Ifosfamide

Brand Names: Ifosfamide

Drug Class: Alkylating Drug

Overview

11 DESCRIPTION Ifosfamide for Injection (ifosfamide for injection, USP) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile ifosfamide. Ifosfamide is a alkylating drug chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide.

Mechanism of Action

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4‑hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard isophosphoramide mustard. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death. 12.

Indications

  • 1 INDICATIONS AND USAGE Ifosfamide for Injection is indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. Ifosfamide for Injection is an alkylating drug indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. ( 1 )

Common Doses

  • 20 mL
  • 50 mg
  • 60 mL
  • 20 mg

Dosage

2 DOSAGE AND ADMINISTRATION • Administer Ifosfamide for Injection with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity. ( 2.1 , 5.3 ) • Administer mesna with Ifosfamide for Injection to reduce the incidence or severity of hemorrhagic cystitis. ( 2.1 , 5.3 ) • Administer Ifosfamide for Injection as a slow intravenous infusion (at least 30 minutes) at a dose of 1.2 grams per m 2 per day for 5 consecutive days. Repeat every 3 weeks or after recovery from hematologic toxicity. ( 2.

Black Box Warning

WARNING: MYELOSUPPRESSION, ENCEPHALOPATHY, NEPHROTOXICITY and UROTOXICITY • Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle [see Warnings and Precautions (5.1) ]. • Encephalopathy can be severe and may result in death. Monitor for CNS toxicity and discontinue treatment for encephalopathy [see Warnings and Precautions (5.2) ]. • Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe and can be reduced by the prophylactic use of mesna [see Warnings and Precautions (5.3) ].

Contraindications

  • 4 CONTRAINDICATIONS Ifosfamide for Injection is contraindicated in patients with: • Known hypersensitivity to administration of ifosfamide. • Urinary outflow obstruction. • Known hypersensitivity to administration of ifosfamide. ( 4 ) • Urinary outflow obstruction. ( 4 )

Side Effects

  • 6 ADVERSE REACTIONS The most common (≥ 10%) adverse reactions were alopecia, nausea/vomiting, hematuria, leukopenia, anemia, CNS toxicity, infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at phone: 1 866 888 2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical...

Interactions

  • 7 DRUG INTERACTIONS • CYP3A4 Inducers: Monitor for increased toxicity when used in combination with CYP3A4 inducers. ( 7.1 ) • CYP3A4 Inhibitors: Use in combination with CYP3A4 inhibitors could decrease the effectiveness of ifosfamide. ( 7.2 ) 7.1 Inducers of CYP3A4 CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment. 7.