Amphotericin B

Amphotericin B belongs to the pharmacological class of Polyene Antifungal.

Amphotericin B has been approved to relieve symptoms and also for the treatment and maintenance of Fungal Infection, Empiric Therapy, Systemic Fungal Infections, Cryptococcal Meningitis, Visceral Leishmaniasis, Candida auris (Off-label).

Amphotericin B is completely absorbed when administered through intravenous infusion, resulting in a bioavailability of 100%. The volume of distribution for this medication is not specified. Once in the bloodstream, amphotericin B has a high affinity for plasma proteins, with over 90% of the drug binding to these proteins. Metabolism of amphotericin B occurs exclusively in the kidneys. However, the exact route of elimination for this medication is not specified in the available information.

The common side effects involved in using Amphotericin B are Fever, Chills , Headache, Muscle or joint pain, Nausea, Vomiting, Changes in blood pressure, Changes in urine output, Increased creatinine and blood urea nitrogen (BUN) levels, Electrolyte imbalances, Low potassium levels, Low magnesium levels

Amphotericin B is available in the form of Intravenous liposomal formulation.

Amphotericin B is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Amphotericin B belongs to the pharmacological class of Polyene Antifungal.

Depending on the concentration achieved in body fluids and the susceptibility of the fungus, amphotericin B can exhibit either fungistatic or fungicidal effects. Its mechanism of action involves binding to sterols, specifically ergosterol, present in the cell membrane of susceptible fungi. This binding creates a transmembrane channel, leading to a change in membrane permeability and subsequent leakage of intracellular components. Ergosterol, the primary sterol found in the fungal cytoplasmic membrane, serves as the target site for amphotericin B and the azoles. As a polyene, amphotericin B binds irreversibly to ergosterol, resulting in the disruption of membrane integrity and ultimately causing cell death.

Amphotericin B has been approved to relieve symptoms and also for the treatment and maintenance of Fungal Infection, Empiric Therapy, Systemic Fungal Infections, Cryptococcal Meningitis,Visceral Leishmaniasis, Candida auris (Off-label).

The elimination half-life of amphotericin B ranges from 24 hours to 15 days.

Amphotericin B is found to be available in the form of Intravenous liposomal formulation.

Amphotericin B can be used in the following treatment:

• Fungal Infection, Empiric Therapy
• Systemic Fungal Infections
• Cryptococcal Meningitis
• Visceral Leishmaniasis
• Candida auris (Off-label)

Amphotericin B can help to relieve symptoms and also for the treatment and maintenance of Fungal Infection, Empiric Therapy, Systemic Fungal Infections, Cryptococcal Meningitis, Visceral Leishmaniasis, Candida auris (Off-label).

Amphotericin B is approved for use in the following clinical indications:

• Fungal Infection, Empiric Therapy
• Systemic Fungal Infections
• Cryptococcal Meningitis
• Visceral Leishmaniasis
• Candida auris (Off-label)

Fungal Infection, Empiric Therapy

• Purpose: For the initial treatment of presumed fungal infection in febrile, neutropenic patients.
• Dosage: Administered intravenously at a dose of 3 mg/kg once daily.

Systemic Fungal Infections

• Purpose: For the treatment of infections caused by Aspergillus species, Candida species, and/or Cryptococcus species that are resistant to amphotericin B deoxycholate or when the use of amphotericin B deoxycholate is not possible due to renal impairment or unacceptable toxicity.
• Dosage: Administered intravenously at a dose of 3-5 mg/kg once daily.

Cryptococcal Meningitis

• Purpose: For the treatment of Cryptococcal meningitis in HIV-infected patients.
• Dosage: Administered intravenously at a dose of 6 mg/kg once daily.

Visceral Leishmaniasis

• Purpose: For the treatment of visceral leishmaniasis.
• Note: In immunocompromised patients, there is a high relapse rate with amphotericin B liposomal following initial parasite clearance.
• Immunocompetent patients: Administered intravenously at a dose of 3 mg/kg once daily on days 1-5, 14, and 21. Repeat therapy if parasitic clearance is not achieved.
• Immunocompromised patients: Administered intravenously at a dose of 4 mg/kg once daily on days 1-5, 10, 17, 24, 31, and 38. Consult an infectious disease specialist if parasitic clearance is not achieved.

Candida auris (Off-label)

• The CDC recommends considering a switch to liposomal amphotericin B if the patient is clinically unresponsive to echinocandin treatment or has persistent fungemia for more than 5 days.
• Dosage: Administered intravenously at a dose of 5 mg/kg once daily.

Intravenous liposomal formulation : 50 mg/vial

Intravenous liposomal formulation.

Dosage Adjustments in Pediatric Patients:

Fungal Infection, Empiric Therapy

• Purpose: Used as initial therapy for presumed fungal infection in febrile, neutropenic patients.
• Adult Dosage: Administered intravenously at a dose of 3 mg/kg once daily.

Systemic Fungal Infections

• Purpose: Used for the treatment of infections caused by Aspergillus species, Candida species, and/or Cryptococcus species that are resistant to amphotericin B deoxycholate or if its use is not possible due to renal impairment or unacceptable toxicity.
• Adult Dosage: Administered intravenously at a dose of 3-5 mg/kg once daily.

Cryptococcal Meningitis

• Purpose: Used for the treatment of Cryptococcal meningitis in HIV-infected patients.
• Adult Dosage: Administered intravenously at a dose of 6 mg/kg once daily.

Visceral Leishmaniasis

• Purpose: Used for the treatment of visceral leishmaniasis.
• Note: Relapse rates may be high in immunocompromised patients following initial clearance of parasites.
• Immunocompetent patients: Administered intravenously at a dose of 3 mg/kg once daily on days 1-5, 14, and 21. Repeat therapy if parasitic clearance is not achieved.
• Immunocompromised patients: Administered intravenously at a dose of 4 mg/kg once daily on days 1-5, 10, 17, 24, 31, and 38. Consult an infectious disease specialist if parasitic clearance is not achieved.

Candida auris (Off-label)

Neonates and Infants (<2 months)

• Consider switching to liposomal amphotericin B if unresponsive to amphotericin B deoxycholate.
• Dosage: 5 mg/kg/day intravenously.

Children (≥2 months)

• Consider switching to liposomal amphotericin B if clinically unresponsive to echinocandin treatment or if persistent fungemia lasts for more than 5 days.

• Dosage: 5 mg/kg once daily intravenously.

There are no specific dietary restrictions associated with the use of amphotericin B. However, it is important to maintain a balanced and healthy diet during treatment to support overall well-being and immune function.

Amphotericin B may be contraindicated under the following conditions:

Amphotericin B should not be used in patients who have shown or are known to have a hypersensitivity to amphotericin B deoxycholate or any other components of the product unless the treating physician determines that the potential benefits of therapy outweigh the risks involved.

The adverse reactions related to Amphotericin B can be categorized as follows:

Common:

• Fever and chills
• Headache
• Nausea and vomiting
• Muscle and joint pain
• Decreased appetite
• Anemia (low red blood cell count)
• Renal (k;idney) dysfunction

Less common:

• Hypotension (low blood pressure)
• Hypokalemia (low potassium levels)
• Electrolyte imbalances
• Allergic reactions, including rash and itching
• Fatigue and weakness
• Increased liver enzyme levels

Rare:

• Cardiac arrhythmias (abnormal heart rhythms)
• Neurological symptoms, such as confusion or seizures
• Respiratory distress or difficulty breathing
• Thrombophlebitis (inflammation of a vein)
• Pancreatitis (inflammation of the pancreas)
• Hemolysis (breakdown of red blood cells)

Antineoplastic Agents

• Concurrent use of antineoplastic agents may increase the risk of renal toxicity, bronchospasm, and hypotension.
• Caution should be exercised when administering antineoplastic agents concomitantly.

Corticosteroids and Corticotropin (ACTH)

• Concurrent use of corticosteroids and ACTH may potentiate hypokalemia, which can predispose the patient to cardiac dysfunction.
• If used together, close monitoring of serum electrolytes and cardiac function is recommended.

Digitalis Glycosides

• Concurrent use of digitalis glycosides may cause hypokalemia and potentiate digitalis toxicity.
• Serum potassium levels should be closely monitored when administered concurrently.

Flucytosine

• Concurrent use of flucytosine may increase its toxicity by potentially affecting its cellular uptake and/or renal excretion.

Azoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.)

• In vitro and in vivo animal studies suggest that the combination of amphotericin B and azoles may induce fungal resistance to amphotericin B.
• Combination therapy should be approached with caution, especially in immunocompromised patients.

Leukocyte Transfusions

• Simultaneous administration of intravenous amphotericin B and leukocyte transfusions has been associated with acute pulmonary toxicity.

Other Nephrotoxic Medications

• Concurrent use of amphotericin B and other nephrotoxic medications may increase the risk of drug-induced renal toxicity.
• Close monitoring of renal function is recommended in patients receiving a combination of nephrotoxic medications.

Skeletal Muscle Relaxants

• Amphotericin B-induced hypokalemia may enhance the effect of skeletal muscle relaxants, such as tubocurarine, due to hypokalemia.
• Close monitoring of serum potassium levels is advised when administering them together.

The following are the side effects involving Amphotericin B:

• Fever
• Chills
• Headache
• Muscle or joint pain
• Nausea
• Vomiting
• Changes in blood pressure
• Changes in urine output
• Increased creatinine and blood urea nitrogen (BUN) levels
• Electrolyte imbalances
• Low potassium levels
• Low magnesium levels
• Low calcium levels
• Fatigue
• Weakness
• Shortness of breath
• Elevated liver enzymes
• Rash
• Itching
• Swelling
• Difficulty breathing
• Changes in heart rhythm
• Confusion
• Dizziness
• Seizures
• Peripheral neuropathy
• Pain
• Inflammation
• Tissue damage
• Nausea
• Vomiting
• Diarrhea
• Loss of appetite

Pregnancy:

Teratogenic Effects - Category B

There is a lack of sufficient and well-controlled studies on the use of Amphotericin B in pregnant women. Although amphotericin B deoxycholate has been successfully used to treat systemic fungal infections in pregnant women, the number of reported cases is limited. Studies conducted on rats and rabbits (Segment II studies) have indicated that Amphotericin B does not possess teratogenic potential in these animal species. Studies have shown that the safe dose of Amphotericin B for pregnant rats is 5 mg/kg (which is equivalent to 0.16 to 0.8 times the recommended human clinical dose range), while for rabbits it is 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), after taking into account body surface area. However, it is important to note that rabbits who received higher doses of Amphotericin B (equivalent to 0.5 to 2 times the recommended human dose) had a higher rate of spontaneous abortions compared to the control groups. If the potential benefits of using Amphotericin B during pregnancy outweigh the potential risks, it may be considered, but only under close medical supervision.

Lactation:

The excretion of many drugs in human milk is well-documented, but it remains unclear whether Amphotericin B is excreted in human milk. As there is a possibility of serious adverse reactions in breastfed infants, it is crucial to make a decision regarding either discontinuing nursing or discontinuing the use of the drug. This decision should consider the significance of the drug for the mother's health.

Amphotericin B has been successfully used to treat fungal infections in pediatric patients aged one month to 16 years, including those with confirmed systemic fungal infections or visceral leishmaniasis. Studies have shown that Amphotericin B is just as effective and safe for pediatric patients as it is for adults, with no differences observed in 302 pediatric patients who were treated with the medication. Since pediatric patients can receive the same doses of Amphotericin B as adults based on their body weight, no dosage adjustment is necessary. However, it is important to note that the safety and efficacy of Amphotericin B in pediatric patients under the age of one month has not yet been established.

Geriatric Use:

A total of 72 elderly patients (aged 65 years or older) were included in the experience with Amphotericin B. There was no need to adjust the dose of Amphotericin B for this particular population. However, it is important to exercise caution and closely monitor elderly patients, as is typically done with other medications.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Amphotericin B.

Overdose-related toxicity of Amphotericin B has not been clearly defined. Clinical trials have administered repeated daily doses of up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients without reporting any dose-related toxicity. However, if an overdose occurs, administration of Amphotericin B should be stopped immediately. Symptomatic supportive measures should be initiated, with careful monitoring of renal function being of utmost importance. It should be noted that hemodialysis or peritoneal dialysis does not seem to significantly impact the elimination of Amphotericin B.

Pharmacodynamics

Amphotericin B exhibits potent in vitro activity against a wide range of fungal species. Concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL have been found to inhibit the growth of fungi such as Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus. Although Candida albicans is generally highly susceptible to amphotericin B, non-albicans species may exhibit lower susceptibility. On the other hand, certain fungi, such as Pseudallescheria boydii and Fusarium sp., are frequently resistant to the effects of amphotericin B. It is important to note that amphotericin B does not exert any significant activity against bacteria, rickettsiae, or viruses

Pharmacokinetics

Absorption:

The pharmacokinetic profile of amphotericin B after administration of Amphotericin B is based on total serum concentrations of the drug, as the assay used does not distinguish between amphotericin B complexed with the phospholipids of Amphotericin B and uncomplexed amphotericin B. The study on febrile neutropenic cancer and bone marrow transplant patients who received Amphotericin B infusions for 3 to 20 days revealed that the pharmacokinetics of amphotericin B were nonlinear, with serum concentrations increasing more than proportionally with higher doses (1 to 5 mg/kg/day). The table below shows the pharmacokinetic parameters of total amphotericin B after the first dose and at steady state.

Distribution:

The mean half-life of amphotericin B based on total concentrations measured within a dosing interval (24 hours) was 7-10 hours.After Amphotericin B dosing, it takes up to 49 days to measure concentrations accurately. The mean half-life is between 100-153 hours, indicating a slow redistribution from tissues. Steady-state concentrations are usually reached within 4 days of dosing. There is no significant drug accumulation in the serum, as mean trough concentrations of amphotericin B remain relatively constant with repeated administration of the same dose (1 to 5 mg/kg/day).

The metabolic pathways of amphotericin B after administration are currently unknown.

The mean clearance of amphotericin B at steady state is independent of the dose administered. However, the excretion of amphotericin B after administration has not yet been studied.

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