring and / or adjustment of doses.
Cyclosporine (CYP3A4 substrate): In patients undergoing kidney transplantation and are in stable condition, voriconazole increases the Cmax and AUCτ of cyclosporine and at least 70%) by 13%. In the appointment of voriconazole in patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine twice and monitor its levels in plasma. Increasing concentrations of cyclosporin nephrotoxicity is accompanied. After the cancellation of voriconazole is necessary to control the levels of the cyclosporin and increase the dose if necessary.
Tacrolimus (substrate CYP3A4): Voriconazole increases Cmax and AUCτ (area under the concentration-time curve to the last quantitative measurement) tacrolimus (0.1 mg / kg, single dose) at 117% and 221%, respectively. In the appointment of voriconazole in patients receiving tacrolimus, it is recommended to reduce the dose of the latter to a third and to control its levels in plasma. Increased levels of tacrolimus accompanied nephrotoxicity. After the cancellation of voriconazole is necessary to control the concentration of tacrolimus and increase the dose if necessary.
Warfarin (CYP2C9 substrate): Concomitant use of voriconazole (300 mg, 2 times a day), warfarin (30 mg dose) was accompanied by an increase in maximum prothrombin time to 93% >. When concomitant administration of warfarin and voriconazole is recommended to monitor the prothrombin time.
Other oral anticoagulants eg phenprocoumon, acenocoumarol (substrates of CYP2C9, CYP3A4): Voriconazole may increase the plasma concentrations of coumarins and prothrombin time. If patients receiving coumarin preparations prescribed voriconazole, it is necessary to monitor the prothrombin time with short intervals and accordingly select doses antikoagulyangov.
Sulfonylureas (substrates CYP2C9): Voriconazole can increase the concentration of sulfonylureas (e.g. tolbutamide, glipizide and glibenclamide) in the plasma and cause hypoglycemia. At the same time their application must carefully monitor blood glucose levels.
Statins (substrates CYP3A4): in vitro metabolism of voriconazole inhibits lovastatin (in human liver microsome). In this regard, voriconazole may cause an increase in plasma concentrations of statins metabolized by the action of CYP3A4. When odnovremenennom their recommended application to evaluate the feasibility of correction dose statin. Increasing levels of statins are sometimes accompanied by the development of rhabdomyolysis.
Benzodiazepines (substrates CYP3A4): Although clinical studies have not studied the interaction, midazolam metabolism of voriconazole inhibits in vitro (human liver microsome). In this regard, voriconazole may cause an increase in plasma levels of the benzodiazepine that are metabolized by the action of CYP3A4 (midazolam, triazolam, alprazolam), and the development of prolonged sedation. With the simultaneous use of these drugs is recommended to discuss whether dose adjustment benzodiazepine.
Vinca alkaloids (substrates CYP3A4): Voriconazole may increase vinca alkaloid content in the plasma (e.g., vincristine and vinblastine) and cause neurotoxicity.
It is recommended to discuss the feasibility of dose adjustment of vinca alkaloids.
With simultaneous use of voriconazole with the following significant pharmacokinetic drug interactions have been identified, therefore a correction dose is not required:
Prednisolone (substrate CYP3A4): Voriconazole increases Cmax and AUCτ of prednisolone (60 mg single dose) by 11% and 34% respectively. No dose adjustment is recommended.
Digoxin (transport mediated by P-glycoprotein): Voriconazole has no significant influence on the Cmax and AUCτ digoxin (0.25 mg once a day).
Mycophenolic acid (substrate UDP-glucuronyl) Voriconazole has no effect on Cmax and AUCτ mycophenolic acid (1 g single dose).
Phenytoin (CYP2C9 substrate and potent inducer of CYP450): The simultaneous use of voriconazole and phenytoin should be avoided unless the expected benefit outweighs the potential risk.
Phenytoin (300 mg once a day) reduced Cmax and AUCτ of voriconazole by 49% and 69% respectively. Voriconazole (400 mg. Twice daily. See section 4.2) increases Cmax and AUCτ phenytoin (300 mg once daily) by 67% and 81% respectively. With simultaneous use of voriconazole with phenytoin is recommended close monitoring of phenytoin levels in plasma.
Phenytoin may be used in conjunction with voriconazole if the maintenance dose of the latter is increased to 5 mg / kg every 12 h intravenously or from 200 to 400 mg every 12 hours inside (from 100 to 200 mg every 12 hours inwardly in patients weighing less than 40 kg) ; cm. partition Dosing and dose).
Rifabutin (inductor CYP450): Rifabutin (300 mg once a day) reduced Cmax and AUCτ voriconazole (200 mg twice daily) by 69% and 78% respectively. When concomitant administration of rifabutin Cmax and AUCτ voriconazole dose of 350 mg 2 times a day up 96% and 68% of the indicators when using voriconazole alone at a dose of 200 mg 2 times a day. When applied in a dose of voriconazole of 400 mg twice daily Cmax and AUCτ, respectively, 104% and 87% higher than when voriconazole monotherapy at a dose of 200 mg 2 times a day. Voriconazole 400 mg 2 times a day increases Cmax and AUCτ rifabutin at 195% and 331%, respectively.
If the expected benefit of treatment outweighs the risk, rifabutin can be used simultaneously with voriconazole. In this case, a maintenance dose of voriconazole should be raised to 5 mg / kg every 12 h intravenously or from 200 to 350 mg every 12 hours inside (from 100 to 200 mg every 12 hours inwardly in patients weighing less than 40 kg) (see. Section Dosing and dose). With simultaneous treatment of rifabutin and voriconazole full blood count is recommended on a regular basis and monitor the adverse effects of rifabutin (eg, uveitis).
Omeprazole (inhibitor of CYP2C19; substrate CYP2C19 and CYP3A4): omeprazole (40 mg once a day) increases Cmax and AUCτ of voriconazole by 15% and 41% respectively. No dose adjustment of voriconazole is not recommended.
Voriconazole increases Cmax and AUCτ omeprazole by 116% and 280%, respectively. In the appointment of voriconazole in patients receiving omeprazole, the latter recommended dose halved.
Voriconazole may also inhibit the metabolism of other proton pump inhibitors, which are substrates of CYP2C19.
Indinavir (inhibitor and substrate CYP3A4): indinavir (800 mg tid) has no significant effect on the Cmax and AUCτ voriconazole.
Voriconazole is not substantially affect the Cmax, Cmin and AUCτ of indinavir (800 mg 3 times a day).
Other HIV protease inhibitors (CYP3A4 substrates and inhibitors): Studies in vitro indicate that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, nelfinavir and amprenavir). in vitro studies have also shown that HIV protease inhibitors may inhibit the metabolism of voriconazole. In the case of simultaneous use of voriconazole with HIV protease inhibitors, patients should be observed in order to detect possible toxicities.
Non-nucleoside reverse transcriptase inhibitors (substrates CYP3A4, inhibitors or inducers of CYP450): Studies in vitro show that delaverdin efavirenz and may inhibit the metabolism of voriconazole. Efavirenz and nevirapine may induce the metabolism of voriconazole, although this effect has not been studied. Voriconazole may inhibit the metabolism of non-nucleoside reverse transcriptase inhibitors. With simultaneous use of voriconazole with non-nucleoside reverse transcriptase inhibitors Patients should be monitored in order to identify possible toxic effects.
Sampling of the culture and other laboratory studies (serology, histopathology) to isolate and identify pathogens should be performed prior to treatment. Therapy can be started before the results of the culture and other laboratory studies, however if any, treatment should be adjusted accordingly.
Clinical isolated strains having reduced sensitivity to voriconazole.
However, elevated minimum inhibitory concentration (MIC) is not always possible to predict clinical failure; there are cases where voriconazole was effective in patients infected with organisms resistant to other azoles. Evaluate the correlation between in vitro activity and clinical outcome is difficult, given the complexity of the patients, which included the clinical study; voriconazole concentrations border values that allow to evaluate the sensitivity to this drug have not been established.
Hypersensitivity: Patients with hypersensitivity to other azoles, voriconazole should be administered with caution
Adverse events of the cardiovascular system: the use of voriconazole is associated with prolongation of the QT interval on the electrocardiogram, which is accompanied by rare cases of flicker-ventricular flutter in patients receiving therapy with voriconazole (in critically ill patients with multiple risk factors, such as the cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant therapy, which could contribute to the development of this complication). Patients with these potentially proarrhythmic states voriconazole should be used with caution (see Dosage and administration).
Hepatotoxicity: In the treatment of voriconazole observed infrequent (0.1-1 %%) cases of severe reactions in the liver (including manifested clinically hepatitis, cholestasis and hepatocellular insufficiency, including fatal). Adverse events by the liver is mainly observed in patients with severe disease (primarily malignant tumors of blood). In patients without any risk factors observed transient response of the liver, including hepatitis and jaundice. Abnormal liver function are usually reversible and disappear after cessation of treatment.
Monitoring of liver function: During treatment with voriconazole it is recommended to regularly monitor liver function, particularly liver function tests and bilirubin. If clinical signs of liver disease, which may be associated with voriconazole, it is necessary to discuss the feasibility of discontinuing therapy.
Adverse events in the kidneys: In critically ill patients receiving voriconazole, cases of acute renal failure are observed.
Monitoring of renal function:
Patients should be monitored for signs of renal dysfunction. To do this, you must carry out laboratory tests, in particular to determine the serum creatinine level.
Infusion Reactions: When intravenous voriconazole there are infusion reactions, mainly “flushing” and nausea. If these symptoms are, you should discuss the advisability of discontinuing treatment (see. Section Side effects).
Skin reactions: In rare cases, the treatment of patients develop voriconazole exfoliative skin reactions such as Stevens-Johnson syndrome. When the rash appears, patients should be observed. With the progression of skin lesions voriconazole advisable to cancel.
Further, voriconazole accompanied by cutaneous photosensitivity reactions, especially when long-term treatment. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight.
Cyclosporine and tacrolimus (substrates of CYP3A4): In patients receiving cyclosporine or tacrolimus, can be observed clinically significant their interaction with voriconazole (see section Interaction with other drugs and other forms of interaction.)
Phenytoin (CYP2C9 substrate and potent inducer of CYP450): while the use of phenytoin with voriconazole recommended constant monitoring of phenytoin levels. If possible, avoid simultaneous use of voriconazole and phenytoin unless the expected benefit outweighs the potential risk (see. Section Interaction with other drugs and other forms of interaction).
Rifabutin (inductor CYP450): When applied simultaneously with rifabutin voriconazole recommended clinical analysis of blood and to control the undesirable effects of rifabutin (e.g., uveitis). Co-administration of voriconazole and rifabutin should be avoided unless the expected benefit outweighs the potential risk (see. Section Interaction with other drugs and other forms of interaction).
Women of reproductive age
Women of reproductive age during treatment should always use effective methods of contraception.
Effects on ability to drive and use machinery
Voriconazole may cause transient and reversible visual impairment, including mist, violation / enhancement of visual perception and / or photophobia. In the presence of symptoms such patients should avoid performing potentially dangerous operations such as vehicle control or the use of complex equipment. When receiving voriconazole patients should not drive a car at night.
Pregnancy and lactation
Adequate information on the use of voriconazole in pregnant women do not have.
Animal studies have shown that the drug in high doses has a toxic effect on reproductive function. Possible risk is not known to man.
Voriconazole should not be used in pregnant women unless the expected benefit to the mother clearly outweighs the potential risk to the fetus.
Excretion of voriconazole into breast milk has not been studied. Voriconazole should not be used in women who are breastfeeding, unless the expected benefit clearly outweighs the risk.
Antidote voriconazole is not known. In case of overdose symptomatic treatment is shown. Possibility of carrying out gastric lavage.
Voriconazole is removed from the hemodialysis clearance of 121 ml / min. SBECD (sulphobutylether beta-cyclodextrin) and dialyzed with a clearance of 55 ml / min. In the case of hemodialysis overdose can promote excretion of voriconazole from the body and SBECD.