Biflurin - instructions for use, dose, side effects, contraindications

Gipromellose E5 - 1.5 mg / 6.0 mg, silicon dioxide colloid - 2.0 / 8.0 mg, crospovidone - 15.0 mg / 60.0 mg, lactose - 60.0 mg / 240.0 mg, macrogol 6000 - 2.0 mg / 8.0 mg, sodium stearyl fumarate - 1.5 mg / 6.0 mg, sorbitol 15.0 mg / 60.0 mg.

Water-Soluble Film Sheath 3.0 mg / 12.0 mg.

Composition of water-soluble film shell: hypromellose E5 - 0,105 mg / 0,42 mg, hypromellose E15 -1,80 mg / 7.20 mg, propylene glycol - 0.15 mg / 0.60 mg, macrogol 6000 - 0.375 mg / 1.50 mg, talc-0 , 30 mg / 1.20 mg, titanium dioxide 0.15 mg / 0.60 mg, iron oxide yellow oxide 0.12 mg / 0.48 mg.

Description:

For a dosage of 50 mg: the tablets covered with a film cover, round, biconcave, from light yellow to yellow color.

For a dosage of 200 mg: the tablets covered with a film cover, oval, biconcave, from light yellow to yellow color.

On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A. C.03 Voriconazole

Pharmacodynamics:

Voriconazole is a broad-spectrum antifungal agent from the group of triazoles. The mechanism of action of voriconazole is associated with the inhibition of demethylation of 14a-sterol, mediated by fungal cytochrome P450, a key stage in the biosynthesis of ergosterol.

In vitro voriconazole has a broad spectrum of antifungal activity and is active against Candida spp. (including strains of C. krusei, resistant to fluconazole, and resistant strains of C. glabrata and C. albicans), and has a fungicidedayswith respect to all strains studied Aspergillus sp. as well as pathogenic fungi that have become relevant in recent times, including Scedosporium or Fusarium, which are limitedly sensitive to existing antifungal agents.

Clinical efficacy (with partial or complete response) was demonstrated in infections caused by Aspergillus spp., including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including S. albicans, FROM. dubliniensis, FROM. glabrata, FROM. inconspicua, FROM. krusei, FROM. parapsilosis, FROM. tropicalis and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

Other fungal infections in which the drug was used (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. mameffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including T. beigelii.

In vitro voriconazole activity against clinical strains was demonstrated Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 to 2 μg / ml.

In vitro activity of voriconazole in relation to Curvularia spp. and Sporothrix spp.

Pharmacokinetics:

The pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism. When the dose is increased, a disproportionate (more pronounced) increase in the area under the pharmacokinetic concentration-time curve (AUC) is observed. An increase in the oral dose from 200 mg twice a day to 300 mg twice a day leads to an increase in the AUC by an average of 2.5 times.With intravenous administration or ingestion of saturating doses of voriconazole, its concentration in the blood plasma approaches equilibrium within the first 24 hours. If the drug is administered twice a day in medium (but not saturated) doses, then voriconazole is cumulated, and equilibrium concentrations are reached 6th day in most patients.

Suction and distribution

Voriconazole quickly and almost completely absorbed after ingestion: the maximum concentration in the blood plasma (Cmax) is reached 1-2 hours after ingestion. Bioavailability of voriconazole for oral administration is 96%. With repeated intake with foods high in fat, Cmax and AUC decrease by 34% and 24%, respectively. Absorption of voriconazole does not depend on the pH of the gastric juice.

The average volume of distribution of voriconazole in the equilibrium state is about 4.6 l / kg, which indicates the active distribution of voriconazole in the tissue. Binding to plasma proteins is 58%.

Voriconazole penetrates the blood-brain barrier (BBB) and is determined in the cerebrospinal fluid.

Metabolism

According to in vitro studies voriconazole metabolized under the action of isoenzymes CYP2C19, CYP2C9, CYP3A4. An important role in the metabolism of voriconazole is played by the CYP2C19 isoenzyme, exhibiting a pronounced genetic polymorphism, and therefore a reduced metabolism of voriconazole is possible in 15-20% of representatives of Asian descent and 3-5% of representatives of Caucasoid and Negroid races. It was found that patients with reduced metabolism of voriconazole AUC are on average 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with a high metabolism, AUC voriconazole is on average 2 times higher than in homozygous.

The main metabolite of voriconazole is the N-oxide, whose proportion is about 72% of the total number of metabolites circulating in the blood plasma with a radioactive label. This metabolite has minimal antifungal activity and does not contribute to the clinical effect of voriconazole.

Excretion

Voriconazole is excreted as metabolites after biotransformation in the liver; In unchanged form, less than 2% of the administered dose is excreted by the kidneys.

After repeated ingestion or intravenous administration in urine, about 83% and 80% of the dose of the drug are detected, respectively.Most (> 94%) of the total dose is excreted within the first 96 hours after ingestion and intravenously.

The half-life period (T1 / 2) of voriconazole is dose dependent and is approximately 6 hours when taken internally at a dose of 200 mg. In connection with the nonlinearity of pharmacokinetics, the T1 / 2 value does not allow predicting the cumulation or excretion of voriconazole.

Pharmacokinetics in special groups

Floor

With multiple admission of voriconazole, Cmax and AUC in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years). There are no significant differences between Cmax and AUC in healthy elderly men and healthy elderly women (> 65 years). The equilibrium concentration of voriconazole in blood plasma in women was 100% and 91% higher than in men after taking the drug in the form of tablets or suspension, respectively. There is no need to adjust the dose of voriconazole depending on the sex. Concentrations in blood plasma in men and women are similar.

Age

With repeated administration of voriconazole in the form of tablets inside Cmax and AUC in healthy elderly men (> 65 years), 61% and 86%, respectively, higher than in healthy young men (18-45 years). There are no significant differences between Cmax and AUC in healthy elderly women (> 65 years) and healthy young women (18-45 years).There is no need to adjust the dose of voriconazole according to age.

The safety profile of voriconazole in young and elderly patients does not differ, so dose adjustment for elderly patients is not required.

Children

The recommended dose of voriconazole for oral administration to children is based on pharmacokinetic analysis (47 immunocompromised children 2 to 12 years of age who received 4 to 6 mg / kg of voriconazole in the form of a suspension twice a day). Comparative pharmacokinetic studies have shown that for children to reach a drug concentration comparable to that of administering a maintenance dose of voriconazole for ingestion of adults 200 mg twice a day, the same dose of voriconazole for oral administration (200 mg twice daily, regardless of body weight). It is noted that the bioavailability of voriconazole directly depends on the patient's body weight - the higher the child's body weight, the greater the bioavailability and vice versa. The data obtained indicate that dose adjustments for taking voriconazole in children aged 2 to 12 years at a dose of 200 mg 2 times a day are not required.

Nevertheless, the bioavailability of the drug when ingested in children can be limited to a violation of absorption and a sufficiently low body weight at this age. In accordance with the results of the population pharmacokinetic analysis, the administration of a saturating dose is not required, as well as dose adjustment of voriconazole depending on the age for children within the age range of 2 to 12 years.

Impaired renal function

With a single dose of voriconazole administered 200 mg in patients with normal renal function and patients with impaired renal function from mild (creatinine clearance <41-60 ml / min) to severe (KC <20 ml / min) drug pharmacokinetics does not depend on the degree of impaired renal function. The binding of voriconazole to plasma proteins is approximately the same in patients with varying degrees of renal insufficiency (see the sections on "Dosage and administration" and "Special instructions").

Impaired liver function

After a single dose of 200 mg AUC of voriconazole in patients with mild to moderate liver cirrhosis (classes A and B according to Child-Pugh classification) was 233% higher than in patients with normal liver function.Dysfunction of the liver does not affect the binding of voriconazole with plasma proteins.

With repeated administration of the drug inside the AUC voriconazole is comparable in patients with moderate liver cirrhosis (class B according to the Child-Pugh classification) who received the drug in a maintenance dose of 100 mg 2 times / day, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day. There is no information about the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (class C according to the Child-Pugh classification). For recommendations on how to dose the drug, see "Method of administration and dose".

Indications:

- invasive aspergillosis;

- severe invasive forms of candidiasis infections (including C. krusei);

Candidiasis of the esophagus;

- Candidemia in patients without neutropenia;

- severe fungal infections caused by Scedosporium spp and Fusarium spp.;

- prevention of breakthrough fungal infections in patients with reduced function of the immune system with fever and neutropenia from the high-risk group (allogeneic bone marrow recipients, patients with relapse of leukemia).

Contraindications:

Hypersensitivity to voriconazole or any other component of the drug.
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (since the drug contains lactose).
The simultaneous use of voriconazole and terfenadine, astemizole, cisapride, pimozide, quinidine, sirolimus, everolimus, rifampicin, carbamazepine and long-acting barbiturates (eg, phenobarbital), ergot alkaloids (ergotamine, dihydroergotamine), efavirenz (400 mg and higher once per day), ritonavir in high doses (400 mg and more 2 times a day), preparations of St. John's wort (per section "Interaction with other medicinal products)." The use of voriconazole in a standard dose (200 mg twice a day) at one-time enno with rifabutin (see. the section "Interaction with other drugs). Children under 3 years (for this dosage form).

Carefully:

Severe failure of liver function.

Ta severe degree of kidney failure.

Hypersensitivity to other azole derivatives.

In patients with proarrhythmic conditions (with congenital or acquired lengthening of the interval QT, cardiomyopathy, especially with heart failure, sinus bradycardia, symptomatic arrhythmia).

In patients who are simultaneously receiving drugs that are able to lengthen the interval QT. Electrolyte disorders such as hypokalemia, hypomagnesemia and hypocalcemia should be monitored and, if necessary, adjusted before therapy with voriconazole and during the administration of the drug.

Pregnancy and lactation:

Adequate information on the use of voriconazole in pregnant women is not. Studies in animals have shown that the drug in high doses has a toxic effect on reproductive function. The possible risk to a person is not known.

Voriconazole should not be used in pregnant women, except when the expected benefit to the mother clearly outweighs the possible risk to the fetus. The excretion of voriconazole with breast milk has not been studied. For the period of drug treatment, breastfeeding should be discontinued.

Women of reproductive age when using voriconazole, should use reliable methods of contraception.

Dosing and Administration:

Voriconazole should be taken orally for 1 hour before or 1 hour after meals.

Application in adults and adolescents over 12 years (from 12 to 14 years - with body weight ≥50 kg; 15 years and older - regardless of body weight)

The use of voriconazole should be started with the recommended saturating dose, in order to achieve a serum concentration near the equilibrium on the first day.

The saturation dose - all indications (first 24 hours): patients with a body weight of 40 kg and more, 400 mg every 12 hours; patients with a body weight of less than 40 kg of 200 mg every 12 hours.

Maintenance dose - all indications (after the first 24 hours): patients with a body weight of 40 kg and more, 200 mg every 12 hours; patients with a body weight of less than 40 kg at 100 mg every 12 hours.

Dose selection

If treatment is not effective, a maintenance dose in patients with a body weight of 40 kg or more can be increased to 300 mg every 12 hours. In patients with a body weight of less than 40 kg, the dose may be increased to 150 mg every 12 hours.

If the patient does not tolerate the drug in a high dose, then it is reduced in steps of 50 mg every 12 hours to 200 mg (or 100 mg every 12 hours in patients with a body weight of less than 40 kg). Phenytoin can be used with voriconazole if the maintenance dose of the latter is increased from 200 to 400 mg every 12 hours (from 100 to 200 mg every 12 hours in patients weighing less than 40 kg).

The simultaneous use of rifabutin and voriconazole should be avoided, except when the expected benefit of treatment outweighs the risk.If the simultaneous use of drugs can not be avoided, the maintenance dose of voriconazole should be increased from 200 to 350 mg every 12 hours (from 100 to 200 mg every 12 hours inside in patients weighing less than 40 kg).

With simultaneous use of efavirenz and voriconazole, the dose of voriconazole should be increased to 400 mg twice a day and the dose of efavirenz should be reduced to 300 mg once daily. When discontinuing voriconazole therapy, it is necessary to increase the dose of efavirenz to gthe original

Application in the elderly

Correction of dose in the elderly is not required.

Use in patients with impaired renal function

Violation of kidney function does not affect the pharmacokinetics of voriconazole. In this regard, correction of the dose of voriconazole in patients with mild, moderate or severe degree of renal dysfunction is not required.

Voriconazole is excreted during hemodialysis with a clearance of 121 ml / min. A four-hour session of hemodialysis does not lead to the removal of a significant portion of the dose of voriconazole and does not require its correction.

Use in patients with impaired liver function

In acute liver damage, manifested by increased activity of "liver" transaminases (ALT, ACT), dose adjustment is not required.In such cases it is recommended to continue monitoring the liver function indicators in order to detect their further increase.

In patients with impaired liver function of mild or moderate severity (classes A and B on the Child-Pugh scale), it is recommended that a standard dose of voriconazole be prescribed and the maintenance dose reduced 2-fold. Patients with severe impairment of liver function voriconazole should be prescribed only in those cases where the expected benefit outweighs the possible risk, treatment should be carried out under constant monitoring to identify signs of drug toxicity.

Use in children

The drug should be given to children only if the child can swallow the pill.

Children aged 3 to <12 years and adolescents aged 12 to 14 years with a body weight <50 kg

If the child can swallow the pill, then the dose is rounded to the nearest dose in mg / kg, a multiple of 50 mg, and is given as whole tablets.

The saturation dose (the first 24 hours): 9 mg / kg every 12 hours intravenously; oral administration is not recommended;

Maintenance dose (after the first 24 hours): 9 mg / kg every 12 hours (maximum dose of 350 mg twice a day).

Recommendations for the use of voriconazole in children are given on the basis of studies of its use in the form of a powder for the preparation of a suspension for oral administration.The bioequivalence of voriconazole in the form of a powder for the preparation of a suspension for ingestion and tablets when used in children has not been studied. Given that children have slowed down the passage of food through the gastrointestinal tract, it is likely that the absorption of voriconazole when taken in the form of tablets will be different than in adults.

The pharmacokinetics and tolerability of higher doses in children have not been studied.

The use of voriconazole in children aged 2 to <12 years with impaired liver or kidney function has not been studied.

Correction of dose

In case of an inadequate clinical response, the dose of voriconazole can be increased by 1 mg / kg (or 50 mg in the event that a maximum dose of 350 mg was initially administered). If the patient does not tolerate the drug in a high dose, then it is reduced in steps of 1 mg / kg (or 50 mg if the original maximum dose of 350 mg was used).

Side effects:

The most common side effects are visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. Adverse reactions are usually mild or moderate. Clinically significant dependence of drug safety on age, race or sex was not revealed.Below are the undesirable reactions observed with the use of the drug and probably related to ongoing therapy.

Criteria for assessing the incidence of adverse reactions: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1 000); very rarely (<1/10000), including individual messages.

On the part of the hematopoiesis system: often - pancytopenia, oppression of bone marrow hematopoiesis, thrombocytopenia, leukopenia, purpura, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic); infrequently - agranulocytosis, disseminated intravascular coagulation syndrome, lymphadenopathy, eosinophilia.

From the endocrine system: infrequently - insufficiency of the adrenal cortex; rarely - hyperthyroidism, hypothyroidism.

From the immune system: often sinusitis; infrequently - hypersensitivity reactions, anaphylactoid reactions.

From the side of metabolism: often hypokalemia, hypoglycemia.

Mental disorders: often - hallucinations, depression, anxiety; rarely - insomnia.

From the nervous system: very often - headache; often - dizziness, agitation, tremor, paresthesia,confusion of consciousness; infrequently - ataxia, diplopia, cerebral edema, vertigo, hypoesthesia; rarely - convulsions, encephalopathy, Guillain-Barre syndrome, extrapyramidal disorders, peripheral neuropathy.

From the sense organs: very often - visual disturbances (including impaired / increased visual perception, the appearance of "shrouds" before the eyes, andcolor perception, photophobia); infrequently - edema of the nipple of the optic nerve, scleritis, blepharitis, optic neuritis, nystagmus; rarely - bleeding in the retina of the eye, atrophy of the optic nerve, corneal opacity, oculogic crisis, hypoacusia, noise (ringing) in the ears.

From the cardiovascular system: very often peripheral edema; often - lowering blood pressure, thrombophlebitis, phlebitis; infrequently ventricular fibrillation, ventricular arrhythmias, syncope, supraventricular arrhythmia, supraventricular tachycardia, bradycardia, tachycardia; rarely - ventricular tachycardia (including ventricular tachycardia of the "torsade de pointes"), complete atrioventricular block, bundle branch blockade, nodal arrhythmias, lengthening of the interval QT, lymphangitis.

From the respiratory system: often - respiratory distress syndrome, pulmonary edema, respiratory failure.

From the digestive system: very often - nausea, vomiting, diarrhea, abdominal pain; infrequently - constipation, duodenitis, dyspepsia, gingivitis, glossitis, pancreatitis, edema of the tongue, peritonitis; rarely - a violation of taste perception.

From the hepatobiliary system: often jaundice, cholestatic jaundice; infrequently - cholecystitis, cholelithiasis, liver enlargement, hepatitis, liver failure; rarely - hepatic coma.

From the skin and subcutaneous fat: very often - a rash; often - edema of the face, cheilitis, erythema, pruritus, macular rash, papular rash, photosensitization, alopecia, exfoliative dermatitis; infrequently - Stevens-Johnson syndrome, angioedema, allergic dermatitis, drug-induced erythema, psoriasis, urticaria; rarely - discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis, pseudoporphyria; frequency not established - squamous cell carcinoma.

From the musculoskeletal system: often - pain in the back; infrequently - arthritis; rarely hypertonus; frequency is unknown - periostitis.

From the urinary system: often acute renal failure, hematuria; infrequently - albuminuria, nephritis; rarely - necrosis of the renal tubules.

Laboratory indicators: often - increased functional liver tests (including increased activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, lactate dehydrogenase, bilirubin concentration), increased creatinine concentration in the blood plasma; infrequent increase of residual urea nitrogen, hypercholesterolemia.

Infections and infestations: often - gastroenteritis; rarely - pseudomembranous colitis

On the part of the body as a whole: very often - fever; often - chills, asthenia, chest pain, flu-like syndrome.

Visual disorders

In the treatment with voriconazole, approximately 21% of patients experience visual impairment: blurred vision, changes in color vision or photophobia. Visual disturbances are transient and completely reversible; in most cases they spontaneously disappear within 60 minutes. With repeated use of voriconazole, there is a weakening of their severity. Visual disturbances are usually easily expressed, rarely require discontinuation of treatment and do not lead to any remote consequences.

The mechanism of action of voriconazole is unknown, although the target organ, most often, is the retina of the eye. Determined that voriconazole reduces the amplitude of waves on the electroretinogram (ERG) in healthy volunteers. These changes do not grow ERG with continued treatment for 29 days and completely disappeared after withdrawal of voriconazole.

Long-term voriconazole therapy (for an average of 169 days) in patients with paracoccidioidomycosis did not have a clinically significant effect on visual function, which was confirmed by the results of tests on visual acuity, visual fields, color vision and contrast sensitivity.

Skin Reactions

When voriconazole therapy often develop skin reactions, mostly in patients with serious underlying diseases, while taking other medicines. In most cases, a mild to moderate skin rash was noted. Infrequently voriconazole in the treatment developed severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. When rashes appear, careful monitoring of the patient's condition should be carried out,and with the progression of skin rashes it is advisable to cancel voriconazole. In patients receiving long-term treatment voriconazole, skin reactions of photosensitivity can develop (see section "Special instructions").

Indicators of liver function

The frequency of clinically significant increase in the activity of "hepatic" transaminases in patients receiving voriconazole, is 13.4 %. In most cases indicators of liver function are normalized both during the continuation of treatment without changing the dose, or after its correction, and after discontinuation of therapy. When using voriconazole, cases of severe hepatotoxicity (jaundice, hepatitis and liver failure leading to death) were rare in patients with serious underlying diseases.

Use in children

The undesirable effects in treatment with voriconazole in children are similar to those in adult patients. In the course of postmarketing studies, a more frequent occurrence of skin reactions was detected. In addition, cases of development of pancreatitis in the treatment of voriconazole in children have been reported.

Overdose:

It is known about three cases of accidental overdose of voriconazole.All of these cases occurred in children who received a dose of voriconazole intravenously, five times the recommended dose. There is a report of a single case of photophobia, lasting 10 minutes.

The antidote of voriconazole is unknown. In case of an overdose, symptomatic and supportive therapy is indicated.

Voriconazole is removed during hemodialysis with a clearance of 121 ml / min. In case of an overdose, hemodialysis can help to remove voriconazole from the body.

Interaction:

Voriconazole is metabolized by cytochrome P450 isoenzymes - CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes can cause, respectively, an increase or decrease in the concentrations of voriconazole in plasma. Voriconazole inhibits the activity of isoenzymes CYP2C19, CYP2C9 and CYP3A4. In connection with this voriconazole can increase the plasma concentrations of substances that are metabolized by these isofermings CYP450.

With the simultaneous use of voriconazole with drugs that can lengthen the interval QT, care must be taken. The simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since these drugs are metabolized with the participation of the isoenzyme CYP3A4, and with simultaneous application with voriconazole, there is a possibility of an increase in their plasma concentrations.

Carbamazepine and long-acting barbiturates (powerful inducers CYP450): carbamazepine and long-acting barbiturates (for example, phenobarbital), probably significantly reduce the concentrations of voriconazole in plasma, although their interaction has not been studied. The simultaneous use of voriconazole with carbamazepine and long-acting barbiturates is contraindicated.

Efavirenz (inducer CYP450, inhibitor and substrate CYP3A4): while simultaneous use of efavirenz at a dose of 400 mg per day with voriconazole at a dose of 200 mg every 12 hours, two types of interaction were identified. Stable area values under the pharmacokinetic curve "concentration-time" (AUC) and C_mOh voriconazole declined an average of 77% and 61%, respectively, while stable values AUC and C_mOh efavirenz increased by an average of 44% and 38%, respectively. The simultaneous use of therapeutic doses of voriconazal and efavirenz is contraindicated. With simultaneous use of efavirenz and voriconazole, the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be reduced to 300 mg once daily.When discontinuing voriconazole therapy, it is necessary to increase the dose of efavirenz to the initial dose (400 mg per day).

Other non-nucleoside reverse transcriptase inhibitors (substrates CYP3A4, inhibitors or inducers CYP450)

Research in vitro showed that non-nucleoside reverse transcriptase inhibitors (NNRTIs), for example, delaverdine or nevirapine can inhibit the metabolism of voriconazole. Voriconazole can suppress the metabolism of NNRTIs.

As efavirenz may cause a decrease AUC and C_max voriconazole, we can assume the possibility of a similar effect of other NNRTIs on the metabolism of voriconazole. With the simultaneous use of voriconazole and NNRTI, patients should be observed in order to identify possible toxic effects and / or lack of therapeutic effect, if necessary, dose adjustments.

Terfenadine, astemizole, 1(isapride, pimozide and quinidine (substrates CYP3A4): although interaction with these drugs has not been studied, nevertheless the simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since an increase in their plasma concentration may lead to an elongation of the interval QT and in rare cases to the development of ventricular tachycardia such as "pirouette." Simultaneous application with these drugs is contraindicated.

Ergot alkaloids (substrates CYP3A4): although interaction with these drugs has not been studied, voriconazole can cause an increase in the concentrations of ergot alkaloids (ergotamine and dihydroergotamine) in plasma and the development of ergotism. Simultaneous use of ergot alkaloids with voriconazole is contraindicated.

Rifampicin (a powerful inductor CYP450): rifampicin (600 mg once daily) reduces C_mOh and AUCo-t voriconazole by 93% and 96%, respectively. The simultaneous use of voriconazole and rifampicin is contraindicated.

Rifabutin (a powerful inductor CYP450): rifabutin (300 mg once daily) reduces C_mOh and AUCo-t voriconazole (200 mg twice daily) by 69% and 78%, respectively. With the simultaneous administration of rifabutin at a dose of 300 mg once a day and voriconazole at a dose of 350 mg twice a day Cmah and AUCo-t voriconazole is 96% and 68% of the indices with monotherapy with voriconazole at a dose of 200 mg 2 times a day. With simultaneous application of voriconazole at a dose of 400 mg twice a day and rifabutin at a dose of 300 mg once a day Cmah and AUCo-t voriconazole, respectively, by 104% and 87% higher than with isolated administration of voriconazole at a dose of 200 mg twice a day. Voriconazole in a dose of 400 mg twice a day increases Cmah and AUCo-t rifabutin by 195% and 331%, respectively. The simultaneous use of rifabutin and voriconazole should be avoided, except when the expected benefit of treatment outweighs the risk. In this case, the maintenance dose of oral voriconazole should be increased from 200 mg to 350 mg twice a day (from 100 mg to 200 mg twice a day in patients weighing less than 40 kg). When treating rifabutin and voriconazole concomitantly, it is recommended that a detailed blood test be performed regularly and that unwanted effects of rifabutin (for example, uveitis) are monitored.

Ritonavir (powerful inductor CYP450, inhibitor and substrate CYP3A4):at simultaneous application with voriconazole ritonavir in a dose of 400 mg every 12 hours reduced C_m_Oh in the equilibrium state and AUC voriconazole taken internally, on average by 66% and 82%, respectively. Voriconazole did not exert a significant influence on Cmax in the equilibrium state and AUC ritonavir. With simultaneous administration of voriconazole and low doses of ritonavir, a decrease in Cmax and AUC ritonavir, respectively, by 25% and 13%, Cmax and AUC voriconazole at the same time decreased by 24% and 39%, respectively. Simultaneous use of voriconazole and high doses of ritonavir (400 mg and above) is contraindicated. Avoid concurrent use of voriconazole with low doses of ritonavir, unless the expected benefit of voriconazole therapy outweighs the risk.

Hypericum perforated (cytochrome P450 inducer and P-glycoprotein):at simultaneous application with preparations of St. John's wort AUC voriconazole by 59%. Simultaneous use of voriconazole and preparations of St. John's wort is contraindicated.

Fluconazole (inhibitor CYP2C9, CYP2C19 and CYP3A4): with the simultaneous use of voriconazole and fluconazole, there was an increase in Cmax and AUC voriconazole by 57% and 79%, respectively. The effect of voriconazole on the pharmacokinetics of fluconazole has not been studied. The simultaneous use of voriconazole and fluconazole at any dose is not recommended, the drugs should be administered sequentially.

Phenytoin (substrate CYP2C9 and a powerful inductor CYP450): with the simultaneous use of phenytoin at a dose of 300 mg once a day and voriconazole at a dose of 200 mg twice a day, there is a decrease in Cmax and AUCo-t voriconazole by 49% and 69%, respectively. Voriconazole in a dose of 400 mg twice a day increases Cmax and AUCo-t phenytoin (300 mg once daily) by 67% and 81%, respectively. The simultaneous use of voriconazole and phenytoin should be avoided, except when the expected benefit outweighs the possible risk. With the simultaneous use of phenytoin with voriconazole, careful monitoring of the levels of phenytoin in plasma is recommended. Phenytoin can be used together with voriconazole if the maintenance dose of the latter is increased from 200 mg to 400 mg twice a day for oral administration (from 100 mg to 200 mg twice a day inwards in patients weighing less than 40 kg). Warfarin (substrate CYP2C9): simultaneous application of voriconazole (300 mg twice daily) with warfarin (30 mg once) was accompanied by an increase in the maximum prothrombin time by about 2 times. With the simultaneous administration of warfarin and voriconazole, it is recommended to monitor prothrombin time, if necessary, dose correction of warfarin.

Other oral anticoagulants, for example, fenprokumone, acenocoumarol (substrates CYP2C9, CYP3A4): although interaction with these drugs has not been studied, nevertheless voriconazole, probably, can cause an increase in coumarin concentrations in plasma and an increase in prothrombin time. If patients receiving coumarin preparations are prescribed voriconazole, it is necessary to monitor prothrombin time with short intervals and appropriately select doses of anticoagulants. Benzodiazepines (substrates CYP3A4): although interaction with these drugs has not been studied, nevertheless voriconazoleprobably can cause an increase in the increase in plasma concentrations of benzodiazepines, which are metabolized by action CYP3A4 (midazolam, triazolam, alprazolam), and the development of prolonged sedation. With the simultaneous use of these drugs, it is recommended to discuss the advisability of correcting the dose of benzodiazepine.

Sirolimus (substrate CYP3A4): with simultaneous appointment voriconazole increases Cmah and AUC sirolimus (when taken in a dose of 2 mg once) in 6.6 times and 11 times, respectively. The simultaneous use of voriconazole and sirolimus is contraindicated.

Ciclosporin (substrate CYP3A4): in patients who have undergone kidney transplantation and are in a stable state, voriconazole increases Cmax and AUC cyclosporine by 13% and 70%, respectively. When voriconazole is prescribed to patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma concentrations. An increase in the concentration of cyclosporine is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to monitor the plasma cyclosporin concentrations and, if necessary, increase its dose.

Tacrolimus (substrate CYP3A4): with the simultaneous use of voriconazole and tacrolimus (0.1 mg / kg once), there is an increase in Cmah and AUWith tacrolimus on 117% and 221%, respectively. When voriconazole is prescribed to patients already receiving tacrolimus, it is recommended to reduce the dose of the latter to one third and monitor its plasma concentrations. An increase in tacrolimus concentrations is accompanied by nephrotoxicity. After voriconazole withdrawal, it is necessary to control the concentration of tacrolimus in the plasma and, if necessary, increase its dose.

Everolimus (substrate CYP3A4, P-glycoprotein substrate): although interaction with everolimus has not been studied, nevertheless, the use of this combination is contraindicated, since voriconazole can significantly increase the concentration of everolimus when co-administered.

Oxycodone (substrate CYP3A4)

With the simultaneous use of voriconazole inside (400 mg every 12 hours on the first day and 200 mg every 12 hours in the subsequent 2-4 days) and oxycodone orally in a single dose of 10 mg on the third day, Cmoxycodone 1.7 times and AUC oxycodone in 3,6 times. The half-life of oxycodone also doubles. When used concomitantly with voriconazole, a dose reduction of oxycodone and other long-acting opiates should be provided, which are metabolized with the participation of the isoenzyme CYP3A4 (for example, hydrocodone), in order to avoid undesirable effects caused by narcotic analgesics. It is recommended that careful monitoring be conducted to determine the undesirable effects associated with the use of oxycodone and other long-acting narcotic analgesics.

Methadone (substrate CYP3A4)

With simultaneous application with voriconazole, an increase in Cmah and AUC pharmacologically active R-metadone by 31% and 47%, respectively. FROMmah and AUC S- methadone increase by 65% and 103%, respectively.With the simultaneous use of methadone and voriconazole, careful monitoring is recommended to determine the undesirable effects of methadone, including lengthening the interval QT. You may need to reduce the dose of methadone.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Voriconazole increases Cmah and AUC ibuprofen (400 mg once) by 20% and 100%, respectively, and Cmah and AUC diclofenac (50 mg once) - by 114% and 78%, respectively. In the case of simultaneous use of voriconazole and NSAIDs, patients should be monitored to identify possible toxic effects of NSAIDs and, if necessary, adjust the dose of NSAIDs.

Omeprazole (inhibitor CYP2C19, substrate CYP2C19 and CYP3A4)

Omeprazole (40 mg once a day) increases Cmah and AUC voriconazole by 15% and 41%, respectively. Correction of the dose of voriconazole is not required.

Voriconazole increases Cmah and AUC omeprazole by 116% and 280%, respectively. When voriconazole is prescribed to patients receiving omeprazole, the dose of the latter is recommended to be halved. Voriconazole can also inhibit the metabolism of other proton pump blockers that are substrates CYP2C19, which may lead to an increase in the concentrations of these drugs in the plasma.

Oral contraceptives

Ethinylestradiol (inhibitor CYP2C19, substrate CYP3A4)

With the simultaneous use of voriconazole and norethisterone / ethinyl estradiol (at a dose of 1 mg / 0.035 mg once daily) there is an increase in Cmax and AUC norethisterone by 15% and 53%, respectively, and an increase in Cmethinyl estradiol by 61%. With simultaneous use of voriconazole and oral contraceptives should be monitored for side effects of contraceptives.

Narcotic analgesics of short action

Based on the results of the study, with the simultaneous use of voriconazole and fentanyl (at a dose of 5 mg / kg once), there was an increase AUC fentanyl by 1.34 times. With the simultaneous use of voriconazole and alfentanil, there was an increase AUC alfentanil 6 times. When used simultaneously with voriconazole, consideration should be given to reducing the dose of fentanyl, alfentanil or other short-acting opiates similar in structure to alfentanil and metabolized with the participation of an isoenzyme CYP3A4. It is recommended that careful monitoring be conducted to determine the undesirable effects of opiates, including respiratory depression.

Statins (Substrates CYP3A4)

In vitro voriconazole inhibits the metabolism of lovastatin (in human liver microsomes). Concerning voriconazole can cause an increase in plasma concentrations of statins metabolized by action CYP3A4. An increase in the concentration of statins was sometimes accompanied by the development of rhabdomyolysis.

With the simultaneous use of voriconazole and statins, it is recommended to evaluate the feasibility of reducing the dose of statin.

Derivatives of sulfonylureas (substrates CYP2C9)

Voriconazole can increase the concentration of sulfonylureas (e.g. tolbutamide, glipizide and glibenclamide) in the plasma and cause hypoglycemia. With the simultaneous use of these drugs and voriconazole, you need to carefully monitor the concentration of glucose in the blood. It is recommended to consider reducing the dose of sulfonylurea derivatives.

Vinca alkaloids (substrates CYP3A4)

Voriconazole can increase the content of vinca alkaloids in the plasma (e.g., vincristine and vinblastine) and cause neurotoxicity. It is recommended to consider reducing the dose of vinca alkaloids.

Indinavir (inhibitor and substrate CYP3A4)

Indinavir (800 mg three times a day) does not have a significant effect on Cmah and AUC voriconazole. Voriconazole does not significantly affect CmOh, Cmin and AUC indinavir (800 mg 3 times a day). With simultaneous application of correction of doses of drugs is not required.

Other HIV protease inhibitors (substrates and inhibitors CYP3A4)

Research in vitro evidence that voriconazole can inhibit the metabolism of HIV protease inhibitors (eg saquinavir, amprenavir and nelfinavir). Research in vitro also showed that HIV protease inhibitors can suppress the metabolism of voriconazole. In the case of simultaneous use of voriconazole with HIV protease inhibitors, patients should be monitored in order to identify possible toxic effects and / or insufficient action. Dose correction may be required.

Cimetidine (nonspecific inhibitor CYP450, increases the pH of gastric juice)

Cimetidine (400 mg twice a day) causes an increase in Cmah and AUC voriconazole by 18% and 23%, respectively. Correction of the dose with simultaneous application is not required.

Ranitidine (increases the pH of gastric juice)

Ranitidine (150 mg twice a day) does not have a significant effect on Cmah and AUC voriconazole. Correction of the dose of voriconazole is not required.

Antibiotics of the macrolide group

Erythromycin (inhibitor CYP3A4) in a dose of 1 g 2 times a day and azithromycin in a dose of 500 mg once a day do not have a significant effect on Cmah and AUC voriconazole. The effect of macrolides on the pharmacokinetics of voriconazole has not been studied. Correction of the dose with simultaneous application is not required.

Prednisolone (substrate CYP3A4)

Voriconazole increases Cmah and AUC prednisolone (60 mg once) by 11% and 34%, respectively. Correction of the dose with simultaneous application is not required.

Digoxin (P-glycoprotein substrate)

Voriconazole has no significant effect on Cmah and AUC digoxin (when administered at a dose of 0.25 mg once daily). Correction of doses with simultaneous application is not required.

Mycophenolic acid (substrate UDF-glucuronyltransferase)

Voriconazole does not affect Cmah and AUC mycophenolic acid (1 g once). Correction of the dose with simultaneous application is not required.

Special instructions:

Sampling for sowing and other laboratory tests (serology, histopathology) for the purpose of isolating and identifying pathogens should be performed before the start of treatment. Therapy can be started before the results of sowing and other laboratory tests are obtained,However, if they are available, treatment should be adjusted accordingly.

Clinical strains with reduced sensitivity to voriconazole were isolated. However, elevated minimal inhibitory concentrations (MICs) do not always make it possible to predict clinical inefficiency; There are cases when voriconazole was effective in patients infected with microorganisms resistant to other azoles. Assess the correlation between activity in vitro and clinical treatment outcomes are difficult, given the complexity of patients who have been included in clinical studies; the values of borderline concentrations of voriconazole, which allow to assess the sensitivity to this drug, are not established.

Hypersensitivity

Patients with increased sensitivity to other azoles voriconazole should be administered with caution.

Undesirable effects from the cardiovascular system. The use of voriconazole is associated with lengthening of the interval QT on an electrocardiogram, which is accompanied by rare cases of scintillation-fluttering of the ventricles in seriously ill patients with multiple risk factors, such as cardiotoxic chemotherapy,cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of this complication.

Hepatotoxicity

In the treatment with voriconazole, infrequent (OD-1 %%) cases of serious liver reactions are observed, including clinically manifested hepatitis, cholestasis and hepatic cell insufficiency, including fatal outcome. Undesirable phenomena from the liver are mainly observed in patients with serious diseases, mainly malignant blood tumors. In patients without any risk factors, transient reactions from the liver, including hepatitis and jaundice, are observed. Dysfunction of the liver is usually reversible and pass after discontinuation of treatment. During treatment with voriconazole, it is recommended to regularly monitor liver function, especially liver tests and bilirubin. When there are clinical signs of liver disease that may be associated with voriconazole, it is necessary to discuss the advisability of discontinuing therapy. Control of liver function should be carried out both in children and adults.

Undesirable effects of the kidneys

In seriously ill patients, sexcompeting voriconazole, there were cases of development of acute renal failure, which probably was associated with the therapy of primary or concomitant diseases, nephrotoxic drugs.

Monitoring of kidney function

Patients should be observed to identify signs of impaired renal function. To do this, it is necessary to conduct laboratory tests, in particular, to determine the concentration of creatinine in the blood serum.

Monitoring of pancreatic function

Adults and children with risk factors for developing acute pancreatitis (recent chemotherapy, hematopoietic stem cell transplantation) should undergo a screening to determine the feasibility of therapy with voriconazole.

Undesirable skin effects

Infrequent treatment with voriconazole in patients develops exfoliative skin reactions, such as Stevens-Johnson syndrome. If the patient develops exfoliative skin reactions, then voriconazole should be canceled.

In addition, prolonged use of voriconazole is accompanied by skin reactions of photosensitivity. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight.In patients with skin photosensitivity reactions and additional risk factors, cases of development of squamous cell carcinoma of the skin against prolonged therapy were reported. If the patient develops skin lesions associated with squamous cell carcinoma, consideration should be given to discontinuing voriconazole therapy.

Noninfectious periostitis

There have been reports of cases of periostitis with long-term treatment with voriconazole. If there are pains in the bones of the patient against the background of the use of voriconazole, periostitis should be excluded and the possibility of continuing therapy with voriconazole should be considered.

Use in children

The efficacy and safety of voriconazole in children under 2 years of age have not been studied. Voriconazole is indicated for use in children aged 2 years and older with continuous monitoring of liver function. Bioavailability of voriconazole for oral administration in children aged 2 to 12 years can be reduced by impaired absorption or decreased body weight. In such cases intravenous administration of voriconazole is indicated.

Effect on the ability to drive transp. cf. and fur:

Voriconazole can cause transient and reversible visual impairment, including the appearance of a "veil" in front of the eyes, impaired / increased visual perception and / or photophobia. In the presence of such symptoms, patients should avoid performing potentially dangerous actions, in particular, driving or using complex equipment. When taking voriconazole, patients should not drive the car at night.

Form release / dosage:

Tablets, film-coated, 50 mg, 200 mg.

Packaging:

Primary packaging of medicinal product

By 2, 7 or 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered

For 10, 14, 28, 30, 50, 56, 100 tablets in a polymer jar with a cover pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

Secondary packaging of medicinal product

1 contour pack of 2, 7 or 10 tablets together with the instruction for use is placed in a pack of cardboard for consumer containers.For 2, 4 or 8 contour packs of 7 tablets together with the instructions for use are placed in a pack of cardboard for consumer containers. For 3, 5 or 10 contour packs of 10 tablets together with the instructions for use are placed in a pack of cardboard for consumer containers. The packets are placed in a group package.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare. The packets are placed in a shipping container.

Storage conditions:

Store in the original packaging of the manufacturer at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002553

Date of registration:31.07.2014 / 23.03.2016

Expiration Date:31.07.2019

The owner of the registration certificate:FARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspFARM-SYNTHESIS CJSC FARM-SYNTHESIS CJSC Russia

Information update date: & nbsp16.02.2017

Illustrated instructions

Instructions

Biflurin (Biflurin)