a) Various rhythm disturbances can be seen across all dose levels, including premature atrial contractions, premature ventricular contractions, supraventricular tachycardia, atrial fibrillation, atrial flutter, and malignant ventricular dysrhythmias. ST and T-wave changes, as well as QRS voltage reductions have also been reported. Data are insufficient to implicate prior anthracycline exposure as a contributing factor (Cunnion & Cottler-Fox, 1996).
b) In a study of patients receiving fractionated ifosfamide and mesna therapy ranging from 6.5 g/m(2) to 10 g/m(2), 15% experienced acute cardiotoxicity in the form of supraventricular dysrhythmias and ST-T wave changes. These toxicities were reversible with the discontinuation of the drug. In one patient, repeat administration of ifosfamide led to dysrhythmias that were refractory to treatment (Kandylis et al, 1989).

a) A retrospective chart review was conducted to determine the presence and subsequent incidence of cardiotoxicity in a group of patients given high-dose ifosfamide. Fifty-two patients, with advanced lymphoma or carcinoma, were identified as having received high-dose ifosfamide, as combination therapy, with autologous bone marrow transplantation. The combination therapies included ifosfamide, carboplatin, and etoposide (ICE) or vinblastine, ifosfamide, and lomustine (VIC). Ifosfamide was given at the following doses: 10 g/m(2) (n=6), 12.5 g/m(2) (n=12), 15.6 g/m(2) (n=20), 16 g/m(2) (n=12), and 18 g/m(2) (n=3). One patient received both chemotherapy regimens: VIC initially with an ifosfamide dose of 15.6 g/m(2), and then 13 months later following a relapse, ICE with an ifosfamide dose of 16 g/m(2).

a) Somnolence, confusion, hallucinations, and depressive psychosis are the most common CNS adverse effects observed with ifosfamide therapy. The incidence of CNS toxicity appears to be higher in patients with altered renal function (Prod Info IFEX(R) IV injection, 2007).
b) CASE REPORT: A 43-year-old man developed neurotoxicity 2 days after receiving ifosfamide (3.33 g/m(2)/day) intravenously, mesna and etoposide. He experienced dyspnea and progressively worsening mental status (restlessness, irritation, disorientation). Over the next 2 days, his mental status continued to deteriorate and he was unable to follow commands. It is suggested that chloroacetaldehyde, the ifosfamide active metabolite, may be responsible for the neurotoxicity observed with ifosfamide (McVay & Wood, 1999).

a) Changes in mental status, cerebellar dysfunction, seizures, and coma have been reported in approximately 30% of patients on high-dose ifosfamide (Goren et al, 1986).
b) CASE REPORT: A fatal case of subacute progressive encephalopathy in a 5-year-old child was attributed to high-dose ifosfamide. One month after completion of three cycles of cyclophosphamide, doxorubicin, vincristine and mesna for desmoplastic small round-cell tumor, ifosfamide 1800 mg/m(2)/day for 5 days was initiated along with etoposide. Shortly after the second cycle of the ifosfamide-etoposide regimen, a generalized tremor occurred and progressed to severe ataxia. Motor and cognitive abilities deteriorated over the next 10 weeks to the point of a vegetative state, which lasted 9 months until death. Clinicians ruled out other etiologies (Shuper et al, 2000).
c) Grade 3 encephalopathy (confusion, delirium, stupor, delusions, hallucinations, extreme dizziness, and severe extrapyramidal effects) was reported in 4 patients while on ifosfamide therapy. Two of the four patients recovered after receiving treatment with methylene blue. In the other two patients, the encephalopathy was either prevented or its severity was significantly reduced after receiving methylene blue as prophylaxis prior to administration of the next cycle of ifosfamide (Turner et al, 2003).

a) Polyneuropathy is an infrequent side effect of ifosfamide (Prod Info IFEX(R) IV injection, 2007).
b) CASE REPORT: A 16-year-old girl with a Ewing sarcoma developed painful peripheral neuropathy after treatment with high-dose ifosfamide (15 mg/m(2) infused over 5 days). In addition, she developed signs of severe toxicity in the CNS, kidneys and heart. It is suggested that peripheral neuropathy symptoms after high-dose ifosfamide may herald severe multiorgan toxicity (Frisk et al, 2001).

a) Nonconvulsive status epilepticus occurred in a 57-year-old woman (body surface area of 2 m(2)) following ifosfamide 2 g administered intravenously over 1 hour. Twelve hours after the completion of the third course of chemotherapy the patient developed mental status change with upper extremity myoclonus (Wengs et al, 1993).

a) Confusion was reported after a patient received 9.1 g of ifosfamide over 1 hour instead of over 24 hours (Fiedler et al, 2001).

a) Fatigue has been rarely reported, occurring in less than 1% of patients treated with ifosfamide as a single agent during clinical trials (n=2070) (Prod Info IFEX(R) IV injection, 2007)

a) Nausea and vomiting were reported in 58% of patients treated with ifosfamide (n=2070) during single agent clinical trials (Prod Info IFEX(R) IV injection, 2007). It is usually severe and begins within 2 to 4 hours following intravenous infusion and lasts for a period of 1 to 3 days (Trissel et al, 1979; Costanzi et al, 1978; Nelson et al, 1976a). Two percent of cycles have been associated with WHO grade 3 nausea and vomiting when given at a dose of 1.5 g/m(2) every 3 weeks (Highley et al, 1999).

a) Diarrhea may occur (Prod Info IFEX(R) IV injection, 2007)

a) Stomatitis has been rarely reported, occurring in less than 1% of patients treated with ifosfamide as a single agent during clinical trials (n=2070) (Prod Info IFEX(R) IV injection, 2007)

a) Anorexia was reported in less than 1% of patients treated with ifosfamide as a single agent during clinical trials (n=2070) (Prod Info IFEX(R) IV injection, 2007).

a) Elevation of hepatic enzymes has been reported during ifosfamide therapy (Prod Info IFEX(R) IV injection, 2007; Rodriquez et al, 1976; Bruhl et al, 1976; van Dyk et al, 1972).

a) Urotoxicity is reported to be one of the dose-limiting toxicities associated with ifosfamide. Hemorrhagic cystitis, dysuria, urinary frequency, and other symptoms of bladder irritation have been reported. Hematuria may occur in 6% to 92% of treated patients (Prod Info IFEX(R) IV injection, 2007).

a) Transient elevation in BUN or serum creatinine or decrease in creatinine clearance and renal tubular acidosis which progressed to chronic renal failure have been reported (Prod Info IFEX(R) IV injection, 2007).
b) CASE REPORT: Renal failure was reported in a 62-year-old woman with Stage III ovarian carcinoma beginning after 3 cycles of ifosfamide 5 g/m(2) over 24 hours every 4 weeks together with 5 g/m(2) mesna (Willemse et al, 1989).
c) Ifosfamide-related tubular nephrotoxicity has been reported despite co-administration of mesna (Goren et al, 1987).
d) Cumulative doses of ifosfamide (26 g/m(2)/cycle) have been reported to cause irreversible renal failure; however, acute nephrotubular damage has been frequently reported with cumulative doses of 15 g/m(2)/cycle (Fiedler et al, 2001).

a) CASE REPORT: After receiving 9.1 g of ifosfamide over 1 hour (instead of over 24 hours), a 38-year-old man with non-Hodgkin's lymphoma developed confusion and muscle weakness. Approximately 1 hour after the end of the ifosfamide infusion, the overdosage was detected and hemoperfusion combined with hemodialysis was initiated. Four days later, an impairment of renal function (creatinine clearance 46 mL/min) with mild tubular proteinuria (protein 230 mg/L, albumin 31 mg/L, alpha1-microglobulin 41.4 mg/L, beta2-microglobulin 16 mg/L) and increased activity of beta-NAG (34.9 IU/L) in urine was observed. The patient's symptoms then resolved completely (Fiedler et al, 2001).

a) Fanconi syndrome with proximal renal tubular acidosis, phosphaturia, glycosuria, and aminoaciduria occurred in a 2-year-old with rhabdomyosarcoma following ifosfamide administration (Newbury-Ecob et al, 1989). Fanconi syndrome with rickets was reported in another 2-year-old with embryonal sarcoma receiving multiagent chemotherapy including high-dose ifosfamide (De Schepper et al, 1991).
b) Osteomalacia secondary to ifosfamide-induced Fanconi syndrome was described in 3 adults who received high-dose ifosfamide.

a) Ifosfamide doses of 2 to 2.5 g/m(2)/day for 4 days were associated with a 31% incidence of metabolic acidosis in one study (Prod Info IFEX(R) IV injection, 2007).

a) An ifosfamide dose of 12 g/m(2)/cycle has been reported to cause myelosuppression effects and, subsequently, an increased infection rate (Fiedler et al, 2001).

a) Leukopenia is a dose-related and dose-limiting adverse effect of ifosfamide with standard doses. At ifosfamide doses of 1.2 g/m(2)/day for 5 days, 50% of the patients are expected to develop WBC counts less than 3000/microliter. At higher doses (ie, 10 to 12 g/m(2), 50% of the patients treated had WBC counts less than 1000/microliter (Prod Info IFEX(R) IV injection, 2007). A nadir occurs 7 to 14 days after initiation of therapy and lasts anywhere from 3 days to 2 weeks (Fossa & Talle, 1980; Rodriquez et al, 1978; Falkson & Falkson, 1976). Life-threatening infections secondary to severe leukopenia have been reported and leukopenia occurred in 65% to 100% of the patients treated (Fossa & Talle, 1980). Lower doses of 1.5 g/m(2) given every 3 weeks were associated with 1% to 2% WHO grade 3/4 leukopenia (Highley et al, 1999).

a) Thrombocytopenia has also been reported, however, at a much lower incidence than leukopenia. At ifosfamide doses of 1.2 g/m(2)/day for 5 days, approximately 20% of the patients treated developed thrombocytopenia (platelets less than 100,000/microliter). At higher doses (ie, 10 to 12 g/m(2)), 8% of the patients treated had platelet counts less than 50,000/microliter (Prod Info IFEX(R) IV injection, 2007; Falkson & Falkson, 1976; Schnitker et al, 1976; Bruhl et al, 1976).

a) Anemia has been reported with post-marketing surveillance of ifosfamide (Prod Info IFEX(R) IV injection, 2007).

a) Alopecia has occurred in 83% of the patients following administration of ifosfamide as single-agent therapy, and up to 100% of patients treated with ifosfamide as part of a combination chemotherapy regimen (Prod Info IFEX(R) IV injection, 2007; Highley et al, 1999; Bruhl et al, 1976; Schnitker et al, 1976; Creaven et al, 1976; Cohen et al, 1975).

a) Dermatitis has been rarely reported, occurring in less than 1% of patients treated with ifosfamide as a single agent during clinical trials (n=2070) (Prod Info IFEX(R) IV injection, 2007)

a) Muscle weakness was reported after a patient received 9.1 g of ifosfamide over 1 hour instead of over 24 hours (Fiedler et al, 2001)

a) Osteomalacia secondary to ifosfamide-induced Fanconi syndrome was described in 3 adults who received high-dose ifosfamide.

a) Four patients developed severe hypokalemia (fatal in 1 case) following chemotherapy with ifosfamide and mesna. Three patients received ifosfamide 5 g/m(2) with mesna 9 g/m(2), the other patient received 4 g/m(2) and 8 g/m(2), respectively. One patient received ifosfamide and mesna alone, while 1 patient also received etoposide and mitoxantrone, another received doxorubicin and vindesine, and the last patient also received methotrexate and etoposide. None of the patients had identifiable cause for hypokalemia, and none had protracted vomiting or diarrhea, nor received diuretics. Onset of hypokalemia occurred between 2 and 12 days following ifosfamide and mesna therapy. The 1 fatality was due to a cardiac arrest with a plasma potassium of 2.2 millimole/liter (mmol/L). The other plasma potassium nadirs ranged from 1.7 to 2.6 mmol/L (Husband & Watkin, 1988).

a) A case of syndrome of inappropriate antidiuretic hormone (SIADH) was attributed to ifosfamide in a 77-year-old man with prostatic cancer and bone metastases. This syndrome has previously been reported with the use of vincristine, cyclophosphamide, vinblastine and cisplatin. The syndrome occurred in the second cycle of 2 g/m(2) ifosfamide and 2.4 g/m(2) mesna per day continuously for 2 days, every 3 weeks (Culine et al, 1990).
b) CASE REPORT: An 18-year-old patient with olfactory neuroblastoma developed severe, symptomatic hyponatremia related to SIADH on 2 separate occasions after administration of ifosfamide. Before the first episode, the patient received 2400 mg of ifosfamide with mesna followed 5 hours later by cisplatin. The following day the patient received an additional ifosfamide dose of 2400 mg with mesna. On day 3 the patient developed impaired consciousness and was admitted to the intensive care unit with a Glasgow coma score of 8. The patient's serum sodium had decreased to 114 mmol/L from pretreatment values of 140 mmol/L. One month later, the patient again developed hyponatremia secondary to 2 days of treatment with ifosfamide 2400 mg despite careful monitoring, increased sodium intake, and water restriction. On this occasion, the patient's serum sodium decreased from 140 mmol/L to 123 mmol/L (Kirch et al, 1997).

a) Allergic reactions associated with ifosfamide have been reported (Prod Info IFEX(R) IV injection, 2007).

a) Obtain an ECG and institute continuous cardiac monitoring.
b) Monitor for signs of infection or bleeding.