Voriconazole-Teva - instructions for use, dose, side effects, contraindications

1 tablet contains: active substance voriconazole 50.0 mg / 200.0 mg; Excipients: lactose monohydrate 62.5 mg / 250.0 mg, pregelatinized starch 21.5 mg / 86.0 mg, croscarmellose sodium 10.5 mg / 42.0 mg, povidone-K30 4.0 mg / 16.0 mg, magnesium stearate 1 , 5 mg / 6.0 mg; Opadrai II 85F18378 white (polyvinyl alcohol 1,800 mg / 7,200 mg, titanium dioxide (E 171) 1,125 mg / 4,500 mg, macrogol-3350 0.909 mg / 3.636 mg, talc 0.666 mg / 2.664 mg).

Description:

Tablets 50 mg. Round biconvex tablets covered with a film shell of white or almost white color, engraved with "TEVA" on one side and "5289" on the other side.

Tablets 200 mg. Oval biconvex tablets covered with a film shell of white or almost white color, with engraving "TEVA" on one side and "5290" on the other side.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A. C.03 Voriconazole

Pharmacodynamics:

Antifungal preparation of a broad spectrum of action from the group of triazoles. The mechanism of action is associated with the inhibition of demethylation 14α-sterol, mediated by fungal cytochrome P450, this reaction is a key stage in the biosynthesis of ergosterol.

In vitro voriconazole has a broad spectrum of antifungal action, is active against Candida spp. (including Candida krusei strains resistant to fluconazole and resistant strains of Candida glabrata and Candida albicans) and has a fungicidal effect on all the strains of Aspergillus spp., as well as pathogenic fungi that have become relevant in recent times, including Sccdosporium or Fusarium, which, in limited degree of sensitive to antifungal agents. Clinical efficacy of voriconazole has been demonstrated in infections caused by Aspergillus spp. (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus erreus, Aspergillus niger, Aspergillus nidulans), Candida spp. (including strains of Candida albicans, Candida dubliniensis, Candida glabrata, Candida inconspicua, Candida krusei.Candida parapsilosis, Candida tropicalis and Candida guillermondii), Scedosporium spp. (including Sccdosporium apiospermum, Scedosporium prolificans) and Fusarium spp.

Other fungal infections in which the drug was used (often with partial or complete response) included isolated cases of infections caused by Altemaria spp., Blastomyces dermatidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum , Exophiala spinifera, Fonsecaea pcdrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. (including Pmicillium marneffei), Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. (including Trichosporon bcigelii).

ln vitro voriconazole activity was demonstrated in relation to clinical strains A: remonium spp., Altemaria spp., Bipolaris spp., Cladophialophora spp., I listoplasma capsulalum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 to 2 μg / ml.

In vitro, voriconazole activity against Curvularia spp. and Sporothrix spp., however its clinical significance is unknown.

Pharmacokinetics:

Pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

Absorption and distribution. Voriconazole is quickly and almost completely absorbed after ingestion. The maximum concentration (C_max) in the blood plasma is achieved in 1-2 hours after administration. Bioavailability of voriconazole at ingestion is 96%, with repeated admission with a beggar with a high fat content C_max and the area under the concentration-time curve (AUC) is reduced by 34% and 24%, respectively.Absorption of voriconazole does not depend on the pH of the gastric juice.

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 AUC is observed. An increase in the oral dose from 200 mg twice a day to 300 mg twice a day produces an increase in AUC by an average of 2.5 times. If the drug is prescribed 2 times a day in medium doses, then the cumulation of the drug occurs, and equilibrium concentrations are reached by the 6th day in most patients.

The calculated volume of the distribution (V_d) voriconazole in the equilibrium state is 4.6 l / kg, indicating an active distribution of the drug in the tissue. Binding to plasma proteins is 58%.

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

Metabolism and excretion. According to in vitro studies, it is established that voriconazole is metabolized by the action of hepatic isozymes CYP2C19, CYP2C9, CYP3A4, CYP2C19 isozyme thus plays an important role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism expressed, and therefore the reduced metabolism of voriconazole is possible in 15-20% of patients of Asian descent and 3- 5% of patients and Blacks Caucasians.The main metabolite of voriconazole is the N-oxide (72% among the metabolites circulating in the blood plasma labeled with a radioactive label). This metabolite has minimal antifungal activity.

In unchanged form, less than 2% of the administered dose is excreted by the kidneys.

After repeated ingestion in urine, approximately 83% of voriconazole is detected. Most (more than 94%) of the total dose is excreted within the first 96 hours after ingestion.

Half-life (T_1/2) voriconazole in the terminal phase depends on the dose and is approximately 6 hours when taking the drug inside at a dose of 200 mg. In connection with the nonlinearity of pharmacokinetics, the magnitude T_1/2does not allow to predict cumulation or inference

voriconazole.

Pharmacokinetics in special clinical cases

Sex and age. When re-ingesting the drug inside C_max and AUC in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years). Significant differences C_max and AUC in healthy men and women over 65 years of age do not. The need for dose adjustment in relation to sex is not noted. Concentrations in blood plasma in men and women are similar.

When re-ingesting the drug inside C_max and AUC in healthy men over 65 years are 61% and 86%, respectively, higher than in healthy men aged 18-45 years. Significant differences C_max and AUC in healthy women over 65 years of age and healthy women aged 18-45 years.

The safety of voriconazole in young patients and elderly patients is the same, and therefore dose adjustment for elderly patients is not required.

Violation of the function of the nights. At a single dose of the drug inside at a dose of 200 mg in patients with normal renal function and patients from mild (creatinine clearance (KC) -60 ml / min) to a severe degree (KC less than 20 ml / min), renal dysfunction pharmacokinetics of voriconazole is not significantly dependent from the degree of violations. Binding to plasma proteins is similar in patients with varying degrees of renal failure.

Violation of the function of the liver. After a single dose of 200 mg AUC of voriconazole in patients with mild to moderate liver cirrhosis (classes A and B on the Child-Pugh scale), the drug is 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 an average severity of liver cirrhosis (class B on the Child-Pugh scale) who received the drug in a maintenance dose of 100 mg twice a day, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day. There is no information on the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (grade C on the Child-Pugh scale).

Indications:

Invasive aspergillosis;
severe invasive forms of candidiasis (including Candida krusei), resistant to fluconazole;
Candidiasis of the esophagus;
severe fungal infections caused by Scedosporium spp. and Fusarium spp .;
severe fungal infections with intolerance or refractory to other medicines;
prevention of "breakthrough" fungal infections in patients with high-risk fever (allogeneic bone marrow recipients, patients with relapse of leukemia).

Contraindications:

Hypersensitivity to voriconazole and other components of the drug; simultaneous application of SUSAA isoenzyme substrates with drugs: terfenadine astemizole, cisapride, pimozide and quinidine; simultaneous application with sirolimus; rifampicin,carbamazepine and long-acting barbiturates; ritonavir in high doses (400 mg and higher twice a day); efavirenz (in doses of 400 mg and higher once a day with a range of rupees in standard doses); ergot alkaloids (ergotamine, dihydroergotamine); eifabutium; preparations of St. John's wort; children under 3 years of age are not enough data but efficiency and safety); lactose intolerance; deficiency of lactase; glucose-galactose malabsorption.

Carefully:Severe hepatic insufficiency (Child-Pugh class C), severe renal failure, concomitant use with phenytoin. In patients with proarrhythmic conditions: congenital or acquired increase in the QT interval, cardiomyopathy, especially with heart failure, sinus bradycardia, the presence of symptomatic arrhythmia, electrolyte disorders (such as hypokalemia, hypomagnesemia, hypocalcemia). Hypersensitivity to others preparations of azoles; simultaneous application of drugs,causing an elongation interval QT.

Pregnancy and lactation:The drug Voriconazole-Teva should not be used during pregnancy, except when the expected benefit for the mother exceeds the potential risk to the fetus. The excretion of voriconazole with breast milk has not been studied. For the duration of the drug, breastfeeding should be discontinued. Women of reproductive age should use reliable methods of contraception during the entire period of therapy with the drug Vorikonazol-Teva.

Dosing and Administration:

Inside for 1 hour or 1 hour after eating.

The use of the drug Vorikonazol-Teva should begin with intravenous administration in the recommended saturating dose, so that on the first day you can achieve an adequate concentration in the blood plasma. Intravenous administration should be continued for at least 7 days, after which it is possible to switch to oral administration of the drug, provided that the patient is able to take medications for oral administration. Given the high bioavailability of the drug with oral intake, reaching 96% (see the section "Pharmacokinetics"), in the presence of clinical indications, it is possible to switch from intravenous to oral administration of the drug without dose correction.

Indications	Patients with a body weight of 40 kg and more	Patients weighing less than 40 kg
The saturation dose (in the first 24 hours)
For all indications	Not recommended oral administration	Not recommended oral administration
Maintenance dose (after the first 24 hours)
Invasive aspergillosis	200 mg every 12 hours	100 mg every 12 hours
Prevention of breakthrough fungal infections	200 mg every 12 hours	100 mg every 12 hours
Heavy fungal infections caused by Scedosporium spp. and Fusarium spp. with intolerance or refractory to other medicines	200 mg every 12 hours	100 mg every 12 hours
Candidiasis of the esophagus	200 mg every 12 hours	100 mg every 12 hours
Severe invasive forms of candidiasis (including Candida krusei), resistant to fluconazole	200 mg every 12 hours	100 mg every 12 hours

Dose selection

If the effectiveness of the therapy is insufficient, the maintenance dose for ingestion can be increased to 300 mg every 12 hours, and in patients with a body weight of less than 40 kg the dose can be increased to 150 mg every 12 hours.

If the drug is intolerant at this higher dose, it is reduced by 50 mg until a dose of 200 mg is given every 12 hours (or 100 mg every 12 hours for patients with a body weight less than 40 kg).

With simultaneous use with phenytoin, a maintenance dose of Voriconazole-Teva increases e 200 to 400 mg every 12 hours (from 100 mg to 200 mg every 12 hours in patients weighing less than 40 kg).

With simultaneous use with efavirenz, the dose of Voriconazole-Teva should be increased to 400 mg every 12 hours, the dose of efavirenz reduced to 300 mg every 12 hours.

The duration of therapy depends on the clinical effect and the results of mycological examination.

Use in children

PpePapat in the form of tablets prescribe to children in the event that the child can swallow tablets.

The dosage regimen of voriconazole in children (aged 3 (for a given dosage form) to 12 l) and adolescents aged 12 to 14 years and a body weight of less than 50 kg:

The saturation dose (in the first 24 hours)

Not recommended oral administration

The maintenance dose (after the first 24 hours)

9 mg / kg twice daily

(maximum dose of 350 mg twice daily)

It is recommended to start therapy with intravenous administration of the drug, and the possibility of oral administration of the drug Voriconazole-Teva should be considered only after the clinical improvement and the patient's ability to take oral medication.It should be taken into account that the effect of the drug when administered intravenously at a dose of 8 mg / two times higher than when administered orally at a dose of 9 mg / 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, i.e. tablets can not be divided. Pharmacokinetics and tolerability of higher doses of voriconazole for oral administration in children have not been studied.

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 the drug Vorikonazol-Teva 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 are slowed through 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 use of voriconazole in children aged 2 to 12 years with impaired liver or kidney function has not been studied.

In adolescents (aged 12 to 14 years with a body weight of 50 kg or more, 15 to 18 years, regardless of body weight) voriconazole dosed the same way as for adults.

Correction of the dosing regimen in patients old age not required.There is no need to adjust the dosage regimen of Voriconazole-Teva patients with impaired renal function.

When acute liver damage with an increase in the activity of "liver" transaminases (ALT, ACT) correction of the dose of the drug is not required, but the status of the liver function should be monitored in order to reveal a further increase in the activity of "liver" transaminases.

Patients with cirrhosis of mild to moderate liver (class A and B on the Child-Pugh scale) are recommended to prescribe the drug Vorikonazol-Teva in a standard saturating dose, and reduce the maintenance dose by 2 times.

The recommended dose for children aged 3 to 12 years is 200 mg 2 times a day. The use of voriconazole in children aged 3 to 12 years with impaired liver and / or kidney function has not been studied. For children aged 12 to 18 years, the drug is used in the same doses as for adults.

Side effects:

The most common adverse reactions: visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abdominal pain. Adverse reactions were usually mild or moderate.Clinically significant dependence of drug safety on age, race or sex was not revealed.

The frequency of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0.1%, less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

Allergic reactions: infrequently - allergic dermatitis; rarely - anaphylactoid reactions, urticaria; very rarely - angioedema.

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

From the cardiovascular system: often - lowering blood pressure, thrombophlebitis, phlebitis; infrequently - supraventricular arrhythmia, supraventricular tachycardia, ventricular extrasystole, rarely - ventricular tachycardia as pirouette, atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias, QT interval prolongation, ventricular fibrillation; very rarely ventricular tachycardia (including ventricular flutter), complete atrioventricular block, blockade of the bundle of the bundle, nodular arrhythmias.

From the digestive system: very often - nausea, vomiting, diarrhea, abdominal pain; often - increased activity of "liver" transiamnaz, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl, bilirubin concentration in blood plasma, jaundice, cholestatic jaundice, cheilitis, gastroenteritis, cholestasis; rarely - cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, enlargement of the liver, gingivitis, glossitis, hepatitis, hepatic insufficiency, pancreatitis, swelling of the tongue, peritonitis; very rarely - pseudomembranous colitis, hepatic coma.

The overall frequency of a clinically significant increase in transaminase activity is 13.4%. Dysfunction of the liver can be associated with higher plasma concentrations or doses of the drug and in most cases disappear when the therapy continues (without changing the dose or after its correction) or when it is canceled. In patients with severe underlying diseases (haematological malignancies) during treatment with voriconazole rarely were cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular insufficiency, leading to death).

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

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

From the side of metabolism: often - hypokalemia; infrequently - hyponatremia, hypoglycemia; rarely - hypercholesterolemia.

From the musculoskeletal system: often - pain in the back; rarely - arthritis, periostitis.

From the central and peripheral nervous system: very often - headache; often - dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia, hypertension; infrequently - vertigo; rarely - hepatic encephalopathy, convulsions, drowsiness, peripheral neuropathy, ataxia, cerebral edema, intracranial hypertension, hypoesthesia, nystagmus, syncope; very rarely - Guillain-Barre syndrome, oculogic crisis, extrapyramidal disorders, insomnia, encephalopathy.

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

Dermatological reactions: very often - a rash; often - itching, macular rash, papular rash, maculopapular rash, erythema, photosensitivity, alopecia, exfoliative dermatitis, face swelling, purpura; infrequent - drug fixed erythema, eczema, psoriasis; rarely - toxic epidermal necrolysis, pseudoporphyria, syndrome

Stevens-Johnson, squamous cell carcinoma of the skin; very rarely - discoid lupus erythematosus, erythema multiforme.

Dermatological reactions in most cases are easy or moderately pronounced. However, when the rash appears, the patient should be carefully monitored, and with the progression of skin changes the drug should be discarded. Photosensitivity develops with prolonged use of the drug.

From the sense organs: often - visual disturbances (including impaired / increased visual perception, fog before the eyes, change in color perception, photophobia); rarely - blepharitis, optic neuritis, edema of the nipple of the optic nerve, scleritis, a violation of taste perception,diplopia; very rarely - bleeding in the retina, corneal opacity, optic nerve atrophy, hypoacusia, ringing in the ears. Visual disturbances are noted often (about 30% blurred vision, changes in color vision, photophobia), in most cases are transient and completely reversible, disappear spontaneously within 60 minutes, are easily expressed, rarely require discontinuation of treatment and do not lead to any consequences in the long run. With repeated use, there is a weakening of their severity. The mechanism of development is not known, it is assumed the direct effect of voriconazole on the retina, which is confirmed by a decrease in the amplitude of the waves on the electroretinogram when studying the effect of voriconazole on the retina in healthy volunteers. These changes did not increase with the continuation of therapy for 29 days and completely disappeared after voriconazole withdrawal. The effect of a longer (more than 29 days) application of the drug on the visual function is not established.

From the urinary system: often - increased serum creatinine concentration, acute renal failure, hematuria; rarely - increasing residual urea nitrogen, albuminuria,nephritis; very rarely necrosis of the renal tubules.

Overdose:

Symptoms: there is a report of a single case of photophobia.

Treatment: antidote is not known, if necessary, conduct symptomatic therapy, it is possible to conduct hemodialysis.

Interaction:

Voriconazole is metabolized by isozymes CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes can cause respectively an increase or decrease in the concentrations of voriconazole in plasma.

Combinations in which there are significant changes in the concentration of voriconazole in the blood plasma

Combinations that do not require correction of the dose of voriconazole

Cimetidine

When used simultaneously with cimetidine (a non-specific inhibitor of the CYP450 isoenzyme system) at a dose of 400 mg twice a day C_max and AUC voriconazole increased by 18% and 23%, respectively.

Ranitidine

Ranitidine in a dose of 150 mg 2 times a day with simultaneous application does not have a significant effect on C_max and AUC of voriconazole.

Erythromycin

Erythromycin (inhibitor of the isoenzyme CYP3A4) when administered at a dose of 1 g 2 times per day does not significantly affect C_max and AUC of voriconazole.

Azithromycin

Azthromycin at a dose of 500 mg once a day does not have a significant effect on C_max and AUC of voriconazole. The effect of voriconazole on the metabolism of azithromycin is unknown. Correction of the dose is not required.

Voriconazole inhibits the activity of the isoenzymes CYP2C19, CYP2C9, CYP3A4, so it is possible to increase the plasma concentrations of drugs that are metabolized by these isoenzymes.

Combinations are contraindicated

With the simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide and quinidine, a significant increase in their plasma concentration is possible, which may lead to an elongation of the QT interval and, in rare cases, the development of ventricular tachycardia of the pirouette type.

Rifampicin

When used simultaneously with rifampicin (inductor system isoenzymes CYP450) at a dose of 600 mg per day C_max and AUC voriconazole decreased by 93% and 96%, respectively.

Ritonavir

Ritonavir (inducer of the CYP450 isoenzyme system, inhibitor and substrate of the isoenzyme CYP3A4) at a dose of 400 mg twice daily C_max in the equilibrium state and AUC voriconazole, decreased by 66% and 82%, respectively. Moreover, C_max and the AUC of ritonavir does not change.

The simultaneous use of voriconazole and high doses of ritonavir (400 mg and above 2 times a day) is contraindicated.

When combined with low doses of ritonavir 100 mg twice daily C_max and AUC of ritonavir decreased by 25% and 13%, respectively. C_max and AUC voriconazole decreased by 24% and 9%, respectively. The effect of ritonavir at lower doses on the concentration of voriconazole is not known. At the same time, the use of voriconazole and ritonavir in low doses (100 mg 2 times a day) should be given only if the expected benefit of taking voriconazole significantly exceeds the risk of their combined use.

Carbamazepine and barbiturates

When the CYP450 isoenzyme system (carbamazepine) or long-acting barbiturates (phenobarbital) is simultaneously used with powerful inducers, a significant reduction in C_max voriconazole in plasma, although their interaction has not been studied.

Sirolimus

With simultaneous application voriconazole increases C_max and AUC of sirolimus (2 mg once) 6.6 times and 11 times, respectively.

4-hole perforated

With the simultaneous application of St. John's wort 300 mg three times a day with a single dose of voriconazole 400 mg, a decrease in AUC voriconazole by 59% is observed.

Everolimus (substrate of the isoenzyme CYP3A4 and P-glycoprotein)

Interaction has not been studied, however voriconazoleprobably, can significantly increase plasma concentrations of everolimus, so simultaneous use is not recommended. At the moment, there is not enough information to recommend a correction of the dosing regimen.

Rifabutin

With simultaneous application rifabutin (inducer of the CYP450 isoenzyme system), used at a dose of 300 mg once a day, reduces C_max and AUC voriconazole (200 mg once daily) by 69% and 78%, respectively. When used concomitantly with rifabutin C_max and AUC voriconazole (350 mg twice daily) is 96% and 68% of the indices with monotherapy with voriconazole (200 mg twice daily). When using voriconazole in a dose of 400 mg twice a day C_max and AUC, respectively, by 104% and 87% higher than with monotherapy with voriconazole at a dose of 200 mg 2 times a day. Voriconazole in a dose of 400 mg twice a day increases C_max and Rifabutin AUC by 195% and 331%, respectively).

Alkaloids of ergot

At simultaneous application voriconazole can cause an increase in the concentration of ergot alkaloids (ergotamine and dihydroergotamine) in the plasma and the development of ergotism.

Combinations, which require constant clinical control and dosage adjustment

Cyclosporin

With simultaneous use in patients who underwent kidney transplantation and are in a stable state, voriconazole increases C_max and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of developing nephrotoxicity. When using voriconazole in patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and monitor its concentration in the blood plasma. After voriconazole cancellation, it is necessary to control the concentration of cyclosporine and, if necessary, increase its dose.

Tacrolimus

With simultaneous application voriconazole increases C_max and Tacrolimus AUC (applied at a dose of 0.1 mg / kg once) by 117% and 221%, respectively, which may be accompanied by nephrotoxicity. When prescribing voriconazole, patients receiving tacrolimus, it is recommended to reduce the dose of the latter to 1/3 and monitor its concentration in the plasma. After voriconazole cancellation, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.

Long-acting opiates (substrates of the isoenzyme CYP3A4)

Oxycodone (10 mg once)

With simultaneous application of C_max and AUC of oxycodone increased 1.7 times and 3.6, respectively. The possibility of reducing the dose of oxycadone and other long-acting opiates metabolized by the CYP3A4 isoenzyme (eg, hydrocodone) should be evaluated. It may be necessary to monitor the patient's condition at short intervals for the development of unwanted reactions associated with opiates.

Methadone (32-100 mg once daily)

With simultaneous application of C_max and AUC R-methadone (active metabolite) is increased by 31% and 47%, respectively. C_max and AUC of S-methadone increased by 65% and 103%, respectively. An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including the prolongation of the QT interval. It is recommended that the patient be frequently monitored for the development of unwanted reactions and toxicity (including prolongation of the QT interval) associated with methadone. You may need to reduce the dose of methadone.

Non-steroidal anti-inflammatory drugs (NSAIDs) (substrates of the isoenzyme CYP2C9)

Ibuprofen (400 mg once)

With simultaneous application of C_max and AUC S-ibuprofen is increased by 20% and 100%, respectively.

Diclofenac (50 mg once)

With simultaneous application of C_max and AUC of diclofenac increased by 114% and 78%, respectively.

Warfarin

Simultaneous use of voriconazole (300 mg twice daily) and warfarin (30 mg once a day) was accompanied by an increase in the maximum prothrombin time to 93%. With the simultaneous administration of warfarin and voriconazole, it is recommended that prothrombin time be monitored.

Fentprokumone, acenocoumarol

Voriconazole with simultaneous application can cause an increase in plasma concentrations of fenprocumone, acenocumarol (substrates of isoenzymes CYP2C9, CYP3A4) 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.

Derivatives of sulfonylureas

With simultaneous application voriconazole can cause an increase in the concentration of sulfonylurea derivatives (substrates of the isoenzyme CYP2C9) - tolbutamide, glipizide and glibenclamide in plasma and cause hypoglycemia. With their simultaneous use, it is necessary to carefully monitor the concentration of glucose in the blood.

Fluconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4)

With simultaneous application of fluconazole 200 mg once a day C_max and AUC voriconazole increased by 57% and 79%, respectively. Changes in C_max and AUC fluconazole are not established. A suitable regimen for dose adjustment and / or reception frequency of voriconazole and fluconazole is not established. In case if voriconazole is used after fluconazole, it is recommended that careful monitoring of unwanted reactions associated with the use of voriconazole is recommended.

Lovastatin

In vitro voriconazole inhibits the metabolism of lovastatin (the substrate of the isoenzyme CYP3A4). With simultaneous use, it is possible to increase the plasma concentrations of statins metabolized by the CYP3A4 isoenzyme, which may increase the risk of rhabdomyolysis. With their simultaneous application, it is recommended to evaluate the appropriateness of correcting the dose of statin. An increase in the concentration of statins in the blood plasma was sometimes accompanied by the development of rhabdomyolysis.

Benzodiazepines

In vitro voriconazole inhibits the metabolism of midazolam (substrate of the isoenzyme CYP3A4). With simultaneous application, an increase in plasma concentrations of benzodiazepines stabilizing under the action of the CYP3A4 isoform (midazolam, triazolam, alprazolam) and the development of a prolonged sedation effect is possible.With the simultaneous use of these drugs, it is recommended to evaluate the appropriateness of dose adjustment for benzodiazepine.

Vinca alkaloids

With simultaneous application voriconazole can increase the content of vinca alkaloids (substrates of the isoenzyme CYP3A4) - vincristine, vinblastine in plasma and lead to the development of neurotoxic reactions. It is recommended to evaluate the feasibility of correcting the dose of vinca alkaloids.

Prednisolone

Combinations that do not require dose adjustment

Voriconazole increases C_max and prednisolone AUC (substrate of the isoenzyme CYP3A4), applied at a dose of 60 mg once, by 11% and 34%, respectively.

Digoxin

With simultaneous application voriconazole does not have a significant effect on C_max and AUC digoxin, administered at a dose of 0.25 mg once a day.

Mikophenolic acid

With simultaneous application voriconazole does not affect C_max and AUC of mycophenolic acid, administered at a dose of 1 g.

Bilateral interaction

Efavirenz

With simultaneous application with voriconazole (at a dose of 200 mg twice a day) efavirenz (inducer of isoenzyme system of isoenzyme CYP450, inhibitor and substrate for isoenzyme CYP3A4), used at a dose of 400 mg once a day, in equilibrium reduces C_max and AUC voriconazole averaged 61% and 77%, respectively. Voriconazole in an equilibrium state (400 mg orally every 12 hours on the first day, then 200 mg orally every 12 hours for 8 days) increases the equilibrium C_max and AUC of efavirenz on average by 38% and 44%, respectively. This combination is contraindicated.

With the simultaneous use of 300 mg of efavirenz 1 time per day and voriconazole 400 mg 2 times a day, compared with efavirenz 600 mg once a day C_max Efavirenz does not change and AUC of efavirenz increases by 17%. In comparison with voriconazole 200 mg twice a day C_max Voriconazole increased by 23% and VUC of voriconazole decreased by 7%. Simultaneous application is possible if the maintenance dose of voriconazole is increased to 400 m 2 twice a day, and the dose of efavirenz is reduced to 300 mg once a day. With the withdrawal of voriconazole therapy, the initial dose of efavirenz should be restored.

Phenytoin

With simultaneous application phenytoin (substrate of the isoenzyme CYP2C9 and a powerful inductor of the CYP450 isoenzyme system), used at a dose of 300 mg once a day, reduces C_max and AUC voriconazole by 49% and 69%, respectively; a voriconazole (400 mg twice a day) increases C_max and AUC of phenytoin by 67% and 81%, respectively (if simultaneous application is necessary, the ratio of expected benefit and potential risk of combination therapy should be carefully estimated,and also carefully monitor the concentration of phenytoin in the blood plasma).

Omeprazole

With simultaneous application in a dose of 40 mg once a day omeprazole (inhibitor of the isoenzyme CYP2C19, a substrate of isoenzymes CYP2C19 and CYP3A4) increases C_max and AUC voriconazole by 15% and 41%, respectively, and voriconazole increases C_max and AUC of omeprazole by 116% and 280%, respectively, therefore, correction of the dose of voriconazole is not required. When starting voriconazole in patients who are already receiving omeprazole therapy at doses of 40 mg or higher, the dose of omeprazole should be reduced by half. It should be taken into account the possibility of drug interaction voriconazole with other inhibitors H⁺-TO^--ATPase, which are substrates of the isoenzyme CYP2C19.

Oral contraceptives

At simultaneous application in a dose of 1 mg / 0.35 mg once a day norethisterone / ethinyl estradiol (substrates of the isoenzyme CYP3A4, inhibitors of the isoenzyme CYP2C19), C_max and AEC of ethinylestradiol by 36% and 61%, respectively; increases C_max and AEC of norethisterone by 15% and 53%, respectively, C_max and AUC voriconazole by 14% and 46%, respectively.

It is recommended to monitor the patient's condition for the development of unwanted reactions associated with the use of oral contraceptives and voriconazole.

Narcotic analgesics of short action (substrates of the isoenzyme CYP3A4)

When applying a single dose of alfentanil 20 μg / kg with simultaneous application of Naloxone, the AUC of alfentanil is increased by a factor of 6.

When taking a single dose of fentanyl 5 μg / kg, the fentanyl AUC increases 1.34 times. It should evaluate the possibility of reducing the dose of alfentanil, fentanyl and other narcotic analgesics short-acting, having a similar chemical structure with alfentanilom and metabolizable isoenzyme CYP3A4 (e.g., sufentanil). Patients should be under constant surveillance to prevent respiratory depression or other side effects associated with the use of short-acting narcotic analgesics and, if necessary, their dose should be reduced.

Indinavir

Indinavir (the inhibitor and substrate of the isoenzyme CYP3A4), used at a dose of 800 mg 3 times a day, does not significantly affect the value of Cmax and AUC of voriconazole, and voriconazole does not affect C_max and AUC of indinavir.

HIV protease inhibitors

When used simultaneously with other HIV protease inhibitors (inhibitors of the substrate and isoenzyme CYP3A4),monitor the patient's condition in order to prevent the development of possible toxic effects and / or insufficient action, In vitro studies have shown that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) can mutually inhibit each other's metabolism. Probably, correction of a dose of preparations is required.

Non-nucleoside reverse transcriptase inhibitors

In vitro studies have shown that the metabolism of voriconazole can be inhibited by the action of non-nucleoside inhibitors of the image transcriptase (substrates of the isoenzyme CYP3A4, inhibitors or inducers of the CYP450 isoenzymes system), and voriconazole in turn, can inhibit the metabolism of non-nucleoside reverse transcriptase inhibitors.

Based on the results of the study of the effect of efavirenz on voriconazole it can be assumed that non-nucleoside reverse transcriptase inhibitors can enhance the metabolism of voriconazole. It is recommended to carefully monitor the patient's condition for the development of drug toxicity and / or lack of action. You may need to adjust the dose of drugs.

Special instructions:

Before the beginning of therapy it is necessary to correct such electrolyte disturbances as hypokalemia, hypomagnesemia and hypocalcemia.

Sampling for culture and other laboratory tests (serological, histopathological) for the purpose of isolating and identifying pathogens should be performed before the start of treatment. Therapy can be started before receiving the results of laboratory studies, and then, if necessary, corrected. Clinical strains with reduced sensitivity to voriconazole were isolated. However, an elevated minimum inhibitory concentration does not always allow predicting clinical inefficiency: there are cases when voriconazole was effective in infections caused by microorganisms resistant to other azoles.

The use of voriconazole may lead to an elongation of the QT interval on the electrocardiogram, which is accompanied by rare cases of ventricular fibrillation in patients with multiple risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of adverse cardiovascular events).Patients with these potentially proarrhythmic conditions should be cautioned with Voriconazole-Teva.

The adverse events on the part of the liver, observed with the treatment with voriconazole, mainly appeared in patients with serious diseases (mainly malignant blood tumors). Patients without any risk factors have transient liver reactions, including hepatitis and jaundice. Dysfunction of the liver is usually reversible and pass after discontinuation of treatment. During treatment with voriconazole, liver function should be monitored regularly (including liver tests and bilirubin concentration). When clinical signs of liver disease appear, one should discuss the advisability of discontinuing therapy. It is necessary to monitor liver function in both children and adults.

In patients with risk factors for acute pancreatitis (recently transferred chemotherapy, transplantation of hematopoietic stem cells), the parameters of amylase and serum lipase activity should be monitored when using Vorikonazol-Teva.

The patients receiving the drug Vorikonazol-Teva, reported violations from the side of the eye (see section "Side effect"). According to post-marketing research, there are reports of the development of cases of visual disturbances that persist for a long time, in particular, the appearance of a "veil" before the eyes, optic neuritis and edema of the nipple of the optic nerve. It should be noted that these disorders develop most often in seriously ill patients and / or receiving concomitant therapy, which can cause such undesirable phenomena. In patients with skin photosensitivity reactions, additional risk factors are reported for the development of squamous cell carcinoma of the skin and melanoma with prolonged therapy. If the patient develops skin lesions associated with squamous cell carcinoma of the skin or melanoma, consideration should be given to discontinuing therapy with Voriconazole-Teva.

There have been reports of cases of periostitis in patients after transplantation receiving long-term therapy with voriconazole. Therapy with Voriconazole-Teva should be discontinued in case,if the patient has pain in the bones and on the roentgenogram there are changes characteristic of periostitis.

Narcotic analgesics of short action (substrates of the isoenzyme CYP3A4). Since the half-life of alfentanil when it is used simultaneously with the drug Voriconazole-Teva is increased 4-fold, careful monitoring of undesirable phenomena associated with the use of narcotic analgesics, including a longer monitoring of the respiratory function, is necessary.

In patients who received voriconazole and other nephrotoxic drugs and who had concomitant diseases, there were cases of development of acute renal failure. During the use of the drug should monitor the performance of the kidneys (including the level of creatinine in the blood serum).

When allergic reactions occur, the drug should be discarded. Patients using Voriconazole-Teva should avoid exposure to sunlight and ultraviolet radiation.

When need simultaneous applications drug Voriconazole-Teva and phenytoin should carefully evaluate the perceived benefit and potential risk from combination therapy and continuously monitorthe concentration of phenytoin in the blood plasma.

When need simultaneous applications drug Voriconazole-Teva and rifabutin should carefully evaluate the perceived benefit and potential risk from combination therapy and monitor it in the peripheral blood picture, as well as other possible undesirable effects of rifabutin.

Effect on the ability to drive transp. cf. and fur:Because the drug can cause transient visual impairment, including fog before the eyes, impaired / increased visual perception and / or photophobia, when such reactions occur, avoid performing actions requiring increased concentration and speed of psychomotor reactions, including. driving a car. When taking the drug, patients should not drive a car in the dark.

Form release / dosage:

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

Packaging:

For 30 tablets in a vial of HDPE with a lid equipped with a system of protection from opening by children, the neck of the bottle is sealed with an aluminum membrane.

1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003092

Date of registration:14.07.2015

Expiration Date:14.07.2020

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Information update date: & nbsp10.03.2017

Illustrated instructions

Instructions

Voriconazole-Teva (Voriconazole-Teva)