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Mesna * Total daily dose 900 mg/m 2 IV Administer 300 mg/m 2 in NS or 5 percent dextrose (D5W) in water over one hour prior to each daily dose of ifosfamide. Total concentration of mesna should not exceed 20 mg/mL. Repeat at four and eight hours after the initiation of each dose of ifosfamide daily. 1 through 4 Pretreatment considerations: •

Hydration: Adequate hydration (at least two liters of oral or IV fluids per day) should be maintained with ifosfamide to reduce the risk of bladder toxicity [2] . Refer to UpToDate topic on "Cystitis in patients with cancer". The choice of hydration fluid is empiric and may vary by institution and protocol. The original protocol administered 500 mL of D5W containing electrolytes (sodium acetate 120 mEq/L [equal to 120 mmol/L], magnesium sulfate 500 mg/L [equal to 2.03 mmol/L], and potassium acetate 40 mEq/L [equal to 40 mmol/L]) over one hour before the start of each dose of ifosfamide, and maintenance hydration of the same hydration fluid over one hour at the completion of each ifosfamide dose; IV fluid was discontinued after completion of the eight-hour dose of mesna on each treatment day [1] . •

Emesis risk: HIGH (>90 percent risk of emesis). Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting". Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity [3-5] ; its use is avoided at some institutions. Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting". •

Vesicant/irritant properties: Doxorubicin is a vesicant; avoid extravasation. Infusional regimens should be administered through a central venous line. Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-neoplastic vesicants". •

Infection prophylaxis: This regimen was designed to include primary prophylaxis with a granulocyte colony stimulating factor in all cycles [1] . Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". •

Dose adjustment for baseline liver or renal dysfunction: A lower initial ifosfamide dose may be needed for patients with preexisting renal or liver impairment [2] . A lower starting dose of doxorubicin may be needed for patients with preexisting liver impairment [6] . Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease" and "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency". •

Cardiac issues: Doxorubicin is associated with cardiomyopathy, the incidence of which is related to the cumulative dose. Assess baseline LVEF prior to administration. Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin or any other anthracyclines [6] . Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like chemotherapy agents". Monitoring parameters: • CBC with differential and platelet count weekly during treatment. • Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 grams/m 2 . Clinical manifestations may include hypophosphatemia, renal potassium wasting, metabolic acidosis with a normal ion gap, and rarely, polyuria due to nephrogenic diabetes insipidus. Assess creatinine and electrolytes, including potassium and phosphate, daily during treatment and prior to each subsequent treatment cycle. Refer to UpToDate topic on "Ifosfamide nephrotoxicity". • Mesna does not prevent hemorrhagic cystitis in all patients [7] . Monitor a morning specimen of urine for hematuria daily, on days 1 through 4. Refer to UpToDate topic on "Cystitis in patients with cancer". • Monitor for ifosfamide neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily on days 1 through 4. Central nervous system side effects may be especially problematic in those over age 60. Refer to UpToDate topic on "Neurologic complications of non-platinum cancer chemotherapy". • Assay liver function tests prior to each treatment cycle. • Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated. Suggested dose alterations for toxicity: •

Myelotoxicity: Delay treatment cycle until the absolute neutrophil count is ≥1500 cells/mm 3 and platelet count is ≥100,000/mm 3 [1] . Discontinue for >2 week delay in recovery. Reduce doses of doxorubicin and ifosfamide by 10 percent for febrile neutropenia despite the use of hematopoietic growth factors. •

Neurologic toxicity: Although formal guidelines are not provided by the manufacturer, reduce the ifosfamide dose or administer the same dose over a greater number of days for reversible grade 2 central nervous system toxicity. Discontinue for ≥grade 3 toxicity. Refer to UpToDate topic on "Neurologic complications of non-platinum cancer chemotherapy". •

Renal toxicity: In the original protocol, a 50 percent dose reduction for ifosfamide was recommended for creatinine rise to 1.5 times ULN during therapy; treatment was discontinued or rise of >1.5 times ULN [1] . In addition, among patients with a normal baseline serum creatinine level, we suggest ifosfamide dose reduction for a day 1 serum creatinine of 1.8 mg/dL or greater. •

Bladder toxicity: For microscopic hematuria (greater than 10 RBC per high power field) despite mesna, withhold ifosfamide until complete resolution. Although formal guidelines are not available from the US FDA, reduce ifosfamide dose for grade 3 hemorrhagic cystitis not responding to an increase in IV fluids and mesna. If there is a change in body weight of at least 10 percent, doses should be recalculated. This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances to make adjustments, as necessary. IV: intravenous; LVEF: left ventricular ejection fraction; CBC: complete blood count; ULN: upper limit of normal; RBC: red blood cells. * This regimen was designed to be used in the outpatient setting. If necessary, oral mesna may be used; however, oral mesna is not recommended for the initial dose [8] . If the oral route is chosen, patients should receive an initial IV dose of mesna (300 mg/m 2 [20 percent of the total daily ifosfamide dose]) prior to each day's ifosfamide administration, followed by oral mesna tablets at 40 percent of the daily ifosfamide dose (600 mg/m 2 per dose), administered at two and six hours after the initiation of each dose of ifosfamide [8] . This same dosing schedule is repeated on each day that ifosfamide is administered. The total daily mesna dose is 100 percent of the ifosfamide dose when the oral route is used [9] . If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or receive an IV dose of mesna [9] . References: Worden FP, et al. J Clin Oncol 2005; 23:105. Ifex (ifosfamide) injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). Durand JP, et al. Ann Oncol 2007; 18:808. Jarkowski A. Am J Health-Syst Pharm 2008; 65:2229. Howell JE, et al. J Oncol Pharm Practice 2008; 14:157. Adriamycin (doxorubicin hydrochloride) injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012).

Durand JP, et al. Ann Oncol 2007; 18:808. Jarkowski A. Am J Health-Syst Pharm 2008; 65:2229. Howell JE, et al. J Oncol Pharm Practice 2008; 14:157. Adriamycin (doxorubicin hydrochloride) injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). MESNA injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). Hensley ML, et al. J Clin Oncol 2009; 27:127. MESNEX (mesna) tablets. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012).