alkylating agent, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Ifosfamide, like cyclophosphamide, is an oxazophosphorine alkylating agent. Following activation in the liver, ifosfamide interferes with DNA through formation of phosphotriesters and DNA-DNA crosslinks, thereby inhibiting protein synthesis and DNA synthesis.1,4 Ifosfamide is cell cycle-specific, but cell cycle phase non-specific.1,4 Ifosfamide is an immunosuppressive agent.
1,4
| Oral Absorption | 90-100% 1,5 ; time to peak 5 : 1 hour | |
| Distribution | throughout the body | |
| cross blood brain barrier? | yes 1 , in sub-therapeutic amounts 5 | |
| volume of distribution 1,4,5 | 6-49 L, slightly higher if obese 1 | |
| plasma protein binding | negligible 5 | |
| Metabolism | activated by hepatic metabolism | |
| active metabolite(s) | yes, including phosphoramide mustard and acrolein 5 | |
| inactive metabolite(s) | yes | |
| Excretion | primarily renal | |
| urine | 14-50% as unchanged drug 1,4,5 ; 15-41% other metabolites 1,4,5 | |
| feces | no information found | |
| terminal half life 1,4,5 | 4-8 h; high dose (3,800-5,000mg/m 2 ) 11-15 h | |
| clearance 4 | 21 mL/min | |
| Elderly | small differences have been reported that are unlikely to be clinically relevant given interindividual variation | |
| Children | small differences have been reported that are unlikely to be clinically relevant given interindividual variation | |
Adapted from standard reference1 unless specified otherwise.
Primary uses: Other uses:
Acute lymphoblastic leukemia L3 variant6 Brain tumours7 Bladder cancer1 Breast cancer5 Burkett's lymphoma6 *Cervical cancer Ewing's sarcoma8 Chronic lymphocytic leukemia5 Germ cell tumours9,10 (gonadal, extra-gonadal, and non-seminomous) Gastric cancer5 Osteosarcoma8 Peripheral neuroectodermal tumour8 Rhabdomyosarcoma11 Germ cell testicular cancer1 Lung cancer1 Lymphoma, Hodgkin's5 *Soft tissue sarcoma8,12 Lymphoma, non-Hodgkin's1
*Health Canada approved indication
Ovarian cancer1 *Pancreatic cancer
in patients having severe leukopenia, thrombocytopenia, severe renal and/or hepatic impairment, cystitis, obstructions to urine flow, active infections, or advanced cerebral arteriosclerosis.
A uroprotective agent such as mesna must be used4; see paragraph following Side Effects table. Rule out or correct any obstruction or infection of the urinary tract before initiating treatment.4 Rule out or correct any electrolyte imbalances before initiating treatment.4 Do not administer within three months of a unilateral nephrectomy.4 Use caution in all patients with unilateral nephrectomy or impaired renal function Use caution in patients with prior or concomitant use of nephrotoxic drugs.4 Daily fluid intake must be at least 2 liters. If urinary excretion is insufficient, a fast-acting diuretic such as furosemide may be administered.4 Impaired wound healing is a possibility. Do not initiate treatment for at least 10 to 14 days after surgery.4,1
tumour infiltration of the bone marrow prior radiation therapy brain metastases and advanced cerebral arteriosclerosis impaired hepatic function abnormal serum albumin levels Special populations: Ifosfamide has been used in children, but safety and efficacy have not been established. Adverse effects appear similar to those reported in adults.4 Those 5 years of age or younger may be more susceptible to renal toxicity than older children or adults. Severe nephrotoxicity leading to Fanconi's syndrome, which may be irreversible, has been reported in young children who received ifosfamide alone or in conjunction with other antineoplastic agents. Some clinicians recommend that ifosfamide not be used in children with infiltrating renal tumours, prior nephrectomy, or any evidence of renal impairment. Carcinogenicity: Oncogenic in animals.4 Carcinogenic in rats.1 Mutagenicity: Mutagenic in vitro in bacterial systems, in mammalian in vivo mutation test, and in Drosophila in vivo mutation test.1 Adequate methods of contraception are recommended for male and female patients, due to mutagenic potential.4 Fertility: Effect on fertility not fully determined.1 Gonadal suppression, resulting in amenorrhea or azoospermia, has been reported with structurally similar drugs and thus may occur.4 Pregnancy: FDA Pregnancy Category D.5 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Breastfeeding is not recommended as the drug is distributed into breast milk.1 Breastfeeding should be discontinued prior to institution of therapy.4
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.13 When placebo-controlled trials are available, adverse events are included if the incidence is
>
5% higher in the treatment group.
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| allergy/immunology | allergic reactions (<1%) 1 |
| auditory/hearing | auditory hallucinations 1 |
| blood/bone marrow/ febrile neutropenia | anemia |
| leukopenia , 6,000 mg/m 2 /cycle (50%) 1 ; 10,000-12,000 mg/m 2 /cycle (~100%, severe 50%) 1 ; begins around day 5, 4 nadir 7-14 days, 1,4 recovery begins after 10-14 days and is complete after 14-21 days 4 | |
| thrombocytopenia (10%) 5 , 6,000 mg/m 2 /cycle (20%) 1 ; 10,000-12,000 mg/m 2 /cycle (severe 8%) 1 | |
| cardiovascular (arrhythmia) | S-T segment changes |
| supraventricular arrhythmias | |
| ventricular arrhythmias | |
| cardiovascular (general) | heart failure |
| constitutional symptoms | fever of unknown origin (1%) 1 |
| dermatology/skin | extravasation hazard: irritant 1 |
| alopecia (1-83%) 1,4 | |
| dermatitis | |
| hyperpigmentation 1 | |
| inflammation of mucous membranes | |
| gastrointestinal | emetogenic potential: low-moderate; dose-related 14 |
| hematemesis | |
| nausea and/or vomiting (56-81%) 1 | |
| hemorrhage | hematemesis |
| hemorrhagic cystitis (1-10%) 4 ; incidence, severity, and persistence increase with increased dose | |
| petechial bleeding | |
| hepatobiliary/pancreas | pancreatitis (<1%) 1 |
| infection | infection with or without fever (8%) 1 ; see paragraph following Side Effects table |
| metabolic/laboratory | hyperaminoaciduria |
| increased liver enzymes and/or bilirubin (3%) 1 | |
| increased serum creatinine | |
| metabolic acidosis (31%) | |
| phosphaturia | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| musculoskeletal | asthenia |
| neurology | agitation 1 |
| cerebellar symptoms | |
| coma; see paragraph following Side Effects table | |
| confusion, disorientation, dizziness, somnolence, stupor 1 ; see paragraph following Side Effects table | |
| cranial nerve dysfunction | |
| depressive psychosis | |
| encephalitis (<1%); see paragraph following Side Effects table | |
| generalized seizures (<1%) | |
| hallucinations; see paragraph following Side Effects table | |
| mutism 1 | |
| peripheral neuropathy (<1%) 1 | |
| polyneuropathy (<1%) 1 | |
| seizure | |
| ocular/visual | impaired or blurred vision |
| pulmonary | interstitial pneumonitis (<1%) |
| pulmonary edema (<1%) | |
| renal/genitourinary | cylindruria |
| dysuria | |
| hematuria (6-92%) 1 ; 6 g/m 2 /cycle (microscopic 50%, gross 8%) 1 ; typically would occur on day of treatment, 13 and resolves spontaneously upon cessation of ifosfamide therapy 4 ; see paragraph following Side Effects table | |
| hemorrhagic cystitis (1-10%); incidence, severity, and persistence increase with increased dose; see paragraph following Side Effects table | |
| nephrogenic diabetes insipidus 1 | |
| proteinuria | |
| renal failure (<1%) 1 | |
| renal parenchymal necrosis | |
| renal rickets | |
| renal tubular acidosis | |
| renal tubular necrosis | |
| unspecified nephrotoxicity (6%) 1 | |
| urinary frequency, incontinence, and retention | |
| sexual/reproductive function | gonadal suppression (amenorrhea or azoospermia) |
| syndromes | Fanconi syndrome |
| vascular | thrombophlebitis (1%) 1 |
Adapted from standard reference4 unless specified otherwise.
Neurotoxicity1,15-19
: If serious neurotoxicity occurs (e.g., somnolence, confusion, hallucinations, and/or coma), discontinue ifosfamide and institute appropriate supportive therapy. Methylene blue may be effective for the treatment and prophylaxis of encephalopathy.
Urotoxicity
: To decrease the incidence and severity of bladder toxicity, use conventional uroprophylaxis (e.g., adequate hydration, maintenance of fluid balance, frequent urination) and mesna, a uroprotective agent. These measures do not prevent hemorrhagic cystitis in all patients and urine should be examined regularly for erythrocytes, the appearance of which may precede hemorrhagic cystitis. A morning urine specimen should be examined before each scheduled dose of ifosfamide. In patients who develop microscopic hematuria, ifosfamide therapy should be discontinued until the hematuria resolves. Vigorous oral or parenteral hydration as well as mesna should be used for subsequent courses of ifosfamide. Hemorrhagic cystitis can be severe and may be fatal. Therefore, ifosfamide
should be discontinued or dose reduced in patients who develop hematuria despite concurrent use of mesna.1
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| warfarin 4,20 | anticoagulant effect of warfarin may be enhanced | unknown | monitor for bleeding; reduce warfarin dose as necessary |
Ifosfamide is a major substrate of CYP3A4.5 CYP3A4 inducers may increase the serum levels/effects of acrolein. CYP3A4 inhibitors may decrease the serum levels/effects of acrolein.
Ifosfamide is a minor substrate of CYP2A6, 2B6, 2C8, 2C9, 2C19.5 Ifosfamide is a weak inhibitor of CYP3A4.5
Ifosfamide is a weak inducer of CYP2C8, 2C9.5
: Baxter supplies ifosfamide sterile powder in 1 g and 3 g vials.
The following are compatible via Y-site injection: allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, doxorubicin liposome, filgrastim, fludarabine, gatifloxacin, gemcitabine, granisetron, linezolid, melphalan, ondansetron, paclitaxel, piperacillin/tazobactam, propofol, sargramostim, sodium bicarbonate, teniposide, thiotepa, topotecan, vinorelbine.
The following are compatible in the same syringe: epirubicin, mesna. The following are compatible in the same infusion solution: carboplatin, carboplatin with etoposide, cisplatin, cisplatin with etoposide, epirubicin, etoposide, fluorouracil, mesna.
The following are incompatible via Y-site injection: cefepime, methotrexate. The following are incompatible in the same syringe or same infusion solution: ifosfamide with mesna and epirubicin.
BCCA administration guideline noted in bold, italics | |
|---|---|
| Subcutaneous | no information found |
| Intramuscular | no information found |
| Direct intravenous | no information found |
| Intermittent infusion | over 60-120 minutes 5,6,8-10 over a minimum of 30 minutes 4 |
| Continuous infusion 1 | over 24 hours 7,12 |
| Intraperitoneal | no information found |
| Intrapleural | no information found |
| Intrathecal | no information found |
| Intra-arterial | no information found |
| Intravesical | no information found |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: Cycle Length: BCCA usual dose noted in bold, italics *Intravenous: 3 weeks1: 1,200 mg/m2 IV once daily for 5 consecutive days starting on day 1 (total dose per cycle 6000 mg/m2) based on response1: 1,200-2,500 mg/m2 IV once daily for 3-5 days starting on day 1 3 weeks6,8-10: 1,500-1,800 mg/m2 IV once daily for 4-5 consecutive days
3 weeks7,12: 5,000 mg/m2 IV once daily for one dose on day 1 3-4 weeks4: 5,000-8,000 mg/m2 IV once daily for one dose on day 1 3-4 weeks4: 50-60 mg/kg IV once daily for 5 consecutive days starting on day 1 (total dose per cycle range: 250-300 mg/kg, or 2,000- 2,400 mg/m2) May be given every other day or for 10 consecutive days if a lower dose or longer duration is required. *Ifosfamide should not be administered without the use of a uroprotective agent such as mesna.4 See mesna monograph or refer to treatment protocol.
Concurrent radiation:
ifosfamide has been reported to cause increased sensitivity to radiation4
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: modify according to protocol7,9,12; otherwise, refer to table below22:
| Creatinine Clearance (mL/min) | Dose |
| > 10 | 100% |
| <10 | 75% |
Calculated creatinine clearance = N * x (140 - Age) x Weight in kg
Dosage in hepatic failure:
* For males N=1.23; for females N=1.04 adjustment may be required5
Dosage in dialysis:
Children:
no information found
Intravenous:
refer to treatment protocol
McEvoy GK. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2007. p. 1070-6.
Kapty D, editor. Cancer Drug Manual. 2nd ed. Vancouver, British Columbia: British Columbia Cancer Agency; 1994.
National Institute for Occupational Safety and Health (NIOSH). Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings. Cincinnati, OH; 25 March 2004.
Baxter Corporation. Ifosfamide Product Monograph. Mississauga, Ontario; 2002.
Anonymous. Ifosfamide: Drug Information. In: Rose BD, editor. UpToDate(r). Waltham, Massachusetts: UpToDate 15.2; 2007.
BC Cancer Agency Leukemia/BMT Tumour Group. (LYIVACR) BCCA Protocol Summary for Treatment of Burkitt Lymphoma and Leukemia (ALL-L3) with Ifosfamide, Mesna, Etoposide, Cytarabine (IVAC) and Ritumimab. Vancouver, British Columbia: BC Cancer Agency; 1 January 2007.
BC Cancer Agency Neuro-Oncology Tumour Group. (CNIME) BCCA Protocol Summary for Ifosfamide, Mesna and Etoposide in the Treatment of Recurrent Brain Tumours. Vancouver, British Columbia: BC Cancer Agency; 1 October 2005.
BC Cancer Agency Sarcoma Tumour Group. (SAIME) BCCA Protocol Summary for Etoposide, Ifosfamide-Mesna for Patients with Newly Diagnosed Ewing's Sarcoma/Peripheral Neuroectodermal Tumour (PNET) or Rhabdomyosarcoma or Advanced Soft Tissue or Bony Sarcomas (This may be alternated with SAVAC or SAVAC+M). Vancouver, British Columbia: BC Cancer Agency; 1 October 2005.
BC Cancer Agency Genitourinary Tumour Group. (GUVEIP) BCCA Protocol Summary for Consolidation/Salvage Treatment for Germ Cell Cancer Using Vinblastine, Cisplatin, Ifosfamide and Mesna. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
BC Cancer Agency Genitourinary Tumour Group. (GUVIP2) BCCA Protocol Summary for Nonseminoma Consolidation/Salvage Using Etoposide, Cisplatin, Ifosfamide and Mesna. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
BC Cancer Agency. Protocol by drugs index. Vancouver, British Columbia: BC Cancer Agency; 1 June 2007.
BC Cancer Agency Sarcoma Tumour Group. (SAAI) BCCA Protocol Summary for ADRIAMYCIN(r)-Ifosfamide-Mesna For Use In Patients With Advanced Soft Tissue Sarcoma. Vancouver, British Columbia: BC Cancer Agency; 1 August 2003.
Meg Knowling, MD. BC Cancer Agency Sarcoma Tumour Group. Personal communication. Vancouver, British Columbia; 22 September 2007.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005.
Zulian GB, Tullen E, Maton B. Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med 1995; 332(18):1239-40.
Turner AR, Duong CD, Good DJ. Methylene blue for the treatment and prophylaxis of ifosfamide-induced encephalopathy. Clin Oncol 2003; 15(7):435-9.
Pelgrims J, De Vos F, Van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer 2000; 82(2):291-4.
Kupfer A, Aeschlimann C, Wermuth B, et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994; 343(8900):763-4.
Alonso JL, Nieto Y, Lopez JA, et al. Ifosfamide encephalopathy and methylene-blue: a case report. Ann Oncol 1996; 7(6):643-4.
Drug Interaction Facts (database on the Internet). Ifosfamide. Facts and Comparisons 4.0, 2007. Available from http://online.factsandcomparisons.com. Accessed 10 September 2007.
Trissel LA. Handbook on Injectable Drugs. 13 ed. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2005. p. 846-50.
Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing guidelines for adults and children. 5th ed. Philadelphia, Pennsylvania: American College of Physicians; 2007. p. 100.