Amphotericin B (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Sintez PJSC (Russia)

ATC Code

J02AA01 (Amphotericin B)

Active Substance

Amphotericin B

Amphotericin B (Rec.INN registered by WHO)

Dosage Form

Amphotericin B

Lyophilisate for preparation of solution for infusion 50 thousand IU: vial 10 ml 1, 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a yellow porous mass, odorless, or almost odorless, hygroscopic.

Excipients: sodium phosphate monobasic, deoxycholic acid.

50,000 IU – Vials of 10 ml volume (1) – cardboard packs.
50,000 IU – Vials of 10 ml volume (5) – cardboard packs.
50,000 IU – Vials of 10 ml volume (10) – cardboard packs.

Clinical-Pharmacological Group

Antifungal antibiotic

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

A polyene macrocyclic antibiotic with antifungal activity. Produced by Streptomyces nodosus. It has a fungicidal or fungistatic effect depending on the concentration in biological fluids and the sensitivity of the pathogen. It binds to sterols (ergosterols) located in the cell membrane of the fungus sensitive to the drug.

As a result, the permeability of the membrane is disrupted and intracellular components are released into the extracellular space and lysis of the fungus occurs.

Active against most strains of Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides braziliensis, Candida spp., Blastomyces dermatidis, Rhodotorula spp., Cryptococcus neoformans, Sporothrix schenekii, Mucor mucedo, Rhizopus spp., Absidia spp., Basidiobolus ranarum, Aspergillus fumigatus.

Moderately active against some protozoa: Leishmania braziliensis, Leishmania mexicana, Naegleria fowleri.

Generally resistant to amphotericin B: Pseudallescheria boydii, Fusarium spp.

Ineffective against bacteria, rickettsiae, viruses.

Pharmacokinetics

After a single intravenous administration, an effective concentration (dose-dependent) is created in the blood, which persists for 24 hours. After intravenous administration of 1-5 mg/day, the maximum concentration (C_max) in plasma is 0.5-2 µg/ml. Binding to plasma proteins is more than 90%.

Distributed in the lungs, liver, spleen, kidneys, adrenal glands, muscles and other tissues. Concentrations in pleural effusion, peritoneal, synovial fluids, and aqueous humor reach approximately 2/3 of the plasma concentration; in the cerebrospinal fluid, it is usually not detected. The apparent volume of distribution in adults is 4 L/kg, in children – 0.4-8.3 L/kg, in newborns – 1.5-9.4 L/kg.

Metabolized (pathways unknown). In bile and urine, about 98% is present as metabolites. It is slowly excreted by the kidneys, the initial half-life in adults is 24 hours, in children – 5.5-40.3 hours, in newborns – 18.8-62.5 hours; the terminal half-life is 15 days. Despite slow excretion, it accumulates weakly. It is practically not removed during hemodialysis. After discontinuation, it is detected in the body for several more weeks.

Indications

Progressive, life-threatening fungal infections caused by microorganisms sensitive to amphotericin B

• Disseminated cryptococcosis, cryptococcal meningitis;
• Meningitis caused by other fungi;
• Invasive and disseminated aspergillosis;
• North American blastomycosis;
• Disseminated forms of candidiasis;
• Coccidioidomycosis;
• Paracoccidioidomycosis;
• Histoplasmosis;
• Phycomycosis (zygomycosis);
• Chromomycosis;
• Mold mycosis;
• Disseminated sporotrichosis;
• Hyalohyphomycosis;
• Chronic mycetoma;
• Abdominal infections (including peritonitis);
• Endocarditis;
• Endophthalmitis;
• Fungal sepsis;
• Fungal infections of the urinary tract;
• Visceral leishmaniasis (including in patients with immunodeficiency), American cutaneous-visceral leishmaniasis (not the drug of choice).

ICD codes

Dosage Regimen

Intravenously by drip over 2-4 hours, the recommended concentration is 0.1 mg/ml. A test dose of 1 mg (base) is diluted in 20 ml of 5% dextrose solution and administered intravenously over at least 20-30 minutes under the control of blood pressure, pulse, body temperature every 30 minutes for 2-4 hours.

With good tolerance, the recommended daily dose is 0.25-0.3 mg/kg depending on the severity of the disease.

In case of increased sensitivity to the drug, diseases of the cardiovascular system, renal insufficiency, treatment begins with low doses – 5-10 mg and, gradually increasing by 5-10 mg/day, is brought to the recommended daily dose – 0.5-0.7 mg/kg.

The selection of therapeutic doses is carried out individually depending on the type and severity of the infection. When using the drug every other day, the dose should not exceed 1.5 mg/kg (to avoid the development of cardiopulmonary insufficiency). The maximum daily dose is 1.5 mg/kg.

Sporotrichosis: course dose 2.5 g, duration of therapy – 9 months.

Aspergillosis course dose – 3.6 g, duration of treatment – 11 months.

Rhinocerebral phycomycosis course dose – 3-4 g.

If therapy is interrupted for more than 7 days, it should be resumed with the lowest dose (0.25 mg/kg), gradually increasing to the desired level.

Children intravenously, initially 0.25 mg/kg (base) per day in 5% dextrose solution over 6 hours; taking into account tolerance, the dose is gradually increased (usually by 0.125 – 0.25 mg/kg every day or every other day) to a maximum dose of 1 mg/kg or 30 mg per 1 m². Children are administered at the minimum effective doses.

To prepare a solution for intravenous administration, use a solution with an initial concentration of 5 mg/ml. To do this, 10 ml of sterile water for injections without bacteriostatic additives is added with a sterile syringe (needle not less than No. 20) directly into the vial with the drug. The contents of the vial are shaken until a clear colloidal solution is formed. To obtain a solution with a concentration of 0.1 mg/ml, it is diluted with 5% dextrose solution with a pH not lower than 4.2 in a ratio of 1:50. Before dilution, it is necessary to check the acidity of the available dextrose solution. The pH of the dextrose solution usually exceeds 4.2, otherwise, before dilution, 1-2 ml of a buffer solution should be added to it.

The following buffer solution is recommended: sodium hydrogen phosphate (anhydrous) – 1.59 g, sodium dihydrogen phosphate (anhydrous) – 0.96 g, water for injections – up to 100 ml.

Before adding to the dextrose solution, the buffer solution is sterilized by filtration through a bacterial ceramic or membrane filter or by autoclaving for 30 minutes at a pressure of 1 atm and 121°C (249.8°F).

Adverse Reactions

From the digestive system often – decreased appetite, dyspepsia, nausea, vomiting, diarrhea, gastralgia, hepatotoxicity (increased activity of “liver” enzymes, hyperbilirubinemia); infrequently – acute liver failure, hepatitis, jaundice, hemorrhagic gastroenteritis, melena.

From the nervous system often – headache, infrequently – convulsions, transient vertigo, peripheral neuropathy, encephalopathy.

From the sensory organs infrequently – visual impairment, diplopia; hearing loss, tinnitus.

From the hematopoietic organs often – normochromic normocytic anemia; infrequently – agranulocytosis, blood clotting disorder, leukopenia, hemolytic anemia, thrombocytopenia, eosinophilia, leukocytosis.

From the cardiovascular system often – decreased blood pressure; infrequently – arrhythmias, including ventricular fibrillation, ECG changes, increased blood pressure, shock, cardiac arrest, heart failure.

From the respiratory system often – tachypnea; infrequently – shortness of breath, allergic pneumonitis, pulmonary edema.

From the urinary system often – impaired renal function, including azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, nephrocalcinosis; infrequently – acute renal failure, oliguria, anuria, nephrogenic diabetes insipidus. Preliminary administration of 0.9% sodium chloride solution reduces the risk of nephrotoxicity, administration of sodium bicarbonate reduces the risk of renal tubular necrosis.

Allergic reactions often – anaphylactoid reactions, bronchospasm, sneezing; infrequently – rash, especially maculopapular, itching, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Local reactions thrombophlebitis at the injection site, chemical burn.

Other often – fever, weight loss, myalgia, arthralgia, general weakness.

Laboratory parameters hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia, hypercreatininemia.

Contraindications

• Hypersensitivity;
• Chronic renal failure;
• Lactation period.

With caution: kidney diseases (including glomerulonephritis), amyloidosis, hepatitis, liver cirrhosis, anemia, agranulocytosis, diabetes mellitus, pregnancy.

Use in Pregnancy and Lactation

Use with caution during pregnancy. Contraindicated during lactation.

Use in Hepatic Impairment

Use with caution in hepatitis, liver cirrhosis.

Use in Renal Impairment

Use with caution in kidney diseases (including glomerulonephritis).

Pediatric Use

Children are administered at the minimum effective doses.

Special Precautions

Amphotericin B should be used primarily for the treatment of progressive and life-threatening fungal infections. It should not be used to treat non-invasive (superficial) mycoses such as oral, vaginal, or esophageal candidiasis in patients with normal neutrophil counts.

With long-term treatment, the likelihood of toxic effects increases.

During treatment, patients are monitored for body weight, complete blood count, urinalysis, blood potassium concentration, renal and liver function, and ECG. Patients taking potassium preparations should regularly monitor plasma potassium and magnesium concentrations.

Administration of the drug to patients on hemodialysis is possible only after the dialysis procedure is completed.

All procedures with the solution should be carried out in strict compliance with the rules of asepsis, since the drug itself and all solutions intended for its dilution do not contain preservatives or bacteriostatic agents.

When using systems for intravenous administration previously installed for other purposes, the system must be flushed with 5% dextrose solution for injections.

If anemia occurs, the drug should be discontinued.

Overdose

Symptoms cardiac and respiratory arrest.

Treatment symptomatic. It is necessary to monitor cardiac and respiratory activity, liver and kidney function, peripheral blood picture and electrolyte levels and prescribe supportive therapy. Not removed by hemodialysis.

Before resuming treatment, the patient’s condition must be stabilized.

Drug Interactions

Pharmaceutically incompatible with heparin, 0.9% sodium chloride solution and other solutions containing electrolytes.

The presence of bacteriostatic additives (including benzyl alcohol) may lead to precipitation of the drug.

Synergism – with nitrofurans.

Increases the effect and toxicity of anticoagulants, theophylline and sulfonylurea drugs, flucytosine (prolongs the half-life); reduces the effect of ethinyl estradiol – risk of “breakthrough” bleeding.

Inhibitors of liver microsomal enzymes (including cimetidine, non-narcotic analgesics, antidepressants) slow down the rate of metabolism, increase the concentration in the blood serum (increased toxicity).

Inducers of liver microsomal enzymes (including phenytoin, rifampicin, barbiturates, carbamazepine) accelerate metabolism in the liver (reduced effect).

Enhances the toxic effect of cardiac glycosides (especially against the background of an initial potassium deficiency in the body) and curare-like muscle relaxants.

Glucocorticosteroids, carbonic anhydrase inhibitors, adrenocorticotropic hormones increase the risk of hypokalemia.

Should not be prescribed simultaneously with nephrotoxic drugs (aminoglycosides, cyclosporine, pentamidine and others) – the risk of impaired renal function increases.

Antineoplastic drugs, radiation therapy and drugs that suppress bone marrow hematopoiesis increase the risk of anemia and other hematological disorders.

Antineoplastic drugs enhance nephrotoxicity, bronchospasm and decreased blood pressure.

Glucocorticosteroids and corticotropin enhance hypokalemia, which can lead to the development of arrhythmias. If it is necessary to prescribe these drugs simultaneously, monitoring of blood electrolyte composition and ECG should be carried out.

Amphotericin B may enhance the toxicity of cardiac glycosides (due to hypokalemia).

Simultaneous administration with imidazoles (including fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole) may lead to the development of resistance to amphotericin B. Combined treatment with imidazoles and amphotericin B should be prescribed with caution.

Should not be prescribed simultaneously with nephrotoxic drugs (aminoglycosides, cyclosporine, pentamidine and others) – the risk of impaired renal function increases.

Prolongs the muscle relaxant effect of depolarizing muscle relaxants.

Leukocyte mass should be administered with a significant interval after the administration of amphotericin B (risk of complications from the respiratory system).

Storage Conditions

List B. In a dry, light-protected place at a temperature of 2 to 10°C (50°F). Keep out of reach of children.

Shelf Life

Shelf life – 4 years.

Dispensing Status

By prescription.

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.