Ifosfamide / mesna Side Effects
Applies to ifosfamide / mesna: intravenous kit
Cardiovascular side effects are rare. Retrospective data from 52 consecutive patients who were given 10 to 18 g/m2 (in combination with carboplatin and etoposide or lomustine and vincristine) reveal evidence of heart failure in 17% associated with objective evidence of decreased cardiac contractility. Limited data have also revealed the development of atrial fibrillation, paroxysmal SVT associated with ischemic changes, premature ventricular depolarizations, tachycardia, and QRS or ST segment prolongations during ifosfamide therapy.[Ref]
In dogs and rhesus monkeys very high doses of ifosfamide have caused changes in ECG, cardiac histology, and heart function (negative chrono- and inotropic effects).[Ref]
Hyperpigmentation usually occurs on the dorsal surfaces and plantar surfaces of the hands and feet. It can also be seen on large areas of the trunk. Hyperpigmentation is more common in patients that are dark-skinned, and is often reversible.[Ref]
Dermatologic side effects include alopecia which has been reported in approximately 74% of patients (ranging from 29% to 100%). Other dermatologic problems include hyperpigmentation, stomatitis, rashes due to (rare) allergic reactions, and enhanced radiation reactions in patients secondary to IV site extravasation.[Ref]
The case of SIADH was associated with the use of ifosfamide in a patient with adenocarcinoma of the prostate.[Ref]
Endocrine side effects have included a single case of the syndrome of inappropriate antidiuretic hormone (SIADH).[Ref]
Gastrointestinal side effects may be expected in most patients. Nausea or vomiting has been reported in 60% to 80% of patients receiving standard doses and up to 100% of patients receiving high doses. These problems may be seen a few hours after administration, are typically controlled by good antiemetic therapy, and usually last only up to three days. Other GI side effects include anorexia, diarrhea, constipation, mucositis and stomatitis. Pancreatitis has been reported rarely.
Gastrointestinal side effects are relatively common. A disturbing taste and diarrhea have been reported in up to 100% and 70% of patients, respectively. Diarrhea is not a common side effect when mesna and ifosfamide are given together. Nausea, vomiting, and abdominal discomfort have been reported in up to 33% after oral administration.[Ref]
In general, the two most common dose-limiting toxicities are myelosuppression and urotoxicity. Most side effects can be minimized by giving fractionated doses, assuring adequate hydration and frequent urination, and using uroprotective agents, such as mesna.[Ref]
Ifosfamide is more urotoxic than cyclophosphamide. Dose fractionation, vigorous hydration, frequent bladder emptying, and a protector such as mesna can significantly reduce the incidence of hematuria, especially gross hematuria, that is associated with hemorrhagic cystitis.
The diagnosis of ifosfamide-induced hemorrhagic cystitis is based on (a) a history of gross hematuria; (b) laboratory findings of microscopic hematuria; (c) platelet counts of greater than 50,000/mm3; and (d) lack of significant bacterial growth on urine culture.[Ref]
Genitourinary side effects have been reported. Genitourinary epithelial cells within the bladder wall are sensitive to 4-OH-ifosfamide and acrolein, urotoxic metabolites that are probably the causative agents of acute, sterile hemorrhagic cystitis. At daily doses of 1.2 g/m2 for 5 consecutive days without mesna protection, microscopic hematuria is expected in approximately 50% to 100% of patients, and gross hematuria in approximately 8% of patients.[Ref]
Erythropoiesis is rarely affected. Myelosuppression is usually reversible.[Ref]
Hematologic side effects, usually presenting as leukopenia, but occasionally as thrombocytopenia, is usually mild to moderate. A WBC count of less than 3,000/mm3 and a platelet count of less than 100,000/mm3 are expected in 50% and 20% of patients, respectively, treated with 1.2 g/m2/day for 5 days. At higher doses, nearly all patients develop leukopenia, and at total doses of 10 to 12 g/m2/cycle, 50% and 8% of patients develop WBC and platelet counts below 1,000/mm3 and 50,000/mm3, respectively. One case of methemoglobinemia has been reported.[Ref]
Hepatic side effects include elevated hepatic transaminases which have been reported in 1% to 3% of patients.[Ref]
A byproduct of dechloroethylation of ifosfamide, chloroacetaldehyde, has been associated with CNS toxicity. Chloroacetaldehyde is structurally related to the hypnotic agent chloral hydrate and to aldehyde, a metabolite of ethanol alcohol. Limited and indirect data have shown that the metabolism of ifosfamide after oral administration may produce higher concentrations of chloroacetaldehyde than after intravenous administration. Whether this is due to a first-pass effect is questionable since the bioavailability of ifosfamide approaches 100%, suggestive of insignificant first-pass metabolism.
Limited information suggests the average time to onset of encephalopathy in affected patients is 46 hours (range 12 to 146 hours), and the median duration is 3 days (range 1 to 12 days) if this side effect is promptly recognized and ifosfamide is immediately stopped.
Ifosfamide should be stopped in cases of seizure, stupor, severe weakness, ataxia, irritability, anxiety or coma. Other potentially sedating drugs should be stopped (or minimized if they are necessary).
Hypoalbuminemia, renal impairment, and a short infusion schedule may be associated with an increased incidence of neurotoxicity.[Ref]
Nervous system side effects have been observed in 5% to 30% of patients, and can be persistent and serious. High doses administered over a short time, preexisting neurologic or renal dysfunction, and low serum albumin appear to be significant risk factors. Most common are hallucinations (may be the sole or first manifestation of neurotoxicity), somnolence, confusion, and depressive psychosis. Less common symptoms include dizziness, disorientation, anxiety, irritability, cranial nerve dysfunction, blurred vision, extrapyramidal signs and polyneuropathy. Seizures and fatal comas have been occasionally associated with high doses (greater than or equal to 2 g/m2) of orally administered ifosfamide. High doses can rarely cause peripheral sensory neuropathies and distal extremity motor dysfunction.
Nervous system side effects include headache in up to 50% and fatigue in 33% of patients. Rare cases of encephalopathy--sometimes described by confusion, drowsiness, somnolence, and generalized seizures-- have been associated with the use of ifosfamide / mesna. Neurologic toxicity has also been reported to include changes in mental status, cerebellar function, cranial nerve, and cerebellar and motor function system functions including seizures. Most experts suspect neurotoxicity from ifosfamide metabolites, but the pathogenesis remains unclear.[Ref]
Renal side effects including new or worsened (and usually transient) renal insufficiency has been reported in 3% to 7% of patients. Patients with renal carcinoma or underlying renal insufficiency (including poorly hydrated patients) are at increased risk. Other renal side effects include dysuria, urinary frequency, proteinuria, a type II proximal renal tubular acidosis (Fanconi's syndrome), acute tubular necrosis (ATN) with acute renal failure, nephrogenic diabetes insipidus, and renal rickets.[Ref]
Ifosfamide may induce renal tubular damage, with excessive potassium loss, which has partially been described as Fanconi's syndrome. Mesna does not protect against the development of Fanconi's syndrome or any other renal toxicity. Mesna can be protective only against bladder toxicity.
One study (n=33) has reported histological changes in bladders of patient submitted to ifosfamide chemotherapy, even with mesna prophylaxis. Despite treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage.
Close monitoring of serum and urine chemistries (including phosphorus, potassium, and alkaline phosphatase) are strongly recommended. In addition, some experts recommend urinary beta-2 microglobulin and/or lysozyme studies as precise indicators of renal tubular dysfunction.[Ref]
Hypersensitivity side effects to this thiol (sulfur-containing) compound range from mild rashes to systemic anaphylaxis. Rare cases of vasculitides, nephritis, arthralgias, and myalgias have been reported. Limited data have revealed up to 17% of patients experience some allergic reaction to mesna, although the actual incidence in large clinical trials is much lower.[Ref]
Musculoskeletal side effects include joint or limb pain in up to 50% of patients (limited data).[Ref]
Other side effects include laboratory abnormalities. Limited data have shown that mesna may cause fatal positive reactions for ketones on certain multiple reagent strips.[Ref]
1. "Product Information. Ifex (ifosfamide)." Bristol-Myers Squibb, Princeton, NJ.
2. "Product Information. Mesnex (mesna)." Bristol-Myers Squibb, Princeton, NJ.
3. Lima MV, Ferreira FV, Macedo FY, de Castro Brito GA, Ribeiro RA "Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis." Cancer Chemother Pharmacol 59 (2007): 643-50
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