LIPHOLYN INJECTION

Indications

• Severe invasive candidiasis
• Severe systemic fungal infections
• Invasive aspergillosis
• Cryptococcal meningitis
• Disseminated cryptococcosis in HIV patients
• Prophylaxis of candidiasis in patients undergoing bone marrow transplantation
• Visceral leishmaniasis unresponsive to antimonials

Dosage

Children: For neonates, 1 mg/kg once daily for at least 7 days; for children up to 40 kg, 1 mg/kg once daily for at least 7 days; for older children, doses may vary, generally 3-5 mg/kg daily depending on the indication and clinical response.

Adults: For severe systemic fungal infections, 0.5 to 1 mg/kg once daily; may increase based on clinical response and tolerance. For specific indications, consult BNF.

Mechanism of action

Amphotericin B works by binding to ergosterol, a key component of fungal cell membranes, leading to increased permeability and subsequent cell death.

Pharmacodynamics

Amphotericin demonstrates fungicidal activity against a broad spectrum of fungi. Its efficacy is influenced by the extent of fungal cell membrane damage and the concentration of the drug.

Pharmacokinetics

Amphotericin is poorly absorbed from the gastrointestinal tract and is typically administered intravenously. It distributes widely in body tissues but has limited penetration into the central nervous system. It is primarily excreted unchanged in the urine, and its half-life varies depending on the formulation used.

Contra-indications

• Hypersensitivity to amphotericin
• Severe renal impairment

Adverse effects

• Nephrotoxicity
• Electrolyte imbalances
• Infusion-related reactions (fever, chills)
• Nausea and vomiting
• Headache
• Anemia
• Hypotension
• Hepatic dysfunction

Interactions

• Increased risk of nephrotoxicity with other nephrotoxic agents
• Flucytosine may increase risk of toxicity when used with amphotericin
• Micafungin may increase exposure to amphotericin

Precautions

• Monitor renal function regularly
• Monitor liver function
• Use with caution in patients with existing electrolyte imbalances
• Consider potential for infusion reactions

Pregnancy

Use only if potential benefit justifies potential risk to the fetus.

Breast-feeding

Not recommended; use with caution if necessary.

Storage

Store at 2°C to 8°C; protect from light.

Formulations

• Powder for solution for infusion (Amphotericin B)

Indications

• Cancer treatment (chemotherapy)
• Fungal infections (antifungal therapy)
• Pain management (analgesics)
• Inflammatory diseases

Dosage

Children: Refer to specific liposomal drug guidelines for paediatric dosing, as it varies by formulation and indication.

Adults: Refer to specific liposomal drug guidelines for dosing, as it varies by formulation and indication.

Mechanism of action

Liposomal drugs work by encapsulating the therapeutic agent within a lipid bilayer, which facilitates prolonged circulation time in the bloodstream. This can enhance the drug's accumulation at target sites, such as tumors or infected tissues, via passive or active targeting mechanisms. The liposomes can also modulate the release of the drug, allowing for controlled pharmacokinetics.

Pharmacodynamics

Once administered, liposomal drugs interact with cellular membranes through fusion or endocytosis, leading to the release of the encapsulated drug within the target cells. This localized release increases drug concentration at the site of action, potentially enhancing efficacy while minimizing side effects associated with systemic exposure. The pharmacodynamics depend on the specific drug encapsulated and its inherent properties.

Pharmacokinetics

Liposomal formulations often exhibit altered pharmacokinetics compared to their free drug counterparts. They typically have increased half-lives due to their lipid composition, which protects the drug from rapid metabolism and clearance. Distribution is influenced by the size and surface characteristics of the liposomes, affecting their uptake by various tissues. Excretion generally occurs through the reticuloendothelial system, primarily in the liver and spleen.

Adverse effects

• Infusion-related reactions
• Nausea
• Vomiting
• Fever
• Chills
• Fatigue
• Hypersensitivity reactions
• Thrombocytopenia

Precautions

• Monitor for infusion-related reactions
• Use with caution in patients with renal impairment
• Consider potential allergic reactions in patients with a history of hypersensitivity

Pregnancy

Liposomal formulations should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether liposomal formulations are excreted in human milk. Caution is advised.

Storage

Store at 2–8°C. Do not freeze. Protect from light.

Formulations

• Liposomal doxorubicin
• Liposomal amphotericin B
• Liposomal irinotecan

Mechanism of action

Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols (ergosterol) in the cell membrane of susceptible fungi. This creates a transmembrane channel, and the resultant change in membrane permeability allowing leakage of intracellular components. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death. Amphotericin B usually is fungistatic in action at concentrations obtained clinically, but may be fungicidal in high concentrations or against very susceptible organisms. Amphotericin B exerts its antifungal activity principally by binding to sterols (e.g., ergosterol) in the fungal cell membrane. As a result of this binding, the cell membrane is no longer able to function as a selective barrier and leakage of intracellular contents occurs. Cell death occurs in part as a result of permeability changes, but other mechanisms also may contribute to the in vivo antifungal effects of amphotericin B against some fungi. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (eg, bacteria). Binding to sterols in mammalian cells (such as certain kidney cells and erythrocytes) may account for some of the toxicities reported with conventional amphotericin B therapy. At usual therapeutic concentrations of amphotericin B, the drug does not appear to hemolyze mature erythrocytes, and the anemia seen with conventional IV amphotericin B therapy may result from the action of the drug on actively metabolizing and dividing erythropoietic cells. ...Nephrotoxicity associated with conventional IV amphotericin B appears to involve several mechanisms, including a direct vasoconstrictive effect on renal arterioles that reduces glomerular and renal tubular blood flow and a lytic action on cholesterol-rich lysosomal membranes of renal tubular cells. ...

Pharmacodynamics

Amphotericin B shows a high order of <i>in vitro</i> activity against many species of fungi. <i>Histoplasma capsulatum</i>, <i>Coccidioides immitis</i>, <i>Candida species</i>, <i>Blastomyces dermatitidis</i>, <i>Rhodotorula</i>, <i>Cryptococcus neoformans</i>, <i>Sporothrix schenckii</i>, <i>Mucor mucedo</i>, and <i>Aspergillus fumigatus</i> are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL <i>in vitro</i>. While <i>Candida albicans</i> is generally quite susceptible to amphotericin B, non-<i>albicans</i> species may be less susceptible. <i>Pseudallescheria boydii</i> and <i>Fusarium</i> sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.