Voriconazole

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Voriconazole: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Voriconazole

ATX code: J02AC03

Active ingredient: voriconazole (Voriconazole)

Manufacturer: OZON LLC (Russia); Biocad CJSC (Russia); RUE "Belmedpreparaty" (Republic of Belarus)

Description and photo update: 2019-11-07

Prices in pharmacies: from 4546 rubles.

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Voriconazole is an antifungal drug for systemic use.

Release form and composition

lyophilisate for the preparation of a concentrate for the preparation of a solution for infusion: porous mass of white color (200 mg each in a bottle of colorless neutral glass of I hydrolytic class, sealed with a rubber stopper with a rolling aluminum cap with a plastic flip-off cap; in a cardboard box 1 bottle);
lyophilized powder for the preparation of a solution for infusion: from almost white to white, in the form of a layer or separate aggregates, or a free-flowing mass (200 mg each in a 50 ml vial, sealed with a rubber stopper, rolled in an aluminum or combined / alumoplastic cap; 1 bottle in cardboard box; for hospitals - 20 bottles in a group container);
film-coated tablets: biconvex, from almost white to white, 50 mg - round, 200 mg - capsule-shaped, with a line on one side; on the cross section, a core of almost white color stands out (2, 4, 6, 7, 8, 10, 14, 16, 20, 21, 25, 28 or 30 pieces each in a blister strip made of PVC film and aluminum foil, in cardboard a pack of 1-7 or 10 blisters; 2, 4, 6, 7, 8, 10, 14, 16, 20, 21, 28, 30, 35, 40, 42, 49, 50, 56, 70, 80, 98, 100, 112 or 140 pcs. In a can with a lid made of polyethylene terephthalate or polypropylene; in a cardboard box 1 can);
film-coated tablets: biconvex, round, almost white or white, with possible unevenness of the coating (10 pcs. in a blister strip of PVC film and aluminum foil; in a cardboard box 1 package).

Each pack also contains instructions for the use of Voriconazole.

The composition of the lyophilisate for the preparation of the concentrate (for 1 bottle):

active substance: voriconazole - 200 mg;
additional component: sodium betadex sulfobutylate.

Lyophilized powder composition (for 1 bottle):

active substance: voriconazole - 200 mg (which corresponds to the concentration of the solution after dilution of 10 mg / ml);
additional component: sodium salt of β-cyclodextrin sulfobutyl ether.

1 film-coated tablet contains:

active substance: voriconazole - 50 or 200 mg;
additional components: microcrystalline cellulose, lactose monohydrate (milk sugar), povidone-K25, magnesium stearate, croscarmellose sodium;
film casing: Opadray II 85F48105 White (macrogol-3350, polyvinyl alcohol, titanium dioxide, talc).

1 coated tablet contains:

active substance: voriconazole - 50 or 200 mg;
additional components: sodium starch glycolate (type A), pregelatinized starch, povidone, lactose monohydrate, magnesium stearate;
sheath: Opadry II white (85F).

Pharmacological properties

Pharmacodynamics

Voriconazole is a broad-spectrum antifungal agent belonging to the triazole group. The mechanism of action of the antimycotic is to suppress the reaction of 14α-sterol demethylation, mediated through the fungal cytochrome P ₄₅₀ and which is the main stage of ergosterol biosynthesis. Cumulation of 14α-methyl sterol is associated with further loss of ergosterol in the membranes of fungal cells, which explains the antifungal activity of voriconazole. It was found that the preparation is characterized by a higher selectivity towards cytochrome P ₄₅₀ isoenzymes of fungi than towards various enzyme systems of mammalian cytochrome P ₄₅₀.

In the course of therapeutic studies, no positive relationship was found between the minimum, average and maximum plasma levels of voriconazole in the blood and the effect of the drug. But at the same time, a connection was established between the plasma concentration of the active substance and the deviation from the norm of the biochemical parameters of the liver, as well as violations of the organ of vision.

In vitro, voriconazole has been shown to have a broad spectrum of antifungal activity: active against Candida spp. (including strains of C. krusei resistant to fluconazole and resistant strains of C. albicans and C. glabrata), and also exhibits a fungicidal effect against all studied Aspergillus spp. and recent pathogenic fungi, including Fusarium spp. or Scedosporium spp., which are limitedly sensitive to antimycotics.

Clinical efficacy (with partial / complete response) of the drug has been demonstrated against infections caused by Aspergillus spp., Including strains A. flavus, A. terreus, A. fumigatus, A. nidulans, A. niger, Candida spp., Including strains C albicans, C. krusei, C. glabrata, C. tropicalis and C. parapsilosis, as well as a limited number of strains of C. inconspicua, C. dubliniensis and C. guilliermondii, Scedosporium spp., including S. prolificans, S. apiospermum, and Fusarium spp.

Other fungal infections against which voriconazole has been used (with complete or partial response) included isolated cases of infections caused by Alternaria spp., Blastoschizomyces capitatus, Blastomyces dermatitidis, Cladosporium spp., Cryptococcus neoformans, Coccidioides immitisa Conatusio rostratum, Fonsecaea pedrosoi, Paecilomyces lilacinus, Madurella mycetomatis, Penicillium spp., including P. marneffei, Scopulariopsis brevicaulis, Phialophora richardsiae and Trichosporon spp., including T. beigelii.

The activity of the preparation in vitro against clinical strains of Alternaria spp., Acremonium spp., Cladophialophora spp., Bipolaris spp., Histoplasma capsulatum was also recorded. At a voriconazole level of 0.05–2 μg / ml, the growth of most strains was inhibited. Also found in vitro activity of the agent against Sporothrix spp. and Curvularia spp., but the clinical significance of this effect has not been established.

Pharmacokinetics

The pharmacokinetic parameters of voriconazole are highly variable between individuals.

The pharmacokinetics of a substance is non-linear due to the saturation of its metabolism. If the dose is increased, a disproportionate (more significant) increase in the area under the concentration-time curve (AUC _t) is noted. An increase in the oral dose from 200 to 300 mg 2 times a day provides an increase in AUC _t approximately 2.5 times. Oral administration of voriconazole at a maintenance dose of 200 mg (or 100 mg for body weight less than 40 kg) corresponds to intravenous (IV) administration of the drug at a dose of 4 mg / kg.

In the case of taking saturating doses or intravenous infusion of the drug, its stationary concentration (C _ss) is determined during the first 24 hours. If the drug is used in average therapeutic (but not saturating) doses 2 times a day, voriconazole accumulation is noted, and C _{ss is} recorded in most patients by the sixth day of the course.

After oral administration, the antimycotic is absorbed quickly and almost completely, the maximum concentration (C _max) in the blood plasma is reached after 1–2 hours. The oral bioavailability of the drug is 96%, with repeated intake with food rich in fats, its AUC _t and C _max are reduced by 24 and 34%, respectively. The absorption of the drug is not affected by the pH of the gastric juice. In the equilibrium state, the volume of distribution of voriconazole is approximately 4.6 l / kg, which indicates an active distribution of the drug in the tissues. The drug binds 58% to blood plasma proteins, passes through the blood-brain barrier (BBB) and is detected in the cerebrospinal fluid.

In accordance with the data of in vitro studies, the biotransformation of voriconazole is provided by cytochrome isozymes 2C19, 2C9, and 3A4. The most important role in this process belongs to the isoenzyme CYP2C19, which exhibits a pronounced genetic polymorphism, which can cause a reduced metabolism of the drug in 3-5% of patients of Caucasian and Negroid races, and in 15-20% of patients of Asian origin.

The main metabolite of voriconazole is N-oxide, its share is approximately 72% of the total circulating plasma metabolites with a radioactive label. This metabolite exhibits minimal antifungal activity and does not affect the clinical effect of the antimycotic. After biotransformation of the active substance in the liver, it is excreted in the form of metabolites, and less than 2% of the administered dose is excreted unchanged by the kidneys.

After repeated oral administration or intravenous infusion of voriconazole, approximately 83 and 80% of its dose is determined in the urine, respectively. The predominant part of the total dose (over 94%) is excreted during the first 96 hours. The half-life (T _1/2) of the drug depends on the dose and is, when taken orally at a dose of 200 mg, on average 6 hours. Due to the nonlinearity of the pharmacokinetics of the substance, the T _1/2 value cannot be used to assess cumulation or elimination.

There is no need to change the dose of the drug taking into account gender. Plasma levels of voriconazole are similar in men and women.

Indications for use

invasive aspergillosis;
esophageal candidiasis;
candidemia, not accompanied by neutropenia;
severe invasive infections caused by Candida (including C. krusei);
severe fungal infections caused by Fusarium spp. and Scedosporium spp.;
other severe invasive fungal infections in case of intolerance or refractory to other drugs;
prevention of breakthrough fungal infections in patients with a weakened immune system, neutropenia and fever, from high-risk groups (patients with recurrent leukemia, hematopoietic stem cell transplant recipients);
prevention of invasive fungal infections in high-risk patients (adults and adolescents over 12 years of age), such as hematopoietic stem cell transplant recipients.

Contraindications

Absolute:

age up to 2 years or up to 3 years - for film-coated tablets;
glucose-galactose malabsorption, lactose intolerance, lactase deficiency - for oral forms;
combined use with the following drugs: substrates of CYP3A4 isoenzyme - astemizole, terfenadine, quinidine, pimozide and cisapride; carbamazepine, rifampicin, and long-acting barbiturates (phenobarbital); sirolimus; efavirenz (400 mg and more once a day); rifabutin; ritonavir (400 mg or more 2 times a day); St. John's wort (inducer of P-glycoprotein and cytochrome P ₄₅₀); ergot alkaloids (dihydroergotamine, ergotamine), which are substrates of the CYP3A4 isoenzyme;
hypersensitivity to any ingredient in Voriconazole.

Relative (use antimycotic with caution):

failure of liver and / or kidney function in severe degree;
proarrhythmic conditions: congenital / acquired increase in the QT interval, sinus bradycardia, cardiomyopathy (especially with heart failure), the presence of symptomatic arrhythmias, combined use with drugs leading to an extension of the QT interval;
electrolyte disturbances such as hypomagnesemia, hypokalemia, and hypocalcemia;
hypersensitivity to other azoles derivatives.

Voriconazole, instructions for use: method and dosage

Voriconazole film-coated / film-coated tablets are taken orally at least 1 hour before or 1 hour after a meal.

A solution prepared from lyophilized / lyophilized powder for the preparation of a concentrate for the preparation of a solution for infusion Voriconazole is administered only intravenously. Do not administer the drug in a stream (as a bolus injection). The infusion rate should not exceed 3 mg / kg per hour, the infusion time should be from 1 to 3 hours.

Treatment of adult patients

The use of Voriconazole should be started with intravenous administration of the solution at the recommended saturating dose in order to achieve an adequate plasma concentration of the drug in the blood already on the first day of the course. It is recommended to continue IV infusions for at least 7 days, and then, provided that the patient is able to use the drug in oral form, switch to taking tablets. Based on the high bioavailability of the antimycotic when taken orally (96%), with the available clinical indications, it is possible to switch from intravenous to oral administration of the drug without changing the dose.

When taken orally for the purpose of therapy, its maintenance dose after the first 24 hours of treatment in the form of intravenous injections, for all indications is 200 mg every 12 hours - for patients with a body weight of 40 kg or more, and 100 mg every 12 hours - for patients weighing less than 40 kg.

In the absence of the expected effect, the maintenance dose of oral voriconazole may be increased from 200 to 300 mg every 12 hours. With a body weight of less than 40 kg, the dose may be increased from 100 to 150 mg every 12 hours. In the case when the patient cannot tolerate oral administration in a high dose - 300 mg every 12 hours, the maintenance dose is gradually reduced in 50 mg increments to 200 mg every 12 hours (with a body weight of less than 40 kg - up to 100 mg).

For the purpose of therapy, for all indications in the first 24 hours of treatment, the drug is recommended to be administered as an intravenous infusion in a saturating dose every 12 hours at 6 mg / kg.

Recommended maintenance doses of Voriconazole (after the first 24 hours) for intravenous infusions, taking into account indications (frequency of administrations - every 12 hours):

prevention of invasive fungal infections in adults and adolescents over 12 years old who are at high risk (including recipients of hematopoietic stem cell transplantation); prevention of breakthrough fungal infections with concomitant fever; candidemia, not accompanied by manifestations of neutropenia: 3-4 mg / kg;
invasive aspergillosis / Fusarium spp. and Scedosporium spp.; other severe forms of invasive fungal infections: 4 mg / kg;
esophageal candidiasis - not established.

In case of insufficient therapeutic effect, the maintenance dose of Voriconazole with intravenous administration can be increased to 4 mg / kg every 12 hours, and in case of intolerance to a high dose, it can be reduced to 3 mg / kg every 12 hours.

The duration of therapy should be as short as possible depending on the clinical outcome and mycological test responses.

The course of treatment should not exceed 180 days.

Treatment of children and adolescents

The recommended dosage regimen of Voriconazole in children from 2 to 12 years old and adolescents 12-14 years old, with a body weight of less than 50 kg:

saturating dose (first 24 hours): intravenous infusion - 9 mg / kg every 12 hours; oral administration - not recommended;
maintenance dose (after the first 24 hours): intravenous infusion - 8 mg / kg 2 times a day; oral administration - 9 mg / kg 2 times a day (the maximum allowable dose is 350 mg 2 times a day).

Treatment should be started with intravenous injection, transferring the patient to taking pills is allowed only after a significant improvement in the condition and the patient's ability to receive drugs inside.

If the child has no difficulty in swallowing tablets, then the dose of the drug should be rounded up to the nearest multiple of 50 mg, and only whole tablets should be taken, since they cannot be divided.

For adolescents 12-14 years old with a body weight of 50 kg or more, as well as 15-18 years old, regardless of body weight, voriconazole is prescribed in the same doses as for adults.

When an inadequate clinical response is observed, the dose can be increased in increments of 1 mg / kg, or 50 mg if the maximum oral dose (350 mg) was initially used.

If the child does not tolerate treatment with the prescribed dose, it must be reduced in steps of 1 mg / kg, or 50 mg in the case when the initial dose was 350 mg.

Prevention in children and adults

For the purpose of prophylaxis, Voriconazole should be started on the day of transplantation, the course may be 100 days. The course can be extended up to 180 days only if immunosuppressive treatment is continued or a graft versus host reaction (GRT) occurs.

In clinical studies, the efficacy and safety of voriconazole when used for more than 180 days have not been adequately studied.

The dosage regimen for prophylaxis is similar to that for therapy in the respective age groups.

Preparation of solution for infusion

Lyophilisate for concentrate preparation / lyophilized powder for solution preparation is available in single use vials. The contents of the vial should be diluted in 19 ml of water for injection until a transparent concentrate / solution is formed in a volume of 20 ml, containing voriconazole at a dose of 10 mg / ml. If the solvent does not enter the bottle under the influence of vacuum, it is prohibited to use the latter. Before use, in accordance with special tables, the required amount of reconstituted solution / concentrate is added to one of the following recommended compatible infusion solutions to obtain a solution containing voriconazole in concentrations of 0.5–5 mg / ml.

Lyophilisate, for the preparation of a concentrate / solution for infusion, is a sterile, single-dose, lyophilized powder that does not contain preservatives. From a microbiological point of view, the solution prepared from the drug must be injected immediately after dilution. If the reconstituted solution (concentrate) was not used immediately, its storage is possible only for no more than 24 hours at a temperature of 2-8 ° C, if it is prepared under controlled aseptic conditions.

Recommended dilution solutions (all of the following solutions are intended for intravenous administration):

sodium chloride solution 0.9%;
Ringer's Lactate solution for infusion;
dextrose solution 5%;
dextrose solution 5% and Ringer's Lactate solution for infusion;
dextrose solution 5% and sodium chloride solution 0.45%;
dextrose solution 5% and potassium chloride solution 0.15%;
sodium chloride solution 0.45%;
dextrose solution 5% and sodium chloride solution 0.9%.

The compatibility of Voriconazole with solutions other than those indicated above has not been established.

Side effects

cardiovascular system: often - bradycardia, tachycardia, arterial hypotension, supraventricular arrhythmia, phlebitis; infrequently - ventricular / supraventricular tachycardia, ventricular premature beats, ventricular fibrillation, thrombophlebitis; rarely - nodular arrhythmias, bundle branch block, complete atrioventricular block, pirouette-type arrhythmia;
respiratory system, chest and mediastinal organs: very often - respiratory depression; often - acute respiratory distress syndrome, pulmonary edema;
hematopoietic system and lymphatic system: often - anemia, pancytopenia, agranulocytosis (including neutropenia / febrile neutropenia), thrombocytopenia (including immune thrombocytopenic purpura); infrequently - leukopenia, eosinophilia, bone marrow depression, lymphadenopathy, disseminated intravascular coagulation syndrome;
organ of hearing and vestibular apparatus: infrequently - tinnitus, vertigo, hypoacusia;
organ of vision: very often - blurred vision, decreased visual acuity, blurred vision, chloropsia, photophobia, presence of rainbow circles around light sources in the field of vision, color / night blindness, photophobia, chromatopsia, cyanopsia, photopsia, visual brightness, oscillopsia, field defect vision, ciliated scotoma, xanthopsia, floating opacities of the vitreous body; often - hemorrhage in the retina of the eye; infrequently - diplopia, optic neuritis, oculogyric crisis, scleritis, blepharitis, edema of the papilla of the optic nerve; rarely - corneal opacity, optic nerve atrophy;
nervous system: very often - headache; often - drowsiness, tremors, dizziness, nystagmus, syncope, convulsions, paresthesia; infrequently - dysgeusia (violation of taste perception), hypesthesia, ataxia, peripheral neuropathy, encephalopathy, cerebral edema, extrapyramidal disorder; rarely - Guillain-Bare syndrome, hepatic encephalopathy;
mental disorders: often - insomnia, anxiety, agitation, depression, confusion, hallucinations;
gastrointestinal tract: very often - vomiting, nausea, abdominal pain, diarrhea; often - cheilitis, constipation, dyspepsia; infrequently - glossitis, duodenitis, tongue edema, pancreatitis;
hepatobiliary system: very often - increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH); hyperbilirubinemia; often - cholestatic jaundice, jaundice, hepatitis; infrequently - cholelithiasis, cholecystitis, liver failure, liver enlargement (recorded mainly against the background of serious diseases, mainly malignant blood tumors; in the absence of risk factors, there are transient effects, including hepatitis and jaundice);
neoplasms benign, unspecified and malignant (including polyps and cysts): with an unknown frequency - squamous cell carcinoma of the skin;
endocrine system: infrequently - hypothyroidism, adrenal cortex insufficiency; rarely - hyperthyroidism;
kidneys and urinary system: often - hematuria, acute renal failure; infrequently - proteinuria, nephritis, necrosis of the renal tubules;
musculoskeletal system and connective tissue: often - back pain; infrequently - arthritis; with an unknown frequency - periostitis;
skin and subcutaneous tissue: very often - rash (usually mild / moderate); often - pruritus, alopecia, maculopapular rash, erythema, exfoliative dermatitis; infrequently - photosensitivity, purpura, allergic dermatitis, macular rash, eczema, psoriasis, urticaria, papular rash, erythema multiforme, angioedema, toxic epidermal necrolysis, Stevens-Johnson syndrome; rarely - persistent drug erythema, pseudoporphyria; with an unknown frequency - cutaneous form of systemic lupus erythematosus;
immune system: infrequently - allergic reactions; rarely - anaphylactoid reactions;
infections and invasions: often - gingivitis, sinusitis, gastroenteritis; infrequently - lymphangitis, peritonitis, pseudomembranous colitis;
metabolic and nutritional disorders: very often - peripheral edema; often - hypoglycemia, hyponatremia, hypokalemia (found in post-registration studies);
general disorders and disorders at the injection site: very often - fever; often - asthenia, chills, chest pain, swelling of the face (including swelling of the lips, mouth, periorbital edema), flu-like illness; infrequently - reaction / inflammation at the injection site;
studies: often - an increase in the level of creatinine in the blood; infrequently - lengthening of the QT interval on the electrocardiogram (ECG), an increase in the level of cholesterol / urea in the blood.

In children aged 2–12 years, adverse reactions similar to those in adults are recorded.

Overdose

There are data on three cases of unintentional overdose of voriconazole that occurred in children who received an intravenous dose of the drug, five times higher than the recommended one. In one of these episodes, photophobia was recorded lasting 10 minutes.

In case of drug overdose, supportive and symptomatic treatment is recommended. Hemodialysis can promote the elimination of voriconazole and the carrier of the active substance SBECD (betadex sulfobutylate) from the body.

The antidote for voriconazole has not been established.

special instructions

Before the start of the course and during treatment with voriconazole, it is necessary to correct hypokalemia, hypocalcemia, hypomagnesemia and other electrolyte disturbances.

It is required to take samples for inoculation and other laboratory studies (histopathological, serological) in order to isolate / identify pathogens before starting the course of therapy. Treatment can be started before laboratory test results are reported, but then therapy should be adjusted as needed.

In studies of the effects of voriconazole on the QT interval on an ECG with the participation of healthy volunteers, when using single doses that exceed the usual daily dose by no more than 4 times, none of the volunteers showed an increase in the QT interval of 60 ms or more above normal. as well as exceeding this interval above the clinically significant threshold of 500 msec.

Approximately 21% of patients experienced visual disturbances such as color vision changes, blurred vision, or photophobia during drug therapy. These side effects were transient and completely reversible: within 1 hour, in most cases, they disappeared spontaneously. As a rule, visual impairments are easily expressed, do not cause any long-term consequences, and only in rare cases require discontinuation of therapy. However, in the process of post-marketing studies, there were reports of visual impairments that persist for a long time, including optic neuritis, a veil in front of the eyes, and edema of the optic nerve head. These complications were noted most often in critically ill patients and / or undergoing concomitant treatment that can cause similar side effects.

With the use of Voriconazole, there is a risk of photosensitization, as a result of this, during the period of therapy, exposure to direct sunlight should be avoided, as well as wearing clothing that covers the body and using sunscreens with a high protection factor (SPF). With the development of skin photosensitivity reactions and the presence of additional risk factors, during prolonged treatment, the risk of squamous cell skin cancer and melanoma increases. When a patient develops phototoxic reactions, you need to consult with the appropriate specialists and be examined by a dermatologist.

Each vial of lyophilisate contains 217.6 mg of sodium, this should be considered for patients on a low sodium diet.

If the combined use of voriconazole and phenytoin / rifabutin is necessary, it is necessary to carefully assess the expected benefits and the possible risk of combined treatment before starting therapy.

When voriconazole is used with short / long acting narcotic analgesics, careful monitoring of possible adverse events associated with this combination is necessary.

Influence on the ability to drive vehicles and complex mechanisms

During drug therapy, the development of temporary and reversible visual impairments, including impairment / enhancement of visual perception and / or photophobia, a veil in front of the eyes can be observed. In the event of such undesirable reactions, it is necessary to abandon the management of road transport and work with other complex or moving mechanisms. You should also avoid driving at night.

Application during pregnancy and lactation

There is insufficient data on the use of voriconazole in pregnant women to analyze the efficacy and safety of the drug during these periods. The potential threat of therapy with the drug for humans is unknown, however, in the course of preclinical studies in animals, it was revealed that it is capable of having a toxic effect on reproductive function.

An antifungal agent is not recommended during pregnancy unless the intended benefit to the woman outweighs the potential threat to the health of the fetus.

The excretion of voriconazole in breast milk has not been studied. During the period of drug treatment, breastfeeding should be discontinued.

Women of reproductive age need to use reliable contraception during the course of therapy.

Pediatric use

In children, when taken orally with a maintenance dose of 9 mg / kg (but not more than 350 mg) 2 times a day, the estimated level of the total concentration of voriconazole is comparable to that in adults with oral administration of the drug at a dose of 200 mg with the same frequency of administration.

With intravenous infusion at a dose of 8 mg / kg, the drug content is twice as high as when taking tablets at a dose of 9 mg / kg. Due to oral use, the bioavailability of voriconazole in children may be limited by impaired absorption and sufficiently low body weight at this age, in such cases, IV administration may be indicated. According to the data obtained, in children, there is a higher elimination of the drug when compared with adults, as a result of a higher ratio of liver mass to body weight.

The plasma concentration of antimycotic in the blood of the overwhelming majority of adolescents corresponds to this indicator in adults. However, some of them, with low body weight in comparison with adult patients, also had lower values of the plasma level of the drug, closer to the values of this indicator in children. Taking into account the results of population pharmacokinetic analysis, adolescents 12-14 years old with a body weight of less than 50 kg are required to use the dose of voriconazole recommended for children.

Since the safety and efficacy of drug therapy in children under 2 years of age have not been established, its use is contraindicated in patients under 2 years of age (for film-coated tablets - up to 3 years).

The use of Voriconazole in children 2–12 years of age with impaired liver / kidney function has not been studied. Therapy in children and adolescents, as in adults, should be carried out with constant monitoring of liver function.

Since the incidence of phototoxic reactions in pediatric patients is higher, and phototoxic lesions can transform into squamous cell carcinoma (SCC), this category of patients should be provided with the fullest possible protection of the skin from ultraviolet radiation. Children with signs of photoaging of the skin (such as lentigines, freckles) need to avoid the sun and be examined by a dermatologist even after the end of therapy.

With impaired renal function

In patients with varying degrees of severity of renal impairment, the binding of voriconazole to plasma proteins is approximately the same.

With a single oral administration of Voriconazole tablets at a dose of 200 mg in patients with normal renal function and patients with impaired renal function from mild [creatinine clearance (CC) - 41-60 ml / min] to severe (CC less than 20 ml / min) degree, on the pharmacokinetics of the drug there was no significant effect associated with the degree of this violation.

In the presence of moderate / severe renal impairment (serum creatinine concentration ≥ 220 μmol / L or 2.5 mg / dL), accumulation of betadex sodium sulfobutylate, an additional component contained in the lyophilisate for preparing a concentrate for preparing a solution for infusion, was noted. Given this fact, patients at risk should use oral Voriconazole, unless the expected benefit from IV administration outweighs the potential threat. During the infusion of the solution, it is necessary to regularly monitor the level of creatinine, and if an increase in the latter is detected, decide on the possibility of transferring the patient to taking pills.

Voriconazole is excreted during hemodialysis with a clearance of 121 ml / min, for betadex sodium sulfobutylate (a carrier of the active substance) during hemodialysis, the clearance value is 55 ml / min.

For violations of liver function

Liver dysfunction does not affect the binding of voriconazole to blood plasma proteins.

With repeated oral use of the drug, its AUC _{t is} comparable in patients with moderate liver cirrhosis (class B on the Child-Pugh scale), taking voriconazole at a maintenance dose of 100 mg 2 times a day, and in patients with normal liver activity taking the drug in dose of 200 mg 2 times a day.

There are no data on the pharmacokinetics of the drug in patients with severe hepatic failure (class C according to the Child-Pugh classification).

In the presence of acute liver damage, manifested by increased activity of ACT and ALT, dose changes are not required, but it is recommended to continue monitoring liver function indicators.

For mild / moderate liver dysfunction (classes A and B on the Child-Pugh scale), a standard saturating dose of voriconazole is used, but the maintenance dose must be reduced by 2 times. Patients with severe hepatic impairment (class C on the Child-Pugh scale) are prescribed the drug only when the expected benefit exceeds the potential threat, with constant monitoring in order to timely detect symptoms of possible toxic effects of the drug. Control is necessary at the beginning of the course and at least 1 time per week during the first month of therapy. With the continuation of the course and there are no changes in the results of liver tests, the frequency of laboratory tests can be reduced to 1 time per month.

Use in the elderly

The safety profile of the antifungal drug does not differ in young and elderly patients. There is no need to adjust the dose of Voriconazole depending on age.

Drug interactions

inhibitors or inducers of isoenzymes CYP2C19, CYP3A4 and CYP2C9: able to increase or decrease, respectively, the plasma concentration of voriconazole;
rifampicin (inducer of CYP isoenzymes), in a daily dose of 600 mg: reduces the AUC and C _{max of} voriconazole by 96 and 93%, respectively; combination therapy is contraindicated;
ritonavir (an inhibitor and substrate of CYP3A4, an inducer of CYP isoenzymes), every 12 hours at a dose of 400 mg: reduces the AUC and C _{max of the} oral antifungal agent by an average of 82 and 66%, respectively, repeated oral use of the latter does not have a pronounced effect on Ritonavir AUC and C _max; the combination is contraindicated;
warfarin at a dose of 30 mg 1 time per day: against the background of concomitant use of voriconazole at a dose of 300 mg 2 times a day, an increase in the maximum prothrombin time up to 93% is recorded, with a combination it is required to control the latter;
drugs metabolized by isoenzymes CYP2C9, CYP2C19, CYP3A4: there may be an increase in the content of these drugs in plasma;
carbamazepine or long-acting barbiturates, including phenobarbital (potent inducers of CYP isoenzymes): a pronounced decrease in the plasma C _{max of the} antimycotic is possible; despite the fact that the interaction has not been studied, the simultaneous use of drugs is contraindicated;
astemizole, pimozide, terfenadine, quinidine, cisapride: a significant increase in the content of these substances in plasma is possible, which can contribute to a prolongation of the QT interval and, in some cases, provoke ventricular fibrillation / flutter; simultaneous use is contraindicated;
cimetidine (a nonspecific inhibitor of the cytochrome P ₄₅₀ isoenzyme), 2 times a day at a dose of 400 mg: the AUC and C _{max of} voriconazole may increase by 23 and 18%, respectively, no change in the dose of the drug is required;
sirolimus, a single dose of 2 mg: the AUC and C _{max of} this agent increase by 1014 and 556%, respectively (the combination is contraindicated);
cyclosporine: an increase in AUC and C _{max of} this substance can be recorded, not less than 70 and 13%, respectively, which in patients who have undergone kidney transplantation and are in a stable state, aggravates the risk of nephrotoxic reactions; with simultaneous use, it is recommended to reduce the dose of cyclosporine by 2 times and control its plasma level; after completion of voriconazole therapy, it is necessary to monitor the levels of cyclosporine and, if necessary, increase its dose;
tacrolimus, at a dose of 0.1 mg / kg once: its AUC and C _max increase by 221 and 117%, respectively, which may be accompanied by nephrotoxic reactions; it is recommended to reduce the dose of this substance to ⅓ and control the plasma level; after discontinuation of the antimycotic, tacrolimus content should be monitored and, if necessary, its dose should be increased;
acenocoumarol, phenprocoumon (substrates CYP2C9, CYP3A4): their plasma level and prothrombin time increase, it is necessary to control the latter at short intervals and select the dose of anticoagulants accordingly;
lovastatin (CYP3A4 substrate): its metabolism is inhibited, the threat of rhabdomyolysis development increases; dose adjustment of statin may be appropriate;
glipizide, tolbutamide, glibenclamide (sulfonylurea derivatives, CYP2C9 substrates): the concentration of these substances in plasma increases, which aggravates the risk of hypoglycemia; blood glucose should be monitored;
prednisolone (CYP3A4 substrate), at a dose of 60 mg once: the AUC and C _{max of} this agent increase by 34 and 11%, respectively, a dose change is not required;
alprazolam, midazolam, triazolam (substrates of CYP3A4, benzodiazepines metabolized under the influence of CYP3A4): their metabolism is suppressed, plasma concentration increases, a prolonged sedative effect appears, a change in the doses of these substances may be required;
efavirenz (CYP3A4 substrate), at a dose of 400 mg once a day: AUC and C _{max of} voriconazole (200 mg twice a day) decrease by about 77 and 61%, and efavirenz increases by about 44 and 38%, respectively; this combination is contraindicated;
vinca alkaloids (substrates of CYP3A4, vinblastine, vincristine): their level in plasma increases, the risk of neurotoxic reactions increases, it may be necessary to change the doses of these drugs;
rifabutin (inducer of cytochrome P ₄₅₀), at a dose of 300 mg 1 time / day: the AUC and C _{max of} voriconazole (200 mg 1 time / day) decrease by 78 and 69%, respectively; with simultaneous use, it is recommended to regularly carry out a detailed analysis of the picture of peripheral blood and timely identify the side effects of rifabutin (uveitis);
phenytoin (CYP2C9 substrate) 300 mg once a day: the AUC and C _{max of the} antimycotic decrease by 69 and 49%, respectively, and the AUC and C _{max of} phenytoin increase by 81 and 67%, respectively; if necessary, combined use should carefully monitor the plasma content of phenytoin;
amprenavir, saquinavir, nelfinavir and other HIV protease inhibitors (inhibitors and substrates of CYP3A4): these drugs, when combined with an antifungal drug, can lead to a mutual suppression of each other's metabolism; it is required to carefully monitor the patient's condition to identify possible signs of toxic effects;
everolimus: there may be a significant increase in the plasma concentration of this substance in the blood; combined use is not recommended;
omeprazole (at a dose of 40 mg once a day): the AUC and C _{max of} voriconazole increase by 41 and 15%, and omeprazole - by 280 and 116%, respectively; the dose of omeprazole must be reduced by 2 times;
methadone: an increase in the plasma concentration of this substance in the blood is possible, which can cause toxic effects, including prolongation of the QT interval; control of the patient's condition is necessary, a dose reduction may be required.

Analogs

Voriconazole analogs are Voriconazole Sandoz, Vfend, Voriconazole-Teva, Voricoz, Voriconazole-Acri, Voriconazole Canon, Vikand, Biflurin, etc.

Terms and conditions of storage

Store in a place protected from moisture (for tablets) and light, out of reach of children, at a temperature not exceeding 25 ° C, lyophilisate for preparing a concentrate for preparing a solution for infusion - up to 30 ° C.

Shelf life - 2 years (lyophilized powder and film-coated tablets) or 3 years (lyophilisate for concentrate preparation and film-coated tablets).

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Voriconazole

On medical sites, reviews of Voriconazole and its analogues are extremely rare. Most patients consider the drug an effective antimycotic for systemic use with a wide spectrum of action.

The disadvantages of Voriconazole include its high cost.

The price of Voriconazole in pharmacies

There are no reliable data on the price of Voriconazole, since the drug is not currently sold in pharmacies.

The cost of an analogue of the drug, Voriconazole Canon, film-coated tablets (200 mg) can be 14,200–20,200 rubles. per package containing 14 pcs.

Voriconazole: prices in online pharmacies

Drug name

Price

Pharmacy

Voriconazole Sandoz 200 mg lyophilisate for preparation of solution for injection 1 pc.

4546 RUB

Buy

Voriconazole Canon 200 mg film-coated tablets 14 pcs.

RUB 16889

Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!