Salvozole (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Kraspharma, PJSC (Russia)

ATC Code

J02AC03 (Voriconazole)

Active Substance

Voriconazole (Rec.INN registered by WHO)

Dosage Form

Salvozole

Lyophilisate for the preparation of a concentrate for the preparation of an infusion solution: 200 mg fl. 1 or 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a concentrate for the preparation of an infusion solution in the form of a powder or porous mass of white or almost white color.

Excipients: betadex sulfobutyl ether sodium – 3200 mg.

Colorless glass vials with a capacity of 30 ml (1) – cardboard packs.
Colorless glass vials with a capacity of 30 ml (10) – cardboard boxes.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; triazole and tetrazole derivatives

Pharmacological Action

Antifungal agent, a triazole derivative. The mechanism of action is associated with the inhibition of 14α-sterol demethylation mediated by fungal cytochrome P450; this reaction is a key step in ergosterol biosynthesis.

In vitro, Voriconazole has a broad spectrum of antifungal activity, is active against Candida spp. (including strains of Candida krusei resistant to fluconazole, and resistant strains of Candida glabrata and Candida albicans) and has a fungicidal effect against all studied strains of Aspergillus spp., as well as pathogenic fungi that have become relevant recently, including Scedosporium or Fusarium, which have limited sensitivity to antifungal agents.

The clinical efficacy of voriconazole has been demonstrated in infections caused by Aspergillus spp. (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Aspergillus nidulans), Candida spp. (including strains Candida albicans, Candida dubliniensis, Candida glabrata, Candida inconspicua, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida guillermondii), Scedosporium spp. (including Scedosporium apiospermum /Pseudoallescheria boydii/, Scedosporium proliferans) and Fusarium spp.

Other fungal infections in which partial or complete antifungal effect was observed 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 Penicillium marneffei), Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. (including Trichosporon beigelii).

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

In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp. has been identified, but its clinical significance is unknown.

Pharmacokinetics

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

The pharmacokinetics of voriconazole are nonlinear due to saturation of its metabolism. A dose increase leads to a disproportionate (more pronounced) increase in AUC. Increasing the dose from 200 mg twice daily to 300 mg twice daily leads to an average 2.5-fold increase in AUC. With intravenous administration or oral loading doses, plasma concentrations approach steady-state within the first 24 hours. With a frequency of administration of twice daily at average (non-loading) doses, accumulation of the active substance occurs, and C_ss is reached in most cases by day 6.

Voriconazole is rapidly and almost completely absorbed after oral administration; C_max in plasma is reached 1-2 hours after administration. The bioavailability of voriconazole when taken orally is 96%; with repeated administration with high-fat food, C_max and AUC decrease by 34% and 24%, respectively. The absorption of voriconazole does not depend on the pH of gastric juice.

The calculated V_d of voriconazole at steady state is 4.6 L/kg, indicating active distribution of voriconazole into tissues. Plasma protein binding is 58%.

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

According to in vitro studies, it has been established that Voriconazole is metabolized with the participation of hepatic isoenzymes CYP2C19, CYP2C9, CYP3A4, with CYP2C19 playing an important role in the metabolism of voriconazole. This enzyme exhibits pronounced genetic polymorphism, which is why reduced metabolism of voriconazole is possible in 15-20% of patients of Asian origin and in 3-5% of Caucasians and blacks. Studies in Caucasians and Japanese have shown that in patients with poor metabolism, the AUC of voriconazole is on average 4 times higher than in homozygous patients with extensive metabolism. In heterozygous patients with extensive metabolism, the AUC of voriconazole is on average 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide (72% among circulating plasma metabolites labeled with a radioactive label). This metabolite has minimal antifungal activity.

Less than 2% is excreted unchanged in the urine.

After repeated oral or intravenous administration, approximately 83% and 80% of the dose (labeled with a radioactive label) are detected in the urine, respectively. The majority (>94%) of the total dose is excreted within the first 96 hours after oral and intravenous administration.

The T_1/2 of voriconazole in the terminal phase is dose-dependent and is approximately 6 hours when the drug is taken orally at a dose of 200 mg. Due to the nonlinearity of pharmacokinetics, the T_1/2 value does not allow predicting the accumulation or elimination of voriconazole.

Pharmacokinetics in special clinical cases

With repeated oral administration, C_max and AUC in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18-45 years). There are no significant differences in C_max and AUC between healthy elderly men and healthy elderly women (≥ 65 years).

With repeated oral administration of voriconazole, C_max and AUC in healthy elderly men (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young men (18-45 years).

Mean C_ss in plasma in children receiving Voriconazole at a dose of 4 mg/kg every 12 hours are comparable to those in adults receiving Voriconazole at a dose of 3 mg/kg every 12 hours. The mean concentration was 1186 ng/ml in children and 1155 ng/ml in adults. In this regard, the recommended maintenance dose in children aged 2 to 12 years is 4 mg/kg every 12 hours.

After a single oral dose of voriconazole 200 mg in patients with normal renal function and patients with mild (CrCl 41-60 ml/min) to severe (CrCl less than 20 ml/min) renal impairment, the pharmacokinetics of voriconazole do not significantly depend on the degree of impairment. Plasma protein binding is similar in patients with varying degrees of renal failure.

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

With repeated oral administration, the AUC of voriconazole is comparable in patients with moderate liver cirrhosis (Child-Pugh class B) receiving a maintenance dose of 100 mg twice daily and in patients with normal liver function receiving Voriconazole at a dose of 200 mg twice daily.

Indications

Invasive aspergillosis; severe invasive forms of candidal infections (including Candida krusei); esophageal candidiasis; severe fungal infections caused by Scedosporium spp. and Fusarium spp.; severe fungal infections with intolerance or refractoriness to other drugs; prevention of breakthrough fungal infections in patients with fever at high risk (recipients of allogeneic bone marrow, patients with relapse of leukemia).

ICD codes

Dosage Regimen

Administer intravenously as a slow infusion. The dose is set individually based on indication, age, body weight, and clinical response.

Reconstitute the 200 mg vial with 19 ml of Water for Injections to yield a concentrate of 10 mg/ml. Shake the vial until the powder is completely dissolved. Further dilute the required dose in an infusion bag containing 0.9% Sodium Chloride or 5% Dextrose solution to a final concentration of 0.5-5 mg/ml.

Initiate therapy with loading doses to achieve target plasma concentrations rapidly. For adults, administer 6 mg/kg every 12 hours for the first 24 hours. For pediatric patients (2 to 12 years), administer 9 mg/kg every 12 hours for the first 24 hours.

Follow with maintenance doses. For adults, administer 4 mg/kg every 12 hours. For pediatric patients (2 to 12 years), administer 8 mg/kg every 12 hours. Increase the maintenance dose to 5 mg/kg every 12 hours in adult patients if the response is inadequate.

Switch to oral formulation when clinically indicated. Use the same mg-for-mg total daily dose when transitioning from intravenous to oral administration.

Adjust the dosage in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). After the initial loading dose, reduce the maintenance dose by half. Do not use in patients with severe hepatic impairment (Child-Pugh Class C).

Monitor renal function in patients receiving intravenous therapy. Accumulation of the solubilizing excipient, sulfobutyl ether beta-cyclodextrin sodium, may occur. Consider switching to oral therapy in patients with moderate to severe renal impairment (CrCl less than 50 ml/min).

Adverse Reactions

General disorders very common – fever, peripheral edema; common – chills, asthenia, chest pain, injection site reactions and inflammation, flu-like syndrome.

Cardiovascular system common – decreased blood pressure, thrombophlebitis, phlebitis; rare – atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias; very rare – supraventricular tachycardia, complete AV block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), QT interval prolongation, ventricular fibrillation.

Digestive system very common – nausea, vomiting, diarrhea, abdominal pain; common – increased activity of ALT, AST, ALP, LDH, GGT and plasma bilirubin level, jaundice, cheilitis, cholestasis; rare – cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, hepatomegaly, gingivitis, glossitis, hepatitis, hepatic failure, pancreatitis, tongue edema, peritonitis; very rare – pseudomembranous colitis, hepatic coma. In patients with serious underlying diseases (malignant hematological diseases) during the use of voriconazole, rare cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular failure leading to death) were noted.

Endocrine system rare – adrenal cortex insufficiency; very rare – hyperthyroidism, hypothyroidism.

Allergic reactions rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria; very rare – angioedema, erythema multiforme. Anaphylactoid reactions have been described with intravenous infusion, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, fainting, itching, rash.

Hematopoietic system common – thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia; rare – lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, bone marrow depression; very rare – lymphangitis.

Metabolism common – hypokalemia, hypoglycemia; rare – hypocholesterolemia.

Musculoskeletal system common – back pain; rare – arthritis.

Central and peripheral nervous system very common – headache; common – dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia; rare – ataxia, cerebral edema, intracranial hypertension, hypoesthesia, nystagmus, vertigo, syncope; very rare – Guillain-Barré syndrome, oculogyric crisis, extrapyramidal syndrome.

Respiratory system common – respiratory distress syndrome, pulmonary edema, sinusitis.

Dermatological reactions very common – rash; common – itching, maculopapular rash, photosensitivity, alopecia, exfoliative dermatitis, facial edema, purpura; rare – psoriasis; very rare – discoid lupus erythematosus.

Special senses common – visual disturbances (including impaired/enhanced visual perception, blurred vision, altered color perception, photophobia); rare – blepharitis, optic neuritis, papilledema, scleritis, taste perversion, diplopia; very rare – retinal hemorrhage, corneal opacity, optic atrophy.

Urinary system common – increased serum creatinine level, acute renal failure, hematuria; rare – increased blood urea nitrogen, albuminuria, nephritis; very rare – renal tubular necrosis.

Contraindications

Concomitant use of drugs that are substrates of CYP3A4 – terfenadine, astemizole, cisapride, pimozide and quinidine; concomitant use of sirolimus; concomitant use of rifampicin, carbamazepine and long-acting barbiturates; concomitant use of ritonavir; concomitant use of efavirenz; concomitant use of ergot alkaloids (ergotamine, dihydroergotamine); hypersensitivity to voriconazole.

Use in Pregnancy and Lactation

Adequate and strictly controlled studies on the safety of voriconazole use during pregnancy have not been conducted. In experimental studies in animals, it was found that Voriconazole in high doses has a toxic effect on reproductive function. The possible risk to humans is unknown.

The excretion of voriconazole in breast milk has not been studied.

Voriconazole should not be used during pregnancy and lactation, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus or breastfed infant.

During treatment, women of reproductive age should use reliable methods of contraception.

Use in Hepatic Impairment

Use with caution in patients with severe hepatic insufficiency. Liver function should be regularly monitored during treatment (if clinical signs of liver disease appear, the advisability of discontinuing therapy should be discussed).

Use in Renal Impairment

Use with caution in patients with severe renal impairment (with parenteral administration). Renal function (including serum creatinine level) should be regularly monitored during treatment.

Pediatric Use

The safety and efficacy of voriconazole use in children under 2 years of age have not been established.

Special Precautions

Use with caution in patients with severe hepatic insufficiency, with severe renal impairment (with parenteral administration), as well as with hypersensitivity to other drugs – azole derivatives.

Correction of electrolyte disturbances (hypokalemia, hypomagnesemia and hypocalcemia) is required before starting treatment.

Samples for culture and other laboratory tests (serological, histopathological) for the isolation and identification of pathogens should be taken before starting treatment. Therapy can be started before receiving the results of laboratory tests, and then, if necessary, adjusted.

The use of voriconazole may lead to QT interval prolongation on the ECG, which is accompanied by rare cases of ventricular fibrillation/flutter in patients with multiple risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy that could contribute to the development of adverse cardiovascular events). Voriconazole should be used with caution in patients with these potentially proarrhythmic conditions.

Liver function (if clinical signs of liver disease appear, the advisability of discontinuing therapy should be discussed) and renal function (including serum creatinine level) should be regularly monitored during treatment.

If dermatological reactions progress, the drug should be discontinued.

During treatment, patients receiving Voriconazole should avoid sun exposure and UV radiation.

With simultaneous use of voriconazole in patients receiving cyclosporine and tacrolimus, the dose of the latter should be adjusted and their plasma concentration monitored. After discontinuation of voriconazole, the plasma concentration of cyclosporine and tacrolimus should be assessed and their dose increased if necessary.

If concomitant use of voriconazole and phenytoin is necessary, the expected benefit and potential risk of combination therapy should be carefully assessed and phenytoin levels should be constantly monitored.

If concomitant use of voriconazole and rifabutin is necessary, the expected benefit and potential risk of combination therapy should be carefully assessed and it should be carried out under the control of the peripheral blood picture, as well as other possible adverse effects of rifabutin.

The safety and efficacy of voriconazole use in children under 2 years of age have not been established.

Effect on ability to drive vehicles and operate machinery

Since Voriconazole can cause transient visual disturbances, including blurred vision, impaired/enhanced visual perception and/or photophobia, if such reactions occur, patients should not engage in potentially hazardous activities such as driving a car or operating complex machinery. While taking voriconazole, patients should not drive a car at night.

Drug Interactions

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

With simultaneous use with rifampicin (an inducer of CYP isoenzymes) at a dose of 600 mg/day, C_max and AUC of voriconazole decrease by 93% and 96%, respectively (the combination is contraindicated).

When used concomitantly with voriconazole, ritonavir (an inducer of CYP isoenzymes, inhibitor and substrate of CYP3A4) at a dose of 400 mg every 12 hours reduced the steady-state C_max and AUC of orally administered voriconazole by an average of 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. It has been established that repeated oral administration of voriconazole does not have a significant effect on the steady-state C_max and AUC of ritonavir also administered repeatedly (concomitant use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).

When used concomitantly with potent inducers of CYP isoenzymes, carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in the plasma C_max of voriconazole is possible, although their interaction has not been studied. This combination is contraindicated.

When used concomitantly with cimetidine (a non-specific inhibitor of CYP isoenzymes) at a dose of 400 mg twice daily, the C_max and AUC of voriconazole increase by 18% and 23%, respectively (no dose adjustment of voriconazole is required).

Voriconazole inhibits the activity of CYP2C19, CYP2C9, and CYP3A4; therefore, an increase in plasma concentrations of drugs metabolized by these isoenzymes is possible.

When voriconazole is used concomitantly with terfenadine, astemizole, cisapride, pimozide, and quinidine, a significant increase in their plasma concentration is possible, which may lead to QT interval prolongation and, in rare cases, to the development of ventricular fibrillation/flutter (the combination is contraindicated).

When used concomitantly, Voriconazole increases the C_max and AUC of sirolimus (2 mg single dose) by 556% and 1014%, respectively (the combination is contraindicated).

When used concomitantly, Voriconazole may cause an increase in the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and the development of ergotism (such a combination is contraindicated).

When used concomitantly in patients who have undergone kidney transplantation and are in a stable condition, Voriconazole increases the C_max and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of nephrotoxic reactions. When using voriconazole in patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. After discontinuation of voriconazole, cyclosporine levels should be monitored and its dose increased if necessary.

When used concomitantly, Voriconazole increases the C_max and AUC of tacrolimus (administered at a dose of 0.1 mg/kg as a single dose) by 117% and 221%, respectively, which may be accompanied by nephrotoxic reactions. When using voriconazole in patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one-third and monitor its plasma levels. After discontinuation of voriconazole, the concentration of tacrolimus should be monitored and its dose increased if necessary.

Concomitant use of voriconazole (at a dose of 300 mg twice daily) and warfarin (30 mg once daily) was accompanied by an increase in the maximum prothrombin time by up to 93%. When warfarin and voriconazole are prescribed concomitantly, it is recommended to monitor prothrombin time.

Voriconazole, when used concomitantly, may cause an increase in the plasma concentration of phenprocoumon, acenocoumarol (substrates of CYP2C9, CYP3A4) and prothrombin time. When using voriconazole in patients receiving coumarin drugs, prothrombin time should be monitored at short intervals and the doses of anticoagulants should be adjusted accordingly.

When used concomitantly, Voriconazole may cause an increase in the plasma concentration of sulfonylurea derivatives (substrates of CYP2C9) – tolbutamide, glipizide, and glibenclamide and cause hypoglycemia. When used concomitantly, blood glucose levels should be carefully monitored.

In vitro, Voriconazole inhibits the metabolism of lovastatin (a substrate of CYP3A4). When used concomitantly, an increase in the plasma concentration of statins metabolized by CYP3A4 is possible, which may increase the risk of rhabdomyolysis. When used concomitantly, it is recommended to assess the advisability of adjusting the statin dose.

In vitro, Voriconazole inhibits the metabolism of midazolam (a substrate of CYP3A4). When used concomitantly, an increase in the plasma concentration of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and the development of a prolonged sedative effect are possible. When these drugs are used concomitantly, it is recommended to discuss the advisability of adjusting the benzodiazepine dose.

When used concomitantly, Voriconazole may increase the plasma levels of vinca alkaloids (substrates of CYP3A4) – vincristine, vinblastine and lead to the development of neurotoxic reactions. It is recommended to discuss the advisability of adjusting the dose of vinca alkaloids.

Voriconazole increases the C_max and AUC of prednisolone (a substrate of CYP3A4) administered at a dose of 60 mg as a single dose by 11% and 34%, respectively. Dose adjustment is not recommended.

When used concomitantly with voriconazole, efavirenz (a substrate of CYP3A4, according to a number of studies depending on the dose – an inhibitor or inducer of CYP3A4), used at a dose of 400 mg once daily at steady state, reduces the C_max and AUC of voriconazole by an average of 61% and 77%, respectively. Voriconazole at steady state (400 mg orally every 12 hours on the first day, then 200 mg orally every 12 hours for 8 days) increases the steady-state C_max and AUC of efavirenz by an average of 38% and 44%, respectively (such a combination is contraindicated).

When used concomitantly, phenytoin (a substrate of CYP2C9 and a potent inducer of cytochrome P450 isoenzymes), used at a dose of 300 mg once daily, reduces the C_max and AUC of voriconazole by 49% and 69%, respectively; and Voriconazole (400 mg twice daily) increases the C_max and AUC of phenytoin by 67% and 81%, respectively (if concomitant use is necessary, the ratio of the expected benefit and the potential risk of combination therapy should be carefully assessed, and phenytoin plasma levels should be carefully monitored).

When used concomitantly, rifabutin (an inducer of cytochrome P450), used at a dose of 300 mg once daily, reduces the C_max and AUC of voriconazole (200 mg once daily) by 69% and 78%, respectively. When used concomitantly with rifabutin, the C_max and AUC of voriconazole (350 mg twice daily) are 96% and 68%, respectively, of the values during voriconazole monotherapy (200 mg twice daily). When voriconazole is used at a dose of 400 mg twice daily, the C_max and AUC are 104% and 87% higher, respectively, than during voriconazole monotherapy at a dose of 200 mg twice daily. Voriconazole at a dose of 400 mg twice daily increases the C_max and AUC of rifabutin by 195% and 331%, respectively. During concomitant treatment with rifabutin and voriconazole, it is recommended to regularly perform a complete blood count and monitor for adverse effects of rifabutin (e.g., uveitis).

When used concomitantly at a dose of 40 mg once daily, omeprazole (an inhibitor of CYP2C19; a substrate of CYP2C19 and CYP3A4) increases the C_max and AUC of voriconazole by 15% and 41%, respectively, and Voriconazole increases the C_max and AUC of omeprazole by 116% and 280%, respectively (therefore, no dose adjustment of voriconazole is required, but the dose of omeprazole should be reduced by half). The possibility of drug interaction of voriconazole with other H⁺-K⁺-ATPase inhibitors that are substrates of CYP2C19 should be considered.

When used concomitantly with other HIV protease inhibitors (substrates and inhibitors of CYP3A4), the patient’s condition should be carefully monitored for possible toxic effects, as in vitro studies have shown that Voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) may mutually inhibit each other’s metabolism.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.