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Ifosfamide
Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 3778-73-2
Brands: Ifex/Mesnex Kit

Warning(s)
Administer only under supervision of qualified clinicians experienced in the use of cancer chemotherapeutic agents. a

Hemorrhagic cystitis may occur and may require discontinuance of therapy (See Bladder Toxicity under Cautions). a

Severe neurotoxicity (e.g., confusion, coma) may occur and may require discontinuance of therapy (See Nervous System Effects under Cautions). a

Severe myelosuppression reported (See Hematologic Effects under Cautions). a

Introduction
Antineoplastic agent; alkylating agent structurally related to cyclophosphamide. 1 2 3 96 103 111 112

Uses for Ifosfamide

Testicular Cancer
Component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer 1 (designated an orphan drug by FDA for this use). 5

Soft Tissue Sarcomas


Component of various chemotherapeutic regimens in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas 2 3 9 33 34 35 36 37 38 39
40 41 42 43 44 45 46 111
(designated an orphan drug by FDA for this use). 5

Osteosarcoma

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9 35 36 37 40 41 42
Used alone or in conjunction with other drugs (e.g., etoposide) for treatment of localized, metastatic, and recurrent osteosarcoma 9 37 40 41 (designated an
orphan drug by FDA for this use). 5

Bladder Cancer
Used alone 9 143 or in combination with other antineoplastic agents 144 145 146 147 for treatment of advanced or metastatic bladder cancer. 143

Small Cell Lung Cancer


Treatment of small cell lung cancer as part of a combination regimen. 2 3 8 9 10 11 12 13 54 132

Cervical Cancer
Component of various combination regimens (e.g., cisplatin and ifosfamide with or without bleomycin) for the treatment of metastatic or recurrent cervical cancer. 3 9 20 21 22 23
25 152 153 154 155 156 157 158

Ovarian Cancer
Used alone or in conjunction with other antineoplastic agents for second-line (salvage) therapy in patients with advanced or recurrent ovarian carcinoma. 9 26 28 29 135

Non-Hodgkins Lymphoma
Treatment of advanced small noncleaved cell lymphoma (Burkitts and non-Burkitts) in children 9 119 as part of a combination regimen. c

Ifosfamide Dosage and Administration

General
Consult specialized references for procedures for proper handling and disposal of antineoplastics. 1

Adequately hydrate patient prior to and during ifosfamide therapy (e.g., 2 L of oral or IV fluid daily) to minimize urotoxicity. 1 2 58 59 141

Concomitant therapy with a uroprotective agent (e.g., mesna) recommended during ifosfamide therapy to decrease the incidence of bladder toxicity. 1 2 58 59 95 141 160 (See
Bladder Toxicity under Cautions.)

Administration
For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV infusion. 1


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Handle cautiously (e.g., use protective gloves); avoid exposure during handling and preparation of IV solution. 1 If skin or mucosal contact occurs, immediately wash skin with
1

soap and water and flush mucosa with water. 1

IV Administration

Reconstitution

Reconstitute vial containing 1 or 3 g of ifosfamide powder with 20 or 60 mL, respectively, of sterile or bacteriostatic water for injection, to provide a solution containing 50
mg/mL. a

Shake well to ensure complete dissolution. a May be infused directly or further diluted prior to IV infusion. a

Dilution

May be diluted with 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringers injection, or sterile water for injection to a concentration of 0.620 mg/mL. a

Rate of Administration

Administer as a slow IV infusion over a period of 30 minutes. a

Dosage
Consult published protocols for the dosage of ifosfamide and other chemotherapeutic agents and the method and sequence of administration. b

Adults

Testicular Cancer

IV

1.2 g/m 2 daily for 5 consecutive days. a Repeat course of therapy every 3 weeks (or following recovery of patients hematologic functions to within acceptable limits), usually for a
total of 4 courses. a

Cautions for Ifosfamide

Contraindications
Severe bone marrow depression. 1

Known hypersensitivity to ifosfamide or any ingredient in the formulation. 1

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Warnings/Precautions
Warnings

Bladder Toxicity

Hemorrhagic cystitis, hematuria, dysuria, and urinary frequency reported frequently. a Hemorrhagic cystitis can be severe and may be fatal. 95

Attributed to chemical irritation by metabolites (e.g., acrolein) that accumulate in concentrated urine. 1 2 3 38 59 111

Reduce bladder toxicity with conventional uroprophylaxis (e.g., high fluid intake, frequent urination) and use of fractionated ifosfamide dosage schedule, and concurrent
administration of mesna. 1 2 3 59 110

Examine urine prior to administration of each ifosfamide dose for presence of erythrocytes, which may precede hemorrhagic cystitis. a 95

If microscopic hematuria is present (>10 erythrocytes per high power field [HPF]), discontinue ifosfamide until complete resolution; a use vigorous oral or parenteral hydration as
well as mesna for subsequent courses of ifosfamide. 1 141

Discontinue ifosfamide or reduce dosage in patients who develop hematuria (>50 erythrocytes/HPF) while receiving usual dosages of ifosfamide in conjunction with mesna. 95

Hematologic Effects

Dose-dependent myelosuppression, principally leukopenia and, to a lesser extent, thrombocytopenia, occurs commonly. 1 2 3 58 59

Carefully monitor hematologic status during therapy; evaluate leukocyte and platelet counts and hemoglobin concentrations prior to and at appropriate intervals during therapy. 1
2 3 58 59
Do not administer ifosfamide if leukocyte count <2000/mm 3 and/or platelet count <50,000/mm 3. 1 In general, withhold subsequent courses until leukocyte count
>4000/mm 3 and platelet count >100,000/mm 3. 1

Use with caution in patients with compromised bone marrow reserve (i.e., leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior
therapy with other cytotoxic agents). 1

Nervous System Effects

Risk of neurotoxicity, characterized by somnolence, confusion, encephalopathy, coma, confusion, mutism, auditory and/or visual hallucinations, and stupor. 1 2 3 36 58 59 82 84 86 87
126 128

If one or more signs of serious neurotoxicity (i.e., somnolence, confusion, hallucinations, and/or coma) occur during therapy, discontinue therapy and institute appropriate
supportive therapy. 1 82 142 Effects generally are reversible and resolve within 24 days. 1 2 3 36 58 59 80 82 83 84 85 128 Methylene blue has been used in management of ifosfamide-
induced encephalopathy. 126 127 161

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Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals. a

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard. 1

Major Toxicities

Renal Effects

Potentially serious nephrotoxicity (e.g., acute or chronic renal failure, Fanconis syndrome, renal tubular acidosis, nephrogenic diabetes insipidus); may be evidenced by
aminoaciduria, glycosuria, proteinuria, cells or casts in the urine, increase in Scr or BUN, or decreased Clcr. 1 3 19 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 96 124

Nephrotoxicity may develop during therapy or following discontinuance of the drug and can be reversible. 62 64 67 68 69 70 72 74 76 77 122

Increased risk of nephrotoxicity associated with previous or concurrent cisplatin therapy and in patients with preexisting renal impairment, infiltrating renal tumor, or prior
nephrectomy. 3 19 59 62 64 67 68 73 74 76 110 124 125

Electrolyte Disturbances

Potentially fatal electrolyte abnormalities and/or acidosis reported. 65 Closely monitor serum and urine chemistries (i.e, phosphorus, potassium, alkaline phosphatase) and other
appropriate laboratory studies. 1 62 65 68 77 141 If electrolyte abnormalities develop, institute appropriate therapy to correct any imbalance(s). 1 62 65 68 77

General Precautions

Wound Healing

May interfere with normal wound healing. a

Specific Populations

Pregnancy

Category D. a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk. 1 Discontinue nursing or the drug. 1

Pediatric Use

Safety and efficacy not established. 1


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Has been used in children 15 days to 17 years of age for the treatment of certain malignancies (e.g., Ewings sarcoma, rhabdomyosarcoma, Wilms tumor); adverse effects
reported in these children appear to be similar to those reported in adults. 34 61 62 75 121 122 133

Children 5 years of age may be more susceptible to ifosfamide-induced renal toxicity than older children or adults. 3 62 64

Geriatric Use

Select dosage based on the clinical, renal, and hematologic response and tolerance of the patient; consider age-related decrease in hepatic, renal and/or hematopoietic function. 1

Renal Impairment

Use with caution. a Possible increased risk of nephrotoxicity 3 19 59 62 64 67 68 73 74 76 110 124 125 and neurotoxicity. 1 2 3 36 58 59 82 86 (See Nervous System Effects under Cautions.)

Common Adverse Effects


Alopecia, 1 59 nausea/vomiting, 1 2 3 36 hematuria, CNS toxicity, infection, renal impairment. 1 a

Interactions for Ifosfamide


Converted to active metabolites by mixed-function oxidases (cytochrome P-450 system). 2 3 103 111

Drugs Affecting Hepatic Microsomal Enzymes


Potential pharmacokinetic interaction (increased or decreased metabolism of ifosfamide); may result in increased or decreased conversion to active metabolites. 2 79 96 141

Specific Drugs

Drug Interaction Comments

Cisplatin Increased risk of nephrotoxicity 3 19 59 62 64 67 68 73 74 76 110 124 125 Associated with previous or concurrent cisplatin
therapy 3 19 59 62 64 67 68 73 74 76 110 124 125

Mesna Interacts chemically with urotoxic ifosfamide metabolites and precursors to prevent or decrease Used for uroprotection 2 3 62 63 71 95 108 141
incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis) 2 3 62 63 71 95 108 141

Myelosuppressive Possible additive hematologic toxicity 1 2 3 7 10 11 Use concomitantly with caution; monitor carefully 1
3
agents

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Ifosfamide Pharmacokinetics

Absorption
Bioavailability
Following IV administration, peak plasma concentrations of the principal alkylating metabolite are reached within 2030 minutes. 104

Distribution
Extent
Widely distributed throughout the body, including the brain and CSF. 3 98 99 Distributed into milk. 1

Elimination
Metabolism
Extensively metabolized, principally in the liver, to active and inactive metabolites. 3 96 104 105

Metabolized to 4-hydroxyifosfamide (in equilibrium with acyclic tautomer aldoifosfamide), 1 2 3 96 103 104 105 then to 4-ketoifosfamide. 1 2 3 96 Also metabolized to
chloroacetaldehyde, 2-dechloroethylifosfamide, and 3-dechloroethylifosfamide. 1 2 3 96 103 104 105

Aldoifosfamide spontaneously splits into ifosfamide mustard (primary alkylating metabolite) and to acrolein 1 2 3 96 103 and may be enzymatically metabolized to
carboxyifosfamide. 1 2 3 96

Elimination Route
Excreted principally in urine. 1 2 3 96

Half-life
Terminal half-life averages 48 hours in adults. 3 85 86 104

Stability

Storage

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Parenteral

Powder for Injection

2025C; 1 106 113 protect from temperature >30C. 1

Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility HID

Compatible

Dextrose 5% in Ringers injection

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Ringers injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate (1/6) M

Drug Compatibility

Admixture CompatibilityHID
Compatible

Carboplatin

Cisplatin

Cisplatin with etoposide

Epirubicin HCl

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Etoposide

Fluorouracil

Mesna

Y-Site CompatibilityHID
Compatible

Allopurinol sodium

Amifostine

Amphotericin B cholesteryl sulfate complex

Anidulafungin

Aztreonam

Caspofungin acetate

Doripenem

Doxorubicin HCl liposome injection

Etoposide phosphate

Filgrastim

Fludarabine phosphate

Gallium nitrate

Gemcitabine HCl

Granisetron HCl

Linezolid

Melphalan HCl

Ondansetron HCl

Oxaliplatin

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Paclitaxel

Palonosetron HCl

Pemetrexed disodium

Piperacillin sodiumtazobactam sodium

Propofol

Sargramostim

Sodium bicarbonate

Teniposide

Thiotepa

Topotecan HCl

Vinorelbine tartrate

Incompatible

Methotrexate sodium

Actions
Interferes with DNA replication and transcription of RNA, resulting in disruption of nucleic acid function. 1 2 3 143 144 145 146

Also has immunosuppressive activity. 112 144 146

Advice to Patients
Risk of bladder toxicity, myelosuppression, and neurotoxicity. a

Importance of informing clinicians if excessive sleepiness, confusion, or hallucinations occur. a

Advise that alopecia is likely. 1

Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses. 1

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. 1 Advise pregnant women of risk to the fetus. 1

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Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ifosfamide
Dosage
Routes Strengths Brand Names Manufacturer
Forms

Parenteral Kit 1 g, For injection, for IV infusion, Ifosfamide (Ifex Kit) Ifex/Mesnex Kit Bristol-Myers
100 mg/mL (1 g), Injection, Mesna (Mesnex) (with benzyl alcohol) Squibb

100 mg/mL (1 g), Injection, Ifosfamide 100 mg/mL (1 g) Injection, Mesna (with benzyl Ifosfamide Injection/Mesna Injection
alcohol) Kit

3 g, For injection, for IV infusion, Ifosfamide (Ifex) Ifex/Mesnex Kit Bristol-Myers


100 mg/mL (1 g), Injection, Mesna (Mesnex) (with benzyl alcohol) Squibb

100 mg/mL (3 g), Injection, Ifosfamide 100 mg/mL (1 g) Injection, Mesna (with benzyl Ifosfamide Injection/Mesna Injection
alcohol) Kit

AHFS DI Essentials. Copyright 2017, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb. Ifex (ifosfamide for injection) prescribing information. Princeton, NJ; 1998 Jun.

2. Schoenike SE, Dana WJ. Ifosfamide and mesna. Clin Pharm. 1990; 9:179-91. [PubMed 2107997]

3. Dechant KL, Brogden RN, Pilkington T et al. Ifosfamide/mesna: a review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991; 42:428-67. [PubMed 1720382]

4. Loehrer PJ, Lauer R, Roth BJ et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Int Med. 1988; 109:540-6. [PubMed 2844110]

5. Food and Drug Administration. List of orphan product designations & approvals. 1995 Apr.

6. Motzer RJ, Cooper K, Geller NL et al. The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors. Cancer. 1990; 66:2476-81. [PubMed 2174300]

7. Ghosn M, Droz JP, Theodore C et al. Salvage chemotherapy in refractory germ cell tumors with etoposide (VP-16) plus ifosfamide plus high-dose cisplatin. Cancer. 1988; 62:24-7. [PubMed 3133101]

8. Hansen HH, Rorth M. Lung cancer. In: Pinedo HM, Longo DL, Chabner BA eds. Cancer chemotherapy and biological response modifiers annual 14. 1993:442-3.

https://www.drugs.com/monograph/ifosfamide.html 11/17
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9. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

10. Smith IE, Perren TJ, Ashley SA et al. Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small-cell lung cancer. J Clin Oncol. 1990; 8:899-905. [PubMed 2159056]

11. Thatcher N, Lind M, Stout R et al. Carboplatin, ifosfamide and etoposide with mid-course vincristine and thoracic radiotherapy for limited stage small cell carcinoma of the bronchus. Br J Cancer. 1989; 60:98-101.
[PubMed 2553090]

12. Loehrer PJ, Rynard S, Ansari R et al. Etoposide, ifosfamide, and cisplatin in extensive small cell lung cancer. Cancer. 1992; 69:669-73. [PubMed 1309677]

13. Havemann K, Wolf M, Drings P et al. Experience of a german multicenter study group with ifosfamide in small cell lung cancer. Semin Oncol. 1989; 16:9-18. [PubMed 2539648]

14. Eberhardt W, Niederle N. Ifosfamide in non-small cell lung cancer: a review. Semin Oncol. 1992; 19:40-8. [PubMed 1329211]

15. de Schepper J, Hachimi-Idrissi S, Louis O et al. Bone metabolism and mineralization after cytotoxic chemotherapy including ifosfamide. Arch Dis Child. 1994; 71:346-8. [PubMed 7979531]

16. Crino L, Scagliotti GV, Ricci S et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin
Oncol. 1999; 17:3522-30. [PubMed 10550150]

17. Cullen MH. Mitomycin, ifosfamide, and cisplatin in non-small cell lung cancer. Oncology. 1993; 50:31-4. [PubMed 8387176]

18. Krmer A, Goldschmidt H, Hahh U. Progressive renal failure in two breast cancer patients after high-dose ifosfamide. Lancet. 1994; 344:1569.

19. Garcia AA. Ifosfamide-induced fanconi syndrome. Ann Pharmacother. 1995; 29:590-1. [PubMed 7663031]

20. Sutton GP, Blessing JA, McGuire WP et al. Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a gynecologic oncology
group study. Am J Obstet Gynecol. 1993; 168:805-7. [PubMed 8456884]

21. Coleman RE, Harper PG, Gallagher C et al. A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol. 1986; 18:280-3. [PubMed 3802384]

22. Buxton EJ, Meanwell CA, Hilton C et la. Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst. 1989; 81:359-61. [PubMed 2464699]

23. Cervical cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Aug.

24. Sutton GP, Blessing JA, Adcock L et al. Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix. Invest New Drugs. 1989; 7:341-3. [PubMed 2513286]

25. Murad AM, Triginelli SA, Ribolta JCL. Phase II trial of bleomycin, ifosfamide, and carboplatin in metastatic cervical cancer. J Clin Oncol. 1994; 12:55-9. [PubMed 7505808]

26. Ovarian epithelial cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Oct.

27. Lorusso V, Catino A, Leone B et al. Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study. J Clin Oncol. 1993; 11:1952-6. [PubMed 8410121]

28. Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a gynecologic oncology group study. J Clin Oncol. 1989; 7:1672-6. [PubMed 2509641]

29. Markman M, Hakes T, Reichman B et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992; 10:243-8. [PubMed 1732425]

30. Uterine sarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sep 1.

31. Sutton GP, Blessing JA, Rosenshein N et al. Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus (a gynecologic oncology group study). Am J Obstet Gynecol. 1989; 161:309-12. [PubMed
2548382]

32. Sutton GP, Blessing JA, Barrett RJ et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a gynecologic oncology group study. Am J Obstet Gynecol. 1992; 166:556-9. [PubMed 1536229]

33. Ewings sarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sep 1.

34. Meyer WH, Kun L, Marina N et al. Ifosfamide plus etoposide in newly diagnosed Ewings sarcoma of bone. J Clin Oncol. 1992; 10:1737-42. [PubMed 1403056]

35. Miser JS, Kinsella TJ, Triche TJ et al. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987;
5:191-8.

36. Kung FH, Pratt CB, Vega RA et al. Ifosfamide/etoposide combination in the treatment of recurrent malignant solid tumors of childhood. Cancer. 1993; 71:1898-903. [PubMed 8448755]
https://www.drugs.com/monograph/ifosfamide.html 12/17
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g g p g
37. Antman KH. Chemotherapy of advanced sarcomas of bone and soft tissue. Semin Oncol. 1992; 19:13-22. [PubMed 1485169]

38. Jrgens H, Exner U, Khl J et al. High-dose ifosfamide with mesna uroprotection in Ewings sarcoma. Cancer Chemother Pharmacol. 1989; 24:40-44S.

39. Demeocq F, Oberlin O, Benz-Lemoine E et al. Initial chemotherapy including ifosfamide in the management of Ewings sarcoma: preliminary results a protocol of the French Pediatric Oncology Society (SFOP). Cancer
Chemother Pharmacol. 1989; 24:45-47S. [PubMed 2541937]

40. Osteosarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sept 1.

41. Pratt CB. Ifosfamide studies for primary or recurrent pediatric malignant solid tumors and leukemia. Semin Oncol. 1990; 17:31-4. [PubMed 2185546]

42. Marti C, Kroner T, Remagen W et al. High-dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep. 1985; 69:115-7. [PubMed 3855382]

43. Adult soft tissue sarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sept 1.

44. Elias A, Ryan L, Sulkes A et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989; 7:1208-16. [PubMed
2504890]

45. Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;
11:1276-85. [PubMed 8315425]

46. Antman KH, Ryan L, Elias A et al. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol. 1989; 7:126-31. [PubMed 2491883]

47. Childhood rhabdomyosarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Nov 30.

48. Magrath I, Sandlund J, Raynor A et al. A phase II study of ifosfamide in the treatment of recurrent sarcomas in young people. Cancer Chemother Pharmacol. 1986; 18:25-8S.

49. de Kraker J, Voute PA. Ifosfamide, mesna and vincristine in pediatric oncology. Cancer Treat Rev. 1983; 10:165-6. [PubMed 6414690]

50. Otten J, Flamant F, Rodary C et al. Treatment of rhabdomyosarcoma and other malignant mesenchymal tumours of childhood with ifosfamide + vincristine + dactinomycin (IVA) as front-line therapy (a SIOP study).
Cancer Chemother Pharmacol. 1989; 24:30S.

51. Pappo AS, Etcubanas E, Santana VM et al. A phase II trial of ifosfamide in previously untreated children and adolescents with unresectable rhabdomyosarcoma. Cancer. 1993; 71:2119-25. [PubMed 8443761]

52. Testicular Cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Nov 30.

53. Non-small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Aug.

54. Small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Oct.

55. Cabanillas F. Ifosfamide combinations in lymphoma. Semin Oncol. 1990; 17:58-82. [PubMed 2333524]

56. Adult non-Hodgkins lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sept 1.

57. Armitage JO. Treatment of non-hodgkins lymphoma. N Engl J Med. 1993; 328:1023-30. [PubMed 8450856]

58. Antman KH, Elias A, Ryan L. Ifosfamide and mesna: response and toxicity at standard- and high-dose schedules. Semin Oncol. 1990; 17: 68-73.

59. Brade WP, Herdich K, Kachel-Fischer U et al. Dosing and side-effects of ifosfamide plus mesna. Cancer Res Clin Oncol. 1991; 117:5164-86.

60. Wilms tumor. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sept 1.

61. Tournade MF, Lemerle J, Brunat-Mentigny M et al. Ifosfamide is an active drug in Wilms tumor: a phase II study conducted by the French Society of Pediatric Oncology. J Clin Oncol. 1988; 6:793-6. [PubMed 2835442]

62. Skinner R, Sharkey IA, Pearson ADJ et al. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol. 1993; 11:173-90. [PubMed 8418231]

63. Culine S, Ghosn M, Droz J. Inappropriate antidiuretic hormone secretion induced by ifosfamide. Eur J Cancer. 1990; 26:922. [PubMed 2145942]

64. Rossi R, Gdde A, Kleinbrand A et al. Unilateral nephrectomy and cisplatin as risk factors of ifosfamide-induced nephrotoxicity: analysis of 120 patients. J Clin Oncol. 1994; 12:159-65. [PubMed 8270973]

https://www.drugs.com/monograph/ifosfamide.html 13/17
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65. Husband DJ, Watkin SW. Fatal hypokalemia associated with ifosfamide/mesna chemotherapy. Lancet. 1988; :1116. [PubMed 2896952]

66. Newbury-Ecob RA, Nobel VW, Barbor PRH. Ifosfamide-induced fanconi syndrome. Lancet. 1989; :1328.

67. Rossi R, Kleinebrand A, Gdde A et al. Increased risk of ifosfamide-induced renal Fanconis syndrome after unilateral nephrectomy. Lancet. 1993; 341:755. [PubMed 8095648]

68. Burk CD, Restaino I, Kaplan BS et al. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor. J Pediatr. 1990; 117:331-5. [PubMed 2166154]

69. Skinner R, Pearson ADJ, Price L et al. Nephrotoxicity after ifosfamide. Arch Dis Childhood. 1990; 65:732-8.

70. Devalck C, Ismaili K, Ferster A. Acute ifosfamide-induced proximal tubular toxic reaction. J Pediatr. 1991; 118:325-6. [PubMed 1993970]

71. Goren MP, Wright RK, Horowitz ME et al. Ifosfamide-induced subclinical tubular nephrotoxicity despite mesna. Cancer Treat Rep. 1987; 71:127-30. [PubMed 2879626]

72. Willemse PHB, de Jong PE, Elema JD et al. Severe renal failure following high-dose ifosfamide and mesna. Cancer Chemother Pharmacol. 1989; 23:329-30. [PubMed 2495864]

73. Pratt CB, Meyer WH, Jenkins JJ et al. Ifosfamide, Fanconis syndrome, and rickets. J Clin Oncol. 1991; 9:1495-9. [PubMed 1649270]

74. Beckwith C, Flaharty KK, Cheung AK et al. Fanconis syndrome due to ifosfamide. Bone Marrow Transplant. 1989; 11:71-3.

75. Ifosfamide-induced fanconis syndrome with growth failure in a 2-year-old child. Am J Pediatr Hematol/Oncol. 1991; 13:39-41.

76. Rossi R, Ehrich JHH. Partial and complete de Toni-Debre-Fanconi syndrome after ifosfamide chemotherapy of childhood malignancy. Eur J Clin Pharmacol. 1993; 44:43-5S.

77. Heney D, Wheeldon J, Rushworth P et al. Progressive renal toxicity due to ifosfamide. Arch Dis Childhood. 1991; 66:966-70.

78. Patterson WP, Khojasteh A. Ifosfamide-induced renal tubular defects. Cancer. 1989; 63:649-51. [PubMed 2914270]

79. Simonian NA, Gilliam FG, Chiappa KH. Ifosfamide causes a diazepam-sensitive encephalopathy. Neurology. 1993; 43:2700-2. [PubMed 8255482]

80. Salloum E, Flamant F, Ghosh M et al. Irreversible encephalopathy with ifosfamide mesna. J Clin Oncol. 1987; 5:1303-4. [PubMed 3114437]

81. DiMaggio JR, Brown R, Baile WF et al. Hallucinations and ifosfamide-induced neurotoxicity. Cancer. 1994; 73:1509-14. [PubMed 8111719]

82. Miller LJ, Eaton VE. Ifosfamide-induced neurotoxicity: a case report and review of the literature. Ann Pharmacother. 1992; 26:183-7. [PubMed 1554927]

83. Danesh MM, De Giorgio CM, Beydoun SR et al. Ifosfamide encephalopathy. J Toxicol Clin Toxicol. 1989; 27:293-8. [PubMed 2600992]

84. Watkin SW, Husband DJ, Green JA et al. Ifosfamide Encephalopathy: a reappraisal. Eur J Clin Oncol. 1989; 25:1303-10.

85. Gieron MA, Barak LS, Estrada J. Severe encephalopathy associated with ifosfamide administration in two children with metastatic tumors. J Neuro-Oncol. 1988; 6:29-30.

86. Meanwell CA, Kelly KA, Blackledge G. Avoiding ifosfamide/mesna encephalopathy. Lancet. 1986; 2:406. [PubMed 2874408]

87. Anderson NR, Tandon DS. Ifosfamide extrapyramidal neurotoxicity. Cancer. 1991; 68:72-5. [PubMed 2049756]

88. Pallotta MG, Velazco A, Sadler A. Ifosfamide extrapyramidal neurotoxicity. Cancer. 1992; 70:2743-4. [PubMed 1423208]

89. Patel SR, Forman AD, Benjamin RS. High-dose ifosfamide-induced exacerbation of peripheral neuropathy. J Natl Cancer Inst. 1994; 86:305-6. [PubMed 8158686]

90. Teresi ME, Murry DJ, Cornelius AS. Ifosfamide-induced hyperpigmentation. Cancer. 1993; 71:2873-5. [PubMed 8385568]

91. Yule SM, Pearson AD, Craft AW. Ifosfamide-induced hyperpigmentation. Cancer. 1994; 73:240-1. [PubMed 8275433]

92. Baker WJ, Fistel SJ, Jones RV et al. Interstitial pneumonitis associated with ifosfamide therapy. Cancer. 1990; 65:2217-21. [PubMed 2112039]

93. Choonara IA, Overend M, Bailey CC. Blurring of vision due to ifosfamide. Cancer Chemother Pharmacol. 1987; 20:349. [PubMed 3690810]

94. Quezado ZMN, Wilson WH, Cunnion RE et al. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Int Med. 1993; 188:31-6.

https://www.drugs.com/monograph/ifosfamide.html 14/17
10/26/2017 Ifosfamide Monograph for Professionals - Drugs.com
95. Bristol-Myers Squibb. Mesnex (mesna) injection prescribing information. Princeton, NJ; 1998 Mar.

96. Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994; 26:439-56. [PubMed 8070218]

97. Pearcey R, Calvert R, Mehta A. Disposition of ifosfamide in patients receiving ifosfamide infusion therapy for the treatment of cervical carcinoma. Cancer Chemother Pharmacol. 1988; 22:353-5. [PubMed 3168149]

98. Allen LM, Creaven PJ, Nelson RL. Studies on the human pharmacokinetics of isophosphamide (NSD-109724). Cancer Treat Rep. 1976; 60:451-8. [PubMed 1277221]

99. Allen LM, Creaven PJ. Pharmacokinetics of ifosfamide. Clin Pharmacokinet. 1994; 26:439-56. [PubMed 8070218]

100. Lind MJ, Margison JM, Cerny T et al. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol. 1989; 25:139-42. [PubMed 2557169]

101. Lind MJ, Margison JM, Cerny T et al. The effect of age on the pharmacokinetics of ifosfamide. Br J Clin Pharmacol. 1990; 30:140-3. [PubMed 2167716]

102. Lewis LD, Fitzgerald DL, Mohan P et al. The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients. Br J Clin Pharmacol. 1991; 31:77-82. [PubMed 2015174]

103. Kaijser GP, Korst A, Beijnen JH et al. The analysis of ifosfamide and its metabolites (review). Anticancer Res. 1993; 13:1311-24. [PubMed 8239501]

104. Kurowski V, Cerny T, Kpfer A et al. Metabolism and pharmacokinetics of oral and intravenous ifosfamide. J Cancer Res Clin Oncol. 1991; 117:148-53.

105. Kurowski V, Wagner T. Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloracetaldehyde, and 2- and 3-dechlorethylifosfamide in patients on fractionated intravenous ifosfamide therapy. Cancer
Chemother Pharmacol. 1993; 33:36-42. [PubMed 8269587]

106. US Dept. of Health and Human Services. Ifosfamide pharmaceutical data. In: NCI investigational drugs. National Institutes of Health. 1987.

107. Boddy AV, Yule SM, Wyllie R et al. Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children. Cancer Res. 1993; 53:3758-64. [PubMed 8339288]

108. Mead Johnson. Mesnex (mesna injection) dosing and administration guide. Princeton, NJ; 1989 Jun.

109. Mesna. In: Trissel LA. Handbook on injectable drugs. 8th ed. Bethesda, MD. American Society of Hospital Pharmacists; 1994:664-6.

110. Goren MP, Wright RK, Pratt CB et al. Potentiation of ifosfamide neurotoxicity, hematotoxicity, and tubular nephrotoxicity by prior cis-diamminedichloroplatinum(II) therapy. Can Res. 1987; 47:1457-60.

111. DeVita VT JR, Hellman S, Rosenberg SA, eds. Cancer: principles & practice of oncology. 4th 3d. Philadelphia, PA. JB Lippincott Company. 1993: 400-9,1473-9.

112. Holland JF, Frei E, Bast RC et al, eds. Cancer medicine. 3rd ed. Philadelphia, PA. Lea & Febiger. 1993:733-43.

113. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:

114. Ifosfamide. In: Trissel LA. Handbook on injectable drugs. 8th ed. Bethesda, MD. American Society of Hospital Pharmacists; 1994:S73-6.

115. Le Cesne A, Antoine E, Spielmann M et al. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol. 1995; 13:1600-8. [PubMed 7541449]

116. Loehrer PJ, Williams SD, Nichols CR et al. Clinical trials with ifosfamide: the Indiana University experience. Semin Oncol. 1992; 19(Suppl 1):35-9. [PubMed 1329210]

117. Santoro A, Tursz T, Mouridsen H et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for
Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995; 13:1537-45. [PubMed 7602342]

118. Edmonson JH. Needed: qualitative improvement in antisarcoma therapy. J Clin Oncol. 1995; 13:1531-3. [PubMed 7602340]

119. Childhood non-Hodgkins lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Sept 1.

120. Furusawa S, Fujimura T, Sasaki K et al. Potentiation of ifosfamide toxicity by chlordiazepoxide, diazepam and oxazepam. Chem Pharm Bull. 1989; 37:3420-2. [PubMed 2632092]

121. Valdivieso Torres MJ, Lopez Perez J, Melero C et al. Ifosfamide-induced renal tubular defect. Med Pediatr Oncol. 1994; 22:144-6. [PubMed 7505048]

122. Hanquinet S, Wouters M, Devalck C et al. Increased renal parenchymal echogenicity in ifosfamide-induced renal fanconi syndrome. Med Pediatr Oncol. 1995; 24:116-8. [PubMed 7990759]

123. Ashraf MS, Brady J, Breatnach F et al. Ifosfamide nephrotoxicity in pediatric cancer patients. Eur J Pediatr. 1994; 155:90-4.

https://www.drugs.com/monograph/ifosfamide.html 15/17
10/26/2017 Ifosfamide Monograph for Professionals - Drugs.com
124. Jones DP, Chesney RW. Renal toxicity of cancer chemotherapeutic agents in children: ifosfamide and cisplatin. Curr Sci. 1995; 7:208-13.

125. Raney B, Ensign LG, Foremen J et al. Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor. Am J Pediatr Hematol Oncol. 1994; 16:286-95.
[PubMed 7978043]

126. Kpfer A, Aeschlimann C, Wermuth B et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet. 1994; 343:763-4. [PubMed 7510815]

127. Zulian GB, Tullen E, Maton B. Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med. 1995; 332:1239-40. [PubMed 7700329]

128. Bruggers CS, Friedman HS, Tien R et al. Cerebral atrophy in an infant following treatment with ifosfamide. Med Pediatr Oncol. 1994; 23:380-3. [PubMed 8058012]

129. Heim M, Fiene R, Schick E at al. Central nervous side effects following ifosfamide monotherapy of advanced renal carcinoma. J Cancer Res Clin Oncol. 1981; 100:113-6. [PubMed 7240342]

130. Izraeli S, Adamson PC, Blaney SM et al. Acute pancreatitis after ifosfamide therapy. Cancer. 1994; 74:1267-8.

131. Mateu J, Alzamera M, Franco M et al. Ifosfamide extravasation. Ann Pharmacother. 1994; 28:1243-4. [PubMed 7849337]

132. Ettinger DS. The place of ifosfamide in chemotherapy of small cell lung cancer: the Eastern Cooperative Oncology Group experience and a selected literature update. Semin Oncol. 1995; 22:23-7. [PubMed 7846538]

133. Marina NM, Wilimas JA, Meyer WH et al. Refining therapeutic strategies for patients with resistant Wilms tumor. Am J Pediatr Hematol/Oncol. 1994; 16:296-300.

134. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995; 311:899-909.
[PubMed 7580546]

135. NIH Consensus Development Panel on Ovarian Cancer. NIH consensus conference on ovarian cancer: screening, treatment, and follow-up. JAMA. 1995; 273:491-7. [PubMed 7837369]

136. Petru E, Schmhl D. Second malignanciesrisk reduction. Cancer Treat Rev. 1987; 14:337-43. [PubMed 3125969]

137. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979;
44:37434-67.

138. Department of Health and Human Services, Food and Drug Administration. Subpart BLabeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1(4-1-87 Ed.)). 1987:18-24.

139. Shaw IC, Graham MI. Mesnaa short review. Cancer Treat Rev. 1987; 14:67-86. [PubMed 3119211]

140. Burkert H. Clinical overview of mesna. Cancer Treat Rev. 1983; 10:175-81. [PubMed 6414692]

141. Reviewers comments (personal observations).

142. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

143. Witte RS, Elson P, Bono B et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997; 15:589-93. [PubMed 9053481]

144. McCaffrey J, Hilton S, Mazumdar M et al. A phase II trial of ifosfamide, paclitaxel and cisplatin (ITP) in patients (pts) with advanced urothelial tract tumors. Proc Am Soc Clin Oncol. 1996; 15:251.

145. Dreicer R, Propert KJ, Roth BJ et al. Vinblastine, ifosfamide, and gallium nitratean active new regimen in patients with advanced carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group
(E5892). Cancer. 1997; 79:110-4. [PubMed 8988734]

146. Einhorn LH, Roth BJ, Ansari R et al. Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol. 1994; 12:2271-6. [PubMed 7525884]

147. Schmidt AS, Ruther U, Eisenberger F. First line therapy with ifosfamide and etoposide for the treatment of advanced bladder cancer. J Urol. 1993; 149:318. [PubMed 8426410]

148. Stadler WM, Kuzel T, Roth B et al. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997; 15:3394-8. [PubMed 9363871]

149. Roth BJ. Ifosfamide in the treatment of bladder cancer. Semin Oncol. 1996; 23(Suppl 6):50-5. [PubMed 8677450]

150. Loehrer PJ Sr, Ansari R, Gonin R et al. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol. 1995; 13:2594-9. [PubMed 7595712]

151. Sculier JP, Paesmans M, Thiriaux J et al. Phase III randomized trial comparing cisplatin and carboplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer. J Clin Oncol. 1998; 16:1388-96.
[PubMed 9552042]
https://www.drugs.com/monograph/ifosfamide.html 16/17
10/26/2017 Ifosfamide Monograph for Professionals - Drugs.com
152. Omura GA, Blessing JA, Vaccarello L et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group
study. J Clin Oncol. 1997; 15:165-71. [PubMed 8996138]

153. Kumar L, Pokharel YH, Kumar S et al. Single agent versus combination chemotherapy in recurrent cervical cancer. J Obstet Gynaecol Res. 1998; 24:401-9. [PubMed 10063235]

154. Buxton EJ. Experience with bleomycin, ifosfamide, and cisplatin in primary and recurrent cervical cancer. Semin Oncol. 1992; 19(2 Suppl 5):9-18. [PubMed 1384148]

155. Alberts DS, Kronmal R, Baker LH et al. Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J
Clin Oncol. 1987; 5:1791-5. [PubMed 2445932]

156. Thigpen T, Vance R, Khansur T et al. The role of ifosfamide and systemic therapy in the management of carcinoma of the cervix. Semin Oncol. 1996; 23(3 Suppl 6):56-64. [PubMed 8677451]

157. Meanwell CA, Mould JJ, Blackledge G et al. Phase II study of ifosfamide in cervical cancer. Cancer Treat Rep. 1986; 70:727-30. [PubMed 3089596]

158. Sutton GP, Blessing JA, DiSaia PJ et al. Phase II study of ifosfamide and mesna in nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1993; 49:48-50. [PubMed 8482560]

159. Reviewers comments (personal observations) on cervical cancer.

160. Sicor. Ifosfamide injection prescribing information. Irvine, CA; 2004 Feb.

161. Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother. 2006; 40:299-303. [PubMed 16391008]

a. Bristol Myers Squibb. Ifex (ifosfamide for injection) prescribing information. Princeton, NJ; 2002 Nov.

b. AHFS drug information 2005. McEvoy GK, ed. Ifosfamide. Bethesda, MD: American Society of Health-System Pharmacists; 2005:1046-51.

c. Treatment Guidelines from the Medical Letter Drugs of Choice for Cancer. Abramowicz M, ed. New Rochelle, NY: The Medical Letter, Inc.; 2003 Mar: 41-51.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:650-3.

https://www.drugs.com/monograph/ifosfamide.html 17/17