Ifex Side Effects

Generic Name: ifosfamide

Note: This page contains information about the side effects of ifosfamide. Some of the dosage forms included on this document may not apply to the brand name Ifex.

Not all side effects for Ifex may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to ifosfamide: intravenous powder for solution, intravenous solution

In addition to its needed effects, some unwanted effects may be caused by ifosfamide (the active ingredient contained in Ifex). In the event that any of these side effects do occur, they may require medical attention.

If any of the following side effects occur while taking ifosfamide, check with your doctor or nurse immediately:

More common
  • Agitation
  • black, tarry stools
  • blood in the urine
  • chest pain
  • confusion
  • cough or hoarseness
  • fever or chills
  • frequent urination
  • hallucinations (seeing, hearing, or feeling things that are not there)
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Less common
  • Abdominal or stomach pain or tenderness
  • bleeding gums
  • bluish color
  • changes in skin color
  • clay colored stools
  • dark urine
  • decreased appetite
  • dizziness
  • headache
  • itching
  • loss of appetite
  • nausea and vomiting
  • pain
  • pinpoint red spots on the skin
  • skin rash
  • swelling of the feet or lower legs
  • yellow eyes or skin
Rare
  • Blurred vision
  • burning, numbness, tingling, or painful sensations
  • confusion
  • convulsions (seizures)
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast or irregular heartbeat
  • sweating
  • troubled breathing
  • unsteadiness or awkwardness
  • weakness in the arms, hands, legs, or feet

Some of the side effects that can occur with ifosfamide may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Diarrhea
  • hair loss or thinning of the hair
  • swelling or inflammation of the mouth
Less common
  • Redness, swelling, or pain at place of injection
  • weight loss

For Healthcare Professionals

Applies to ifosfamide: intravenous powder for injection, intravenous solution

General

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]

Genitourinary

Genitourinary side effects have been reported. Genitourinary epithelial cells within the bladder wall are sensitive to 4-OH-ifosfamide (the active ingredient contained in Ifex) 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]

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]

Renal

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 (the active ingredient contained in Ifex) 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]

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), glomerular dysfunction, hemorrhagic cystitis, acute tubular necrosis (ATN) with acute renal failure, nephrogenic diabetes insipidus, and renal rickets.[Ref]

Hematologic

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]

Gastrointestinal

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.[Ref]

Nervous system

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 (the active ingredient contained in Ifex) High doses can rarely cause peripheral sensory neuropathies and distal extremity motor dysfunction. CNS toxicity may be more likely in his patients with renal dysfunction.[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]

Dermatologic

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]

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]

Hepatic

Hepatic side effects include elevated hepatic transaminases which have been reported in 1% to 3% of patients.[Ref]

Respiratory

Respiratory system side effects include interstitial pneumonitis, allergic alveolitis, and acute pulmonary edema which have rarely been reported.[Ref]

Hypersensitivity

Hypersensitivity side effects to ifosfamide (the active ingredient contained in Ifex) are extremely rare.[Ref]

Cardiovascular

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 (the active ingredient contained in Ifex) 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]

Endocrine

The case of SIADH was associated with the use of ifosfamide (the active ingredient contained in Ifex) 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]

References

1. Zalupski M, Baker LH "Ifosfamide." J Natl Cancer Inst 80 (1988): 556-66

2. "Product Information. Ifex (ifosfamide)." Bristol-Myers Squibb, Princeton, NJ.

3. Costanzi JJ, Morgan LR, Hokanson J "Ifosfamide in the treatment of extensive non-oat cell carcinoma of the lung." Semin Oncol 9(4 Suppl) (1982): 61-5

4. Slavik M, Saiers JH "Phase I clinical study of acetylcysteine's preventing ifosfamide- induced hematuria." Semin Oncol 10(1 Suppl) (1983): 62-5

5. Sutton GP, Blessing JA, Photopulos G, Berman ML, Homesley HD "Gynecologic Oncology Group experience with ifosfamide." Semin Oncol 17(2 Suppl) (1990): 6-10

6. Morgan LR, Harrison EF, Hawke JE, Hunter HL, Costanzi JJ, Plotkin D, Tucker WG, Worrall PM "TOXICITY OF SINGLE- VS. FRACTIONATED-DOSE IFOSFAMIDE IN NON-SMALL CELL LUNG CANCER: A MULTI-CENTER STUDY." Semin Oncol 9(4 Suppl) (1982): 66-701982

7. Sarosy G "Ifosfamide--pharmacologic overview." Semin Oncol 16(1 Suppl) (1989): 2-8

8. Kaijser GP, Beijnen JH, Bult A, Underberg WJ "Ifosfamide metabolism and pharmacokinetics (review)." Anticancer Res 14 (1994): 517-31

9. Watson RA "Ifosfamide: chemotherapy with new promise and new problems for the urologist." Urology 24 (1984): 465-8

10. Mahjoubi M, Azab M, Ghosn M, Theodore C, Droz JP "Phase II trial of ifosfamide in the treatment of metastatic hormone- refractory patients with prostatic cancer." Cancer Invest 8 (1990): 477-81

11. Creaven PJ, Allen LM, Cohen MH, Nelson RL "Studies on the clinical pharmacology and toxicology of isophosphamide (NSC-109724)." Cancer Treat Rep 60 (1976): 445-9

12. Drings P "European experience with ifosfamide in non-small cell lung cancer." Semin Oncol 16(1 Suppl) (1989): 22-30

13. Cohen MH, Creaven PJ, Tejada F, Hansen HH, Muggia F, Mittelman A, Selawry OS "Phase I clinical trial of isophosphamide (NSC-109724)." Cancer Chemother Rep 59 (1975): 751-5

14. Meanwell CA, Mould JJ, Blackledge G, Lawton FG, Stuart NS, Kavanagh J, Latief TN, Spooner D, Chetiyawardana AD "Phase II study of ifosfamide in cervical cancer." Cancer Treat Rep 70 (1986): 727-30

15. Holoye PY, Duelge J, Hansen RM, Ritch PS, Anderson T "Prophylaxis of ifosfamide toxicity with oral acetylcysteine." Semin Oncol 10(1 Suppl) (1983): 66-71

16. Wagner T "Ifosfamide clinical pharmacokinetics." Clin Pharmacokinet 26 (1994): 439-56

17. Harrison EF, Hawke JE, Hunter HL, Costanzi JJ, Morgan LR, Plotkin D, Tucker WG, Worrall PM "SINGLE-DOSE IFOSFAMIDE: EFFICACY STUDIES IN NON-SMALL CELL LUNG CANCER." Semin Oncol 9(4 Suppl) (1982): 56-601982

18. Retsas S "Treatment of refractory malignant neoplasms with ifosfamide as single agent and in combination chemotherapy." Cancer Treat Rev 10 Suppl A (1983): 151-7

19. Fujita J, Matsumoto K, Kakizoe T, Murase T "Prevention of ifosfamide-induced hemorrhagic cystitis by continuous bladder irrigation." Urology 18 (1981): 250-1

20. Pratt CB, Douglass EC, Etcubanas E, Goren MP, Green AA, Hayes FA, Horowitz ME, Meyer WH, Thompson EI, Wilimas JA "Clinical studies of ifosfamide/mesna at St Jude Children's Research Hospital, 1983-1988." Semin Oncol 16(1 Suppl) (1989): 51-5

21. Morgan LR, Donley PJ, Harrison EF, Hunter HL "The control of ifosfamide-induced hematuria with N-acetylcysteine in patients with advanced carcinoma of the lung." Semin Oncol 9 (4 Suppl) (1982): 71-4

22. Holoye PY, Anderson T, Duelge J, Hansen RM, Ritch PS "Use and safety of high-dose ifosfamide." Semin Oncol 9(4 Suppl) (1982): 78-86

23. Brade WP, Herdrich K, Varini M "Ifosfamide--pharmacology, safety and therapeutic potential." Cancer Treat Rev 12 (1985): 1-47

24. Brade WP, Herdrich K, Kachel-Fischer U, Araujo CE "Dosing and side-effects of ifosfamide plus mesna." J Cancer Res Clin Oncol 117 (1991): s164-86

25. Goren MP, Wright RK, Horowitz ME, Pratt CB "Ifosfamide-induced subclinical tubular nephrotoxicity despite mesna." Cancer Treat Rep 71 (1987): 127-30

26. Skinner R, Pearson AD, Price L, Coulthard MG, Craft AW "Nephrotoxicity after ifosfamide." Arch Dis Child 65 (1990): 732-8

27. Beckwith C, Flaharty KK, Cheung AK, Beatty PG "Fanconi's syndrome due to ifosfamide." Bone Marrow Transplant 11 (1993): 71-3

28. Shore R, Greenberg M, Geary D, Koren G "Iphosphamide-induced nephrotoxicity in children." Pediatr Nephrol 6 (1992): 162-5

29. McVay JI, Wood AM "Suspected ifosfamide-induced neurotoxicity." Pharmacotherapy 19 (1999): 1450-5

30. Garcia AA "Ifosfamide-induced Fanconi syndrome." Ann Pharmacother 29 (1995): 590-1

31. Patterson WP, Khojasteh A "Ifosfamide-induced renal tubular defects." Cancer 63 (1989): 649-51

32. Klastersky J "Side effects of Ifosfamide." Oncology 65 Suppl 2 (2003): 7-10

33. Smeitink J, Verreussel M, Schroder C, Lippens R "Nephrotoxicity associated with ifosfamide." Eur J Pediatr 148 (1988): 164-6

34. Husband DJ, Watkin SW "Fatal hypokalaemia associated with ifosfamide/mesna chemotherapy." Lancet 1 (1988): 1116

35. Heney D, Lewis IJ, Bailey CC "Acute ifosfamide-induced tubular toxicity." Lancet 2 (1989): 103-4

36. Kramer A, Goldschmidt H, Hahn U, Andrassy K "Progressive renal failure in two breast cancer patients after high- dose ifosfamide." Lancet 344 (1994): 1569

37. Canpolat C, Pearson P, Robertson R, Jaffe N "Ifosfamide tolerance in osteosarcoma patients previously treated with cis-diamminedichloroplatinum-II: renal, hematologic, and neurologic observations." Med Pediatr Oncol 26 (1996): 36-47

38. Heney D, Wheeldon J, Rushworth P, Chapman C, Lewis IJ, Bailey CC "Progressive renal toxicity due to ifosfamide." Arch Dis Child 66 (1991): 966-70

39. 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

40. Suarez A, Flamant F, Sommelet D, Voute PA, Quintana E, Comoy E "RENAL TOXICITY OF IFOSFAMIDE IN SOFT TISSUE SARCOMA PATIENTS, ONE YEAR MINIMUM AFTER COMPLETION OF CHEMOTHERAPY (SIOP MMT 84 STUDY) (MEETING ABSTRACT)." Proc Annu Meet Am Soc Clin Oncol 9 (1990): a11661990

41. Rossi R, Helmchen U, Schellong G "Tubular function and histological findings in ifosfamide-induced renal fanconi syndrome: a report of two cases." Eur J Pediatr 151 (1992): 384-7

42. Newbury-Ecob RA, Noble VW, Barbor PR "Ifosfamide-induced Fanconi syndrome." Lancet 1 (1989): 1328

43. Moncrieff M, Foot A "Fanconi syndrome after ifosfamide." Cancer Chemother Pharmacol 23 (1989): 121-2

44. Hadjiliadis D, Govert JA "Methemoglobinemia after infusion of ifosfamide chemotherapy - First report of a potentially serious adverse reaction related to ifosfamide." Chest 118 (2000): 1208-10

45. Martin M, Diaz-Rubio E, Gonzalez Larriba JL, Casado A, Sastre J, Lopez-Vega JM, Almenarez J, Dominguez S "Ifosfamide in advanced epidermoid head and neck cancer." Cancer Chemother Pharmacol 31 (1993): 340-2

46. Lind MJ, Margison JM, Cerny T, Thatcher N, Wilkinson PM "Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma." Cancer Res 49 (1989): 753-7

47. Sutton GP, Blessing JA, Barrett RJ, McGehee R "Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study." Am J Obstet Gynecol 166 (1992): 556-9

48. Izraeli S, Adamson PC, Blaney SM, Balis FM "Acute pancreatitis after ifosfamide therapy." Cancer 74 (1994): 1627-8

49. Curtin JP, Koonings PP, Gutierrez M, Schlaerth JB, Morrow CP "Ifosfamide-induced neurotoxicity." Gynecol Oncol 42 (1991): 193-6;disc. 191-2

50. Watkin SW, Husband DJ, Green JA, Warenius HM "Ifosfamide encephalopathy: a reappraisal." Eur J Cancer Clin Oncol 25 (1989): 1303-10

51. Danesh MM, De Giorgio CM, Beydoun SR, Kemp RA "Ifosfamide encephalopathy." J Toxicol Clin Toxicol 27 (1989): 293-8

52. Patel SR, Forman AD, Benjamin RS "High-dose ifosfamide-induced exacerbation of peripheral neuropathy." J Natl Cancer Inst 86 (1994): 305-6

53. Simonian NA, Gilliam FG, Chiappa KH "Ifosfamide causes a diazepam-sensitive encephalopathy." Neurology 43 (1993): 2700-2

54. Cantwell BM, Harris AL "Ifosfamide/mesa and encephalopathy." Lancet 1 (1985): 752

55. Markman M, Ettinger DS, Thigpen T, Nichols CR, Chang AY, Demetri GD, Vose JM, Palackdharry CS "Neurotoxicity of ifosfamide therapy - discussion." Semin Oncol 23 (suppl (1996): 103-4

56. Cameron JC "Ifosfamide neurotoxicity. A challenge for nurses, a potential nightmare for patients." Cancer Nurs 16 (1993): 40-6

57. DiMaggio JR, Brown R, Baile WF, Schapira D "Hallucinations and ifosfamide-induced neurotoxicity." Cancer 73 (1994): 1509-14

58. Miller LJ, Eaton VE "Ifosfamide-induced neurotoxicity: a case report and review of the literature." Ann Pharmacother 26 (1992): 183-7

59. Pallotta MG, Velazco A, Sadler A "Ifosfamide extrapyramidal neurotoxicity." Cancer 70 (1992): 2743-5

60. Bhardwaj A, Badesha PS "Ifosfamide-induced nonconvulsive status epilepticus." Ann Pharmacother 29 (1995): 1237-9

61. Wengs WJ, Talwar D, Bernard J "Ifosfamide-induced nonconvulsive status epilepticus." Arch Neurol 50 (1993): 1104-5

62. Heim ME, Fiene R, Schick E, Wolpert E, Queisser W "Central nervous side effects following ifosfamide monotherapy of advanced renal carcinoma." J Cancer Res Clin Oncol 100 (1981): 113-6

63. Yule SM, Pearson AD, Craft AW "Ifosfamide-induced hyperpigmentation." Cancer 73 (1994): 240-1

64. Mateu J, Alzamora M, Franco M, Buisan MJ "Ifosfamide extravasation." Ann Pharmacother 28 (1994): 1243-4

65. Nicoll JJ "Radiation reaction enhanced by ifosfamide." Br J Radiol 59 (1986): 1039-41

66. Teresi ME, Murry DJ, Cornelius AS "Ifosfamide-induced hyperpigmentation." Cancer 71 (1993): 2873-5

67. Baker WJ, Fistel SJ, Jones RV, Weiss RB "Interstitial pneumonitis associated with ifosfamide therapy." Cancer 65 (1990): 2217-21

68. Quezado ZM, Wilson WH, Cunnion RE, Parker MM, Reda D, Bryant G, Ognibene FP "High-dose ifosfamide is associated with severe, reversible cardiac dysfunction." Ann Intern Med 118 (1993): 31-6

69. Culine S, Ghosn M, Droz JP "Inappropriate antidiuretic hormone secretion induced by ifosfamide." Eur J Cancer 26 (1990): 922

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.

Hide
(web1)