Index of drugs

A broad spectrum antifungal drug from the triazole group is indicated for use in adult patients and children from the age of 2 years in: treatment of invasive aspergillosis; treatment of candidemia in patients without concomitant neutropenia; treatment of severe, invasive infections with fluconazole-resistantCandida (includingC. krusei); treatment of severe fungal infections caused byScedosporium spp. andFusarium spp. Voriconazole should be used primarily in patients with progressive, potentially life-threatening infections. Prevention of invasive fungal infections in high-risk patients after allogeneic hematopoietic stem cell transplantation (HSCT).

1 tabl powl. contains 50 mg or 200 mg of voriconazole. Table. contain lactose. 1 ml of suspension (after diluting the powder with water) contains 40 mg of voriconazole. The suspension contains sucrose.

Antifungal medicine, a triazole derivative. It inhibits the course of the cytochrome P450-dependent 14-α-sterol demethylation, leading to disturbances in the synthesis of ergosterol and destruction of the fungal cell wall. Showsin vitro strong antifungal activity againstCandida spp. (including refractory to fluconazoleC. krusei, C. albicans andC. glabrata) and fungicidal effect onAspergillus spp., Scedosporium spp. andFusarium spp. Full or partial clinical efficacy of voriconazole has been demonstrated in type-induced infectionsaspergillus (A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans), typeCandida (C. albicans, C. krusei, C. glabrata, C. tropicalis, C. parapsilosis and some strainsC. dubliniensis, C. inconspicua, C. guilliermondii) and also againstScedosporium spp. (S. apiospermum, S. prolificans) andFusarium spp. Voriconazole has non-linear kinetics, and pharmacokinetic parameters show significant individual variability. It is quickly and almost completely absorbed from the gastrointestinal tract (bioavailability 96%), reaching a maximum concentration in blood after 1-2 h. Fatty food reduces the bioavailability of the drug. Plasma protein binding is 58%. Voriconazole penetrates well into tissues. It is metabolized in the liver by cytochrome P-450 enzymes (mainly CYP 2C19); the main metabolite is microbiologically inactive. T_0,5 in the blood is about 6 hours. The drug is excreted mainly in the urine, primarily in the form of metabolites; <2% is excreted unchanged.

Hypersensitivity to the active substance or to any of the excipients. Co-administration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine, since increased plasma concentrations of these drugs may lead to QTc prolongation and rarely to the occurrence of arrhythmiatorsades de pointes. Co-administration with rifampicin, carbamazepine or phenobarbital may significantly reduce the plasma concentrations of voriconazole. Co-administration of a standard dose of voriconazole with 400 mg once daily or more is contraindicated because efavirenz significantly reduces voriconazole plasma concentrations in healthy volunteers when used at such doses (voriconazole also significantly increases plasma concentrations of efavirenz). Co-administration with high dose ritonavir (400 mg twice daily or more) as ritonavir significantly reduces plasma voriconazole concentrations in healthy volunteers when used at this dose. Concomitant administration of ergot alkaloids (ergotamine, dihydroergotamine), which are substrates of CYP3A4 due to the fact that increased plasma concentrations of these drugs may lead to ergot poisoning. Co-administration with sirolimus, because it can significantly increase its plasma concentration. Concomitant use with St. John's wort.

Special care should be taken when prescribing to patients with hypersensitivity to other azoles. Due to the risk of QTc prolongation and type-related arrhythmiastorsades de pointesvoriconazole should be used with caution in patients with the following risk factors that may be associated with arrhythmia: congenital or acquired prolongation of the QTc interval; cardiomyopathy, especially with concomitant heart failure, sinus bradycardia, symptomatic arrhythmias, concomitant use of drugs that may prolong the QTc interval. Electrolyte abnormalities such as hypokalemia, hypomagnesaemia and hypocalcaemia should be monitored and, if necessary, corrected before and during treatment with voriconazole. Patients receiving voriconazole must be carefully monitored for hepatotoxicity. Clinical management should include a laboratory assessment of liver function (in particular, AST and ALT activity tests) at the beginning of treatment and at least once a week in the first month of treatment. The duration of therapy should be as short as possible, however, if the treatment is continued on the basis of a risk-benefit assessment, treatment can be reduced and performed once a month, if the liver function tests do not change. In the event of a significant increase in the results of liver function tests, treatment should be discontinued unless the medical assessment of the benefit-risk balance for a given patient justifies continuing the treatment. Monitoring of liver function should be performed in both children and adults. There were reports of prolonged visual adverse events, including blurred vision, optic neuritis and congestive disc. Patients on voriconazole should be monitored for renal function including laboratory evaluation with particular reference to serum creatinine. Patients, in particular children, with risk factors for acute pancreatitis (eg recent chemotherapy, HSCT stem cell transplantation) should be closely monitored during treatment with the product. In this clinical situation, the study of serum amylase or lipase activity may be considered. If a patient's rash occurs, it should be closely monitored and if changes are progressive, voriconazole should be discontinued. Due to the risk of phototoxic reactions and pseudoporfiria, it is recommended that all patients, including children, be informed about the need to avoid exposure to sunlight and the need to wear clothing that protects against sunlight and the use of filters with a UV protection filter the light protection factor (SPF) during treatment with voriconazole. Long-term exposure (treatment or prophylactic use) exceeding 180 days (6 months) requires careful assessment of the risk / benefit ratio, therefore physicians should consider the need to reduce exposure. During long-term treatment with SCC, patients have been observed, some of whom reported previous phototoxic reactions. If a phytotoxic reaction occurs, a multidisciplinary approach should be sought and the patient referred to a dermatologist. Discontinuation of voriconazole and the use of alternative antifungal drugs should be considered. Whenever voriconazole treatment is continued despite the occurrence of phototoxicity related lesions, systematic and regular dermatological examinations are necessary to enable early diagnosis and treatment of pre-cancer lesions. If precancerous lesions or squamous cell carcinoma are found, voriconazole should be discontinued. Non-infectious periostitis with increased fluoride concentration and increased alkaline phosphatase activity was observed in transplant patients. If a patient develops bone pain and radiological results will indicate periostealitis, after obtaining multidisciplinary advice, discontinuation of treatment with the preparation should be considered. The safety and efficacy of the medicine have not been established in patients under the age of 2 years. Bioavailability after oral administration may be reduced in children from 2 to <12 years of age with malabsorption or very low body weight in relation to age. In this case, voriconazole is recommended intravenously. In children and adolescents, the incidence of phototoxic reactions is greater. As the development of squamous cell carcinoma has been reported, in this group of patients it is justified to use strict protective measures against solar radiation. In the case of children with signs of photoaging, such as lentigo or freckles, it is recommended to avoid sun and continue dermatological control even after treatment.In case of adverse events associated with treatment (hepatotoxicity, severe skin reactions, including phototoxicity and squamous cell carcinoma, severe or prolonged visual disturbances and periosteumitis) discontinuation of voriconazole and alternative antifungal drugs should be considered. The tablets contain lactose and should not be used in patients with rare inherited forms of galactose intolerance, Lapp lactase deficiency or poor glucose-galactose absorption. The oral suspension contains sucrose and should not be used in patients with rare hereditary forms of fructose intolerance, sucrase-isomaltase deficiency or poor glucose-galactose absorption.

It must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. There are no adequate data on the use of the preparation during pregnancy. Animal studies have shown reproductive toxicity. Women of childbearing potential must always use effective contraception during treatment with voriconazole. Breastfeeding must be discontinued at the start of treatment with the preparation.

Very common: peripheral edema, headache, blurred vision (including blurred vision, chromatopathy, photophobia), respiratory distress syndrome, abdominal pain, nausea, vomiting, diarrhea, abnormal liver function tests (including: AST, ALAT, alkaline phosphatase) , GGTP, LDH, bilirubin), rash, fever. Common: gastroenteritis, sinusitis, gingivitis, agranulocytosis, pancytopenia, thrombocytopenia, anemia, hypersensitivity, hypoglycemia, hypokalemia, hyponatremia, depression, hallucinations, anxiety, insomnia, agitation, confusion, convulsions, tremors, paresthesia, increased tension muscular, drowsiness, fainting, dizziness, retinal haemorrhage, supraventricular arrhythmia, tachycardia, bradycardia, hypotension, phlebitis, acute respiratory distress syndrome, pulmonary edema, indigestion, constipation, inflammation of the lips, jaundice, cholestatic jaundice, hepatitis, exfoliative inflammation dermatitis, pruritic rash, pruritus, alopecia, erythema, back pain, acute renal failure, hematuria, chest pain, facial edema, weakness, flu-like illness, chills, increased blood creatinine. Uncommon: pseudomembranous colitis, lymphangitis, peritonitis, disseminated intravascular coagulation, bone marrow failure, leukopenia, lymphadenopathy, eosinophilia, anaphylactic reaction, adrenal insufficiency, hypothyroidism, cerebral edema, encephalopathy, extrapyramidal disorder, peripheral neuropathy, ataxia, hypoaesthesia, dysgeusia, nystagmus, forcible vision with ocular rotation, optic nerve disease (including optic neuritis), congestive disc, scleritis, blepharitis, diplopia, hearing loss, dizziness, tinnitus, ventricular fibrillation, additional ventricular contractions, supraventricular tachycardia, ventricular tachycardia, thrombophlebitis, pancreatitis, duodenitis, inflammation of the tongue, swollen tongue, liver failure, hepatomegaly, cholecystitis, cholelithiasis, toxic-dead including separation of the epidermis, Stevens-Johnson syndrome, erythema multiforme, angioneurotic edema, psoriasis, urticaria, allergic dermatitis, phototoxic skin inflammation, macular rash, papular rash, purpura, eczema, arthritis, renal tubular necrosis, proteinuria, nephritis, reaction at the injection site, prolongation of the QTc interval on the ECG, increased blood urea, increased cholesterol in the blood. Rare: thyrotoxicosis, hepatic encephalopathy, Guillain-Barris syndrome, atrophy of the optic nerve, corneal opacity,torsades de pointes, total atrio-ventricular block, bundle branch block, nodal rhythm, pseudoporphiria, fixed drug eruption. Frequency not known: squamous cell carcinoma, cutaneous lupus erythematosus, periostitis. The profile of adverse reactions in children aged 2 to <12 years was similar to that in adults, although post-marketing data suggest that the skin reaction (especially erythema) may be more common in children than in adults. Pancreatitis has been reported in children after the medicine has been introduced.

Orally, at least 1 h before a meal or 1 h after a meal.Treatment. Adults and adolescents (from 12 to 14 years of age and ≥ 50 kg, from 15 to 17 years old regardless of the month). Therapy should be initiated with a specific saturated dose regimen, either intravenously or orally, in order to achieve plasma levels of drug similar to steady state on day 1. Due to the high bioavailability of the oral dosage form (96%), it is possible to change between intravenous and oral route of administration when clinically indicated.Loading dose (first 24 h): intravenously 6 mg / kg every 12 hours or orally: patients with 40 kg and more - 400 mg every 12 hours; patients with mc. less than 40 kg - 200 mg every 12 hours.Maintenance dose (after the first 24 hours): intravenously 4 mg / kg 2 times / day or orally: patients with 40 kg and more - 200 mg 2 times / day; patients with mc. less than 40 kg - 100 mg 2 times / day. The duration of treatment should depend on the clinical and mycological response and be as short as possible. For long-term treatment with voriconazole in excess of 180 days (6 months), the benefit-risk balance should be carefully assessed.Dose adjustment. If the patient's response to treatment is insufficient, the oral maintenance dose can be increased to 300 mg twice daily. In patients with bw below 40 kg, the oral dose may be increased to 150 mg twice daily. If the patient does not tolerate treatment with an increased dose, the oral dose should be gradually reduced by 50 mg until a maintenance dose of 200 mg twice daily (or 100 mg twice daily in patients below 40 kg) is achieved.Children (aged 2 to <12 years) and young people with a low birth rate. (from 12 to 14 years of age <50 kg). The dosage of voriconazole in adolescents should be the same as in children, because their metabolism is more similar to the metabolism of children than adults.Loading dose (first 24 h): intravenously 9 mg / kg every 12 hours, orally - not recommended.Maintenance dose (after the first 24 hours): intravenously - 8 mg / kg 2 times / day or orally - 9 mg / kg 2 times / day (maximum dose of 350 mg 2 times a day). It is recommended to start intravenous therapy. The oral dosage regimen should only be considered if there is a clinically significant improvement. It should be taken into account that in this population an intravenous dose of 8 mg / kg provides about 2-fold greater exposure than the 9 mg / kg dose. administered orally. The oral dosage recommendations for children were determined based on studies in which voriconazole was given as an oral suspension. The bioequivalence of the powder for oral suspension and tablets has not been studied in children. Due to the supposedly short duration of gastrointestinal transit in children, it should be taken into account that there may be differences in the absorption of tablets in children compared to adult patients. Therefore, for children from 2 to <12 years of age, an oral suspension is recommended.Dose adjustment. In the event of insufficient patient response to the treatment, the dose may be increased by 1 mg / kg gradually. (or gradually by 50 mg when the maximum oral dose of 350 mg was used as the starting dose). If the patient does not tolerate treatment, the dose should be gradually reduced by 1 mg / kg. (or gradually by 50 mg when the maximum oral dose of 350 mg was used as the starting dose). Use in children aged 2 to <12 years with hepatic or renal failure has not been studied.Preventive use. Adults and children. The recommended dosage regimen for prophylaxis is the same as for treatment in appropriate age groups. Preventive treatment should be started on the day of transplantation and can last up to 100 days after transplantation. The duration of prophylactic use should be as short as possible and depends on the risk of developing an invasive fungal infection (IFI) determined by neutropenia or immunosuppression. Only if immunosuppression or graft-versus host disease (GvHD) persist, prophylactic use may be continued up to 180 days after transplantation. The clinical safety and efficacy of voriconazole have not been adequately controlled for more than 180 days. For the prophylaxis of voriconazole for more than 180 days (6 months), the benefit-risk ratio should be carefully assessed. The following instructions apply to both treatment and prophylactic use.Dose adjustment. When used prophylactically, no dose adjustment is recommended in the absence of efficacy or adverse effects associated with treatment. If treatment-related adverse reactions occur, discontinuation of voriconazole and the use of alternative antifungal drugs should be considered.Dose adjustment when co-administered with other medicines. Phenytoin may be used concomitantly with voriconazole when the oral maintenance dose of voriconazole is increased from 200 mg to 400 mg twice daily (from 100 mg to 200 mg orally, twice daily for patients below 40 kg ). If possible, concomitant use of voriconazole and rifabutin should be avoided. However, if their use is absolutely necessary, the oral maintenance dose of voriconazole can be increased from 200 mg to 350 mg twice daily (from 100 mg to 200 mg orally, twice daily for patients below 40 kg). Efavirenz can be co-administered with voriconazole if the voriconazole maintenance dose is increased to 400 mg every 12 hours and the efavirenz dose will be reduced by 50%, i.e. up to 300 mg once a day. After stopping treatment with voriconazole, the initial dosing of efavirenz should be resumed.Special groups of patients. There is no need to adjust the dose in elderly patients. There is no need to adjust the oral dosage in patients with mild to severe renal impairment. Voriconazole is hemodialyzed with a clearance of 121 ml / min. A four-hour hemodialysis does not remove the amount of voriconazole required to adjust the dose. In patients with moderate or moderate cirrhosis (Child-Pugh A and B) receiving voriconazole, a standard loading dose of voriconazole is recommended. However, the maintenance dose should be halved. Voriconazole has not been studied in patients with severe chronic cirrhosis (Child-Pugh C). Limited safety data are available in patients with abnormal liver function tests (AST, ALT, alkaline phosphatase or total bilirubin> 5 x ULN). In patients with severe hepatic injury, this drug should only be used if the benefit outweighs the potential risk. Patients with severe hepatic impairment should be monitored for toxicity.