Ifosfamide


Generic Medicine Info
Indications and Dosage
Intravenous
Malignant disease
Adult: Various dosage regimens are available. Regimen 1: 8-12 g/m2 equally divided as single daily doses over 3-5 days, repeated every 2-4 weeks. Regimen 2: 5-6 g/m2 (Max 10 g) as a single 24-hour infusion, repeated every 3-4 weeks. Regimen 3: 2‐2.4 g/m2 (50 ‐ 60 mg/kg) daily for 5 consecutive days, repeated every 3-4 weeks. To be given with mesna and adequate hydration of at least 2 L of oral or IV fluid per day. Dosage, treatment duration and/or intervals depend on patient tolerability, blood count and recovery from any adverse effects.

Intravenous
Germ cell testicular carcinoma
Adult: As 3rd-line chemotherapy for cases in combination with other antineoplastic agents: 1.2 g/m2 daily for 5 consecutive days via slow infusion over at least 30 minutes; repeated every 3 weeks or after recovery from haematological toxicity. To be given with mesna and adequate hydration of at least 2 L of oral or IV fluid per day.
Renal Impairment
Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Reconstitution
Directions for reconstitution may vary among individual products. Refer to specific product guidelines.
Incompatibility
Benzyl alcohol-containing solutions may reduce the stability of ifosfamide.
Contraindications
Acute infections, cystitis, urinary outflow obstruction, severely impaired bone marrow function. Renal and severe hepatic impairment. Pregnancy and lactation.
Special Precautions
Patient with cardiac risk factors or pre-existing cardiac disease, other infections (e.g. active UTI), severe immunosuppression or compromised bone marrow reserve. Patients who have undergone previous radiation therapy. Mild to moderate hepatic impairment.
Adverse Reactions
Significant: Haemorrhagic cystitis, secondary malignancies, veno-occlusive liver disease/hepatic sinusoidal obstruction syndrome (SOS), anaphylactic/anaphylactoid reactions, impaired wound healing, amenorrhoea, azoospermia, sterility, nausea, vomiting, reactivation of latent infections.
Gastrointestinal disorders: Diarrhoea, stomatitis.
General disorders and administration site conditions: Fatigue, malaise, weakness.
Hepatobiliary disorders: Hepatotoxicity.
Metabolism and nutrition disorders: Anorexia, metabolic acidosis.
Nervous system disorders: Drowsiness, encephalopathy.
Renal and urinary disorders: Haematuria.
Skin and subcutaneous tissue disorders: Alopecia, dermatitis, papular rash.
Vascular disorders: Hypotension, phlebitis.
Potentially Fatal: Myelosuppression (resulting in leucopenia, neutropenia, thrombocytopenia, and anaemia), cardiotoxicity (e.g. cardiomyopathy, arrhythmias or other ECG changes, pericardial effusion, pericarditis, epicardial fibrosis), neurotoxicity, severe nephrotoxicity leading to renal failure, pulmonary toxicity (e.g. interstitial pneumonitis, pulmonary fibrosis) leading to respiratory failure, severe immunosuppression (leading to serious infection, sepsis or septic shock).
Patient Counseling Information
Ensure proper hydration. This drug may cause CNS effects that impair mental alertness; if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor CBC with differential (before and after each cycle), urine output, urinalysis (before each dose), hepatic and renal function tests (before and during treatment). Assess for signs of neurotoxicity, pulmonary toxicity, and haemorrhagic cystitis.
Overdosage
Symptoms: Myelosuppression, CNS toxicity, nephrotoxicity, and mucositis. Management: Supportive treatment. Administration of mesna for cystitis prophylaxis may help prevent urotoxic effects.
Drug Interactions
Increased formation of toxic metabolites when used concomitantly with CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin, corticosteroids). CYP3A4 inhibitors (e.g. ketoconazole, fluconazole, itraconazole, sorafenib) may reduce the effectiveness of ifosfamide. Increased risk of haemorrhagic cystitis with previous or concomitant busulfan treatment. Increased haematoxicity with ACE inhibitors, carboplatin, cisplatin, natalizumab. Increased cardiotoxicity with anthracyclines. Increased pulmonary toxicity with amiodarone, granulocyte colony/granulocyte macrophage colony-stimulating factors. Increased nephrotoxicity with aminoglycosides, aciclovir, amphotericin B, carboplatin, cisplatin. Additive CNS effects with antiemetics, antihistamines, narcotics, sedatives. Increased neurotoxicity with aprepitant. Increased gastrointestinal toxicity with IV docetaxel. Increased INR with warfarin. Increased risk of thromboembolic complications with tamoxifen. May enhance the hypoglycaemic effects of antidiabetic agents (e.g. sulfonylureas). May reduce the formation of the active metabolite of irinotecan. Concurrent use of live vaccines may lead to vaccine-induced infection.
Food Interaction
Increased toxicity with St. John's wort. Grapefruit or grapefruit juice may reduce the efficacy of ifosfamide. Alcohol may increase the risk of hepatic dysfunction or ifosfamide-induced nausea and vomiting.
Action
Description: Ifosfamide is converted to its active metabolites via hepatic microsomal enzymes. These active metabolites cause cross-linking of DNA strands by binding with nucleic acids and other intracellular structures, resulting in cell death.
Pharmacokinetics:
Absorption: Rapidly absorbed from the site of administration.
Distribution: Distributed into the CSF. Enters breast milk.
Metabolism: Extensively metabolised in the liver via 2 metabolic pathways including ring oxidation to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloro-ethylifosfamide with the liberation of the toxic metabolite, chloroacetaldehyde.
Excretion: Mainly via urine, as unchanged drug and metabolites. Elimination half-life: Approx 15 hours (high doses); approx 7 hours (lower doses).
Chemical Structure

Chemical Structure Image
Ifosfamide

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3690, Ifosfamide. https://pubchem.ncbi.nlm.nih.gov/compound/Ifosfamide. Accessed July 27, 2021.

Storage
Powder for inj: Store between 20-25°C. Solution for inj: Store between 2-8°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01AA06 - ifosfamide ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.
References
Anon. Ifosfamide. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 12/07/2021.

Anon. Ifosfamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/06/2021.

Baxter Healthcare Ltd. Holoxan data sheet 19 June 2018. Medsafe. http://www.medsafe.govt.nz. Accessed 15/06/2021.

Buckingham R (ed). Ifosfamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/06/2021.

Ifosfamide Injection (Hikma Pharmaceuticals USA Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 16/06/2021.

Ifosfamide Injection 1 g (Baxter Healthcare Ltd). MHRA. https://products.mhra.gov.uk. Accessed 15/06/2021.

Ifosfamide Injection, Powder, for Solution (Baxter Healthcare Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 15/06/2021.

Joint Formulary Committee. Ifosfamide. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/06/2021.

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