No

Antineoplastic Agent, Alkylating Agent

In combination with certain other antineoplastics in treatment of lung cancer, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, acute and chronic lymphocytic leukemia, ovarian cancer, testicular cancer, and sarcomas, pancreatic and gastric carcinoma, osteosarcoma

D

Patients who have demonstrated a previous hypersensitivity to ifosfamide; patients with severely depressed bone marrow function

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. May require therapy cessation if confusion or coma occurs; be aware of hemorrhagic cystitis and severe myelosuppression. Use with caution in patients with impaired renal function or those with compromised bone marrow reserve.

>10%:

Central nervous system: Somnolence, confusion, hallucinations in 12% and coma (rare) have occurred and are usually reversible; usually occur with higher doses or in patients with reduced renal function; depressive psychoses, polyneuropathy

Dermatologic: Alopecia occurs in 50% to 83% of patients 2-4 weeks after initiation of therapy; may be as high as 100% in combination therapy

Gastrointestinal: Nausea and vomiting in 58% of patients is dose and schedule related (more common with higher doses and after bolus regimens); nausea and vomiting can persist up to 3 days after therapy; also anorexia, diarrhea, constipation, transient increase in LFTs and stomatitis noted.

Emetic potential: Moderate (58%)

Time course of nausea/vomiting: Onset: 2-3 hours; Duration: 12-72 hours

Genitourinary: Hemorrhagic cystitis has been frequently associated with the use of ifosfamide. A urinalysis prior to each dose should be obtained. Ifosfamide should never be administered without a uroprotective agent (MESNA). Hematuria has been reported in 6% to 92% of patients. Renal toxicity occurs in 6% of patients and is manifested as an increase in BUN or serum creatinine and is most likely related to tubular damage. Renal toxicity, including ARF, may occur more frequently with high-dose ifosfamide. Metabolic acidosis may occur in up to 31% of patients.

1% to 10%:

Dermatologic: Phlebitis, dermatitis, nail ridging, skin hyperpigmentation, impaired wound healing

Endocrine & metabolic: SIADH

Hematologic: Myelosuppression: Less of a problem than with cyclophosphamide if used alone. Leukopenia is mild to moderate, thrombocytopenia and anemia are rare. However, myelosuppression can be severe when used with other chemotherapeutic agents or with high-dose therapy. Be cautious with patients with compromised bone marrow reserve.

WBC: Moderate

Platelets: Mild

Onset (days): 7

Nadir (days): 10-14

Hepatic: Elevated liver enzymes

Respiratory: Nasal congestion, pulmonary fibrosis

Miscellaneous: Immunosuppression, sterility, possible secondary malignancy, allergic reactions

<1%: Cardiotoxicity, pulmonary toxicity

Symptoms of overdose include myelosuppression, nausea, vomiting, diarrhea, alopecia; direct extension of the drug's pharmacologic effect

Treatment is supportive

CYP2B6 and 3A3/4 enzyme substrate

Store intact vials at room temperature or under refrigeration

Dilute powder with SWI or NS to a concentration of 50 mg/mL as follows. Do not use bacteriostatic SWI or NS - incompatible; solution is stable for 7 days at room temperature and 6 weeks under refrigeration

1 g vial = 20 mL

3 g vial = 60 mL

Further dilution in NS, D₅W or LR is stable for 7 days at room temperature and 6 weeks under refrigeration

Compatible with mesna in NS for up to 9 days at room temperature

Standard I.V. dilution:

I.V. push: Dose/syringe (concentration = 50 mg/mL)

Maximum syringe size for IVP is a 30 mL syringe and syringe should be less than or equal to 75% full

IVPB: Dose/100-1000 mL D₅W or NS

Syringe and IVPB are stable for 7 days at room temperature and 6 weeks under refrigeration

Causes cross-linking of strands of DNA by binding with nucleic acids and other intracellular structures; inhibits protein synthesis and DNA synthesis; an analogue of cyclophosphamide, and like cyclophosphamide, it undergoes activation by microsomal enzymes in the liver. Ifosfamide is metabolized to active compounds, ifosfamide mustard, and acrolein

Pharmacokinetics are dose-dependent

Bioavailability: Estimated at 100%

Distribution: V_d: Has been calculated to be 5.7-49 L; does penetrate CNS, but not in therapeutic levels

Protein binding: Not appreciably protein bound

Metabolism: In the liver to active species; requires biotransformation in the liver before it can act as an alkylating agent; the metabolite acrolein is the toxic agent implicated in the development of hemorrhagic cystitis

Half-life: Beta phase: 11-15 hours with high-dose (3800-5000 mg/m²) or 4-7 hours with lower doses (1800 mg/m²)

Elimination: 15% to 50% excreted unchanged in urine

I.V. (refer to individual protocols):

Adults:

Doses may be given as 50 mg/kg/day or 700-2000 mg/m²/day for 5 days

Alternatives include 2400 mg/m²/day for 3 days or 5000 mg/m² as a single dose

Doses of 700-900 mg/m²/day for 5 days may be given IVP; courses may be repeated every 3-4 weeks

To prevent bladder toxicity, ifosfamide should be given with extensive hydration consisting of at least 2 L of oral or I.V. fluid per day. A protector, such as mesna, should also be used to prevent hemorrhagic cystitis. The dose-limiting toxicity is hemorrhagic cystitis and ifosfamide should be used in conjunction with a uroprotective agent.

Dosing adjustment in renal impairment:

S_cr >3.0 mg/dL: Withhold drug

S_cr 2.1-3.0 mg/dL: Reduce dose by 25% to 50%

Dosing adjustment in hepatic impairment: Although no specific guidelines are available, it is possible that higher doses are indicated in hepatic disease. One author [Falkson G, et al, "An extended phase II trial of ifosfamide plus mesna in malignant mesothelioma," Invest New Drugs: 1992;10:337-343.] recommended the following dosage adjustments:

AST >300 or bilirubin >3.0 mg/dL: Decrease ifosfamide dose by 75%

CBC with differential, hemoglobin, and platelet count, urine output, urinalysis, liver function, and renal function tests

Sedation, confusion, and hallucinations are common

May cause myelosuppression; use caution with clozapine and carbamazepine; barbiturates and chloral hydrate may increase the metabolism of ifosfamide

No information available to require special precautions

No effects or complications reported

This drug can only be administered I.V. Report immediately any pain, stinging, or burning at infusion site. It is vital to maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) for 3 days prior to infusion and each day of therapy. May cause hair loss (will grow back); nausea or vomiting (consult prescriber for antiemetic medication); and you will be susceptible to infection (avoid crowds and exposure to infection). Report immediately pain or irritation on urination, severe diarrhea, CNS changes (eg, hallucinations, confusion, somnolence), signs of opportunistic infection (eg, fever, chills, easy bruising or unusual bleeding), difficulty breathing, swelling of extremities, or any other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Mesna to be used concomitantly for prophylaxis against hemorrhagic cystitis

Powder for injection: 1 g, 3 g

Brade WP, Herdrich K, Kachel-Fischer U, et al, "Dosing and Side-Effects of Ifosfamide Plus Mesna," J Cancer Res Clin Oncol, 1991, 117(Suppl 4):S164-86.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Lotz JP, Bouleuc C, Andre T, et al, "Tandem High-Dose Chemotherapy With Ifosfamide, Carboplatin, and Teniposide With Autologous Bone Marrow Transplantation for the Treatment of Poor Prognosis Common Epithelial Ovarian Carcinoma," Cancer, 1996, 77(12):2550-9.

Ninane J, Baurain R, and de Kraker J, "Alkylating Activity in Serum, Urine, and CSF Following High-Dose Ifosfamide in Children," Cancer Chemother Pharmacol, 1989, 24(Suppl 1):S2-6.

Pinkerton CR, Rogers H, James C, et al, "A Phase II Study of Ifosfamide in Children With Recurrent Solid Tumors," Cancer Chemother Pharmacol, 1985, 15(3):258-62.

Sarosy G, "Ifosfamide - Pharmacologic Overview," Semin Oncol, 1989, 16(1 Suppl 3):2-8.

Wagner T, "Ifosfamide Clinical Pharmacokinetics," Clin Pharmacokinet, 1994, 26(6):439-56.

Wilson WH, Jain V, Bryant G, et al, "Phase I and II Study of High-Dose Ifosfamide, Carboplatin, and Etoposide With Autologous Bone Marrow Rescue in Lymphomas and Solid Tumors," J Clin Oncol, 1992, 10(11):1712-22.