HOLOXAN 500 MG INJECTION

Indications

• Metastatic melanoma
• Soft-tissue sarcomas
• Hodgkin’s disease

Dosage

Children: Refer to local protocol for specific dosing guidelines.

Adults: Refer to local protocol for specific dosing guidelines.

Mechanism of action

Ifosfamide's mechanism of action involves its conversion to active metabolites in the liver via the cytochrome P450 system. These active metabolites primarily alkylate DNA by binding to the N-7 position of guanine, leading to the formation of inter and intra strand cross-links in DNA, which results in cytotoxic effects and ultimately cell death.

Pharmacodynamics

Activation of ifosfamide occurs through microsomal liver enzymes, producing reactive metabolites capable of damaging cellular components. The primary metabolites include 4-hydroxyifosfamide, which degrades to stable urinary metabolites. The alkylation of DNA by these metabolites is responsible for ifosfamide's cytotoxicity. It is classified as a cycle-phase nonspecific drug, meaning it can affect cells at any point in the cell cycle.

Pharmacokinetics

Ifosfamide is administered intravenously and undergoes hepatic metabolism to generate active and inactive metabolites. The drug has a half-life that varies depending on the route of administration and patient factors. Renal function can significantly affect its clearance and the accumulation of toxic metabolites, necessitating monitoring in patients with renal impairment. The drug is primarily excreted in the urine.

Contra-indications

• Acute infection
• Cardiac disease
• Severe renal impairment
• Severe hepatic impairment

Adverse effects

• Anaemia
• Leucopenia
• Thrombocytopenia
• Nausea
• Vomiting
• Diarrhoea
• Fluid retention
• Gynaecomastia
• Headache
• Confusion
• Depression
• Erectile dysfunction
• Hypertension
• Alopecia
• Infection
• Influenza-like illness
• Visual impairment
• Skin reactions
• Hypotension
• Abdominal pain

Interactions

• Pemigatinib may decrease exposure to ifosfamide
• Netupitant may increase exposure to ifosfamide

Precautions

• Caution in handling, irritant to tissues
• Monitor hepatic function in hepatic impairment
• Avoid use in severe renal or hepatic impairment
• Men should use effective contraceptive methods during treatment

Pregnancy

Avoid use during pregnancy as it is carcinogenic and teratogenic.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Powder for solution for infusion
• Intravenous injection
• Intravenous infusion

Mechanism of action

The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death. Mechanism of action: metabolites cause alkylation of DNA. /from table/ Ifosfamide, a structural analog of cyclophosphamide, belongs to the oxazaphosphorine class of antitumor alkylating agents which must be activated by the mixed function oxidase system of the liver. The 4-hydroxy oxazaphosphorines are a reactive species capable of interacting with nucleic acids & cellular materials to cause cell damage & death. The 4-hydroxy metabolite spontaneously liberates acrolein in many sites throughout the body & it is this substance that is responsible for oxazaphosphorine urotoxicity. Both ifosfamide & cyclophosphamide produce cystitis characterized by tissue edema & ulceration followed by sloughing of mucosal epithelial cells, necrosis of smooth muscle fibers & arteries, & culminating in focal hemorrhage. The selective urotoxicity of oxazaphosphorine occurs because the bladder contains a very low concn of thiol cmpds (glutathione, cysteine) which, by virtue of their nucleophilic sulfhydryl groups, are able to react & neutralize many reactive chemicals. Because the metabolic activation of ifosfamide proceeds more slowly than that of cyclophosphamide, doses of ifosfamide are 3-4 times higher than those of cyclophosphamide. This explains the higher incidence of urotoxicity associated with ifosfamide.

Pharmacodynamics

Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific.