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 cancer1 (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 sarcomas2 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

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Osteosarcoma

Used alone or in conjunction with other drugs (e.g., etoposide)9 35 36 37 40 41 42 for treatment of localized, metastatic, and recurrent osteosarcoma9 37 40 41 (designated an orphan drug by FDA for this use).5

Bladder Cancer

Used alone9 143 or in combination with other antineoplastic agents144 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-Hodgkin’s Lymphoma

Treatment of advanced small noncleaved cell lymphoma (Burkitt’s and non-Burkitt’s) in children9 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

Handle cautiously (e.g., use protective gloves);1 avoid exposure during handling and preparation of IV solution.1 If skin or mucosal contact occurs, immediately wash skin with 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 Ringer’s injection, or sterile water for injection to a concentration of 0.6–20 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/m2 daily for 5 consecutive days.a Repeat course of therapy every 3 weeks (or following recovery of patient’s 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

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/mm3 and/or platelet count <50,000/mm3.1 In general, withhold subsequent courses until leukocyte count >4000/mm3 and platelet count >100,000/mm3.1

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 2–4 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

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, Fanconi’s 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

Has been used in children 15 days to 17 years of age for the treatment of certain malignancies (e.g., Ewing’s 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 nephrotoxicity3 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 therapy3 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 incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis)2 3 62 63 71 95 108 141

Used for uroprotection2 3 62 63 71 95 108 141

Myelosuppressive agents

Possible additive hematologic toxicity1 2 3 7 10 11

Use concomitantly with caution; monitor carefully1 3

Ifosfamide Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentrations of the principal alkylating metabolite are reached within 20–30 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 acrolein1 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 4–8 hours in adults.3 85 86 104

Stability

Storage

Parenteral

Powder for Injection

20–25°C;1 106 113 protect from temperature >30°C.1

Compatibility

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

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in Ringer’s injection

Dextrose 5% in sodium chloride 0.9%

Dextrose 5% in water

Ringer’s 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

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

Paclitaxel

Palonosetron HCl

Pemetrexed disodium

Piperacillin sodium–tazobactam 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

  • 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.

Ifosfamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Kit

1 g, For injection, for IV infusion, Ifosfamide (Ifex Kit)

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

Ifex/Mesnex Kit

Bristol-Myers Squibb

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

Ifosfamide Injection/Mesna Injection Kit

3 g, For injection, for IV infusion, Ifosfamide (Ifex)

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

Ifex/Mesnex Kit

Bristol-Myers Squibb

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

Ifosfamide Injection/Mesna Injection Kit

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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