Ifosfamide Monograph For Professionals - Drugs

10/26/2017 Ifosfamide Monograph for Professionals - Drugs.
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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

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
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
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

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
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
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
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 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
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.
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10/26/2017 Ifosfamide Monograph for Professionals - Drugs.

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

Uses for Ifosfamide

Soft Tissue Sarcomas

Small Cell Lung Cancer

Ifosfamide Dosage and Administration

Administer by slow IV infusion. 1

soap and water and flush mucosa with water. 1

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

Cautions for Ifosfamide

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

Nervous System Effects

Fetal/Neonatal Morbidity and Mortality

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

May interfere with normal wound healing. a

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

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

Safety and efficacy not established. 1

Common Adverse Effects

Interactions for Ifosfamide

Drugs Affecting Hepatic Microsomal Enzymes

Drug Interaction Comments

Powder for Injection

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

Solution Compatibility HID

Dextrose 5% in Ringers injection

Dextrose 5% in sodium chloride 0.9%

Ringers injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate (1/6) M

Cisplatin with etoposide

Amphotericin B cholesteryl sulfate complex

Doxorubicin HCl liposome injection

Piperacillin sodiumtazobactam sodium

Also has immunosuppressive activity. 112 144 146

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

Advise that alopecia is likely. 1

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

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

141. Reviewers comments (personal observations).

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

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

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