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Mesna Δ 1200 to 1800 mg/m 2 per day IV (60 percent of the total daily ifosfamide dose), given in three divided doses Dilute one-third of the total daily dose in NS or D5W (total concentration of mesna should not exceed 20 mg/mL) and administer over 15 minutes prior to each daily dose of ifosfamide. Repeat at four and eight hours after the initiation of each dose of ifosfamide daily. Days 1, 2, and 3 Pretreatment considerations: •

Infection prophylaxis: The incidence of febrile neutropenia was not reported in the study; however, severe neutropenia is a frequent adverse event [1] . Primary prophylaxis with hematopoietic growth factors should be considered on an individual basis, particularly for high-risk patients such as those with preexisting neutropenia, advanced disease, poor performance status, or age over 50 years. 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. A lower starting dose of doxorubicin may be needed for patients with preexisting liver impairment [6] . Refer to UpToDate topic 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 3. 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 days 1 to 3. Central nervous system side effects may be especially problematic for those over age 60. Refer to UpToDate topic on "Neurologic complications of non-platinum cancer chemotherapy". • Assess 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: No defined dose alterations for myelosuppression were outlined in this study [1] . However, treatment should be delayed until white blood cell count is >4000 cells/mm 3 and platelet count is >100,000/mm 3 . Reduce doses of ifosfamide and doxorubicin by 25 percent for failure to recover platelets to >100,000/mm 3 by day 28, or for grade 4 neutropenia or febrile neutropenia despite prophylaxis with hematopoietic growth factors, or for platelet count <50,000/mm 3 during any cycle. •

Neurologic toxicity: Although formal guidelines are not provided by the manufacturer, ifosfamide dose adjustment (lower dose, or administering the same dose over a greater number of days) should be considered for patients with reversible grade 2 or 3 neurologic toxicity [2] . Discontinue for ≥grade 3 toxicity. Refer to UpToDate topic on "Neurologic complications of non-platinum cancer chemotherapy". •

Bladder toxicity: For microscopic hematuria (greater than 10 RBC per high power field), withhold ifosfamide until complete resolution. Although formal guidelines are not available, ifosfamide dose adjustment may be needed for patients with grade 3 or worse urotoxicity that has not responded to increases in IV fluids or mesna [2] . •

Renal toxicity: A 50 percent reduction in ifosfamide dose is suggested for creatinine increase up to 1.5 times ULN during therapy, with treatment discontinuation for any increase >1.5 times ULN [8] . In addition, for patients with a normal baseline serum creatinine level, reduce ifosfamide dose for a day 1 serum creatinine of 1.8 mg/dL or greater. Refer to UpToDate topic on "Ifosfamide nephrotoxicity". 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; RBC: red blood cells; ULN: upper limit of normal. * The ifosfamide dose (6000 or 9000 mg/m 2 per cycle) should be chosen based upon clinical judgment. While generally well tolerated, AIM chemotherapy may be associated with severe, potentially fatal neutropenia, thrombocytopenia, and anemia as well as nephrotoxicity and neurotoxicity. A lower dose of ifosfamide may be preferred for patients over the age of 60 [2] . Δ If necessary, oral mesna may be used; however, oral mesna is not recommended for the initial dose [9] . If the oral route is chosen, patients should receive an initial IV dose of mesna (at 20 percent of the daily dose of ifosfamide) prior to the day 1 ifosfamide administration, followed by oral mesna tablets at 40 percent of the daily ifosfamide dose per dose, administered at two and six hours after the initiation of each dose of ifosfamide. 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. If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or receive an IV dose of mesna [10] . References: Grobmyer SR, et al. Ann Oncol 2004; 15:1667. 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.

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; RBC: red blood cells; ULN: upper limit of normal. * The ifosfamide dose (6000 or 9000 mg/m 2 per cycle) should be chosen based upon clinical judgment. While generally well tolerated, AIM chemotherapy may be associated with severe, potentially fatal neutropenia, thrombocytopenia, and anemia as well as nephrotoxicity and neurotoxicity. A lower dose of ifosfamide may be preferred for patients over the age of 60 [2] . Δ If necessary, oral mesna may be used; however, oral mesna is not recommended for the initial dose [9] . If the oral route is chosen, patients should receive an initial IV dose of mesna (at 20 percent of the daily dose of ifosfamide) prior to the day 1 ifosfamide administration, followed by oral mesna tablets at 40 percent of the daily ifosfamide dose per dose, administered at two and six hours after the initiation of each dose of ifosfamide. 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. If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or receive an IV dose of mesna [10] . References: Grobmyer SR, et al. Ann Oncol 2004; 15:1667. 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). MESNA injection (solution). US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). Worden FP, et al. J Clin Oncol 2005; 23:105. Hensley ML, et al. J Clin Oncol 2009; 27:127.

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 (solution). US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). Worden FP, et al. J Clin Oncol 2005; 23:105. 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).