IFEX

4 Administration). 1 Dosing Considerations Chemotherapy with IFEX (ifosfamide), as with other drugs used in cancer chemotherapy, is potentially hazardous and fatal complications can occur. It is recommended that it be administered only by physicians aware of the associated risks.

Dosage must be individualized. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and Monitoring and Laboratory Tests).

IFEX (ifosfamide) should be given cautiously to patients with any of the following conditions: • Prior radiotherapy • Prior therapy with other cytotoxic agents • Extensive bone marrow metastases • Brain metastases • Reduced nephron reserve • Impaired renal function • Hepatic impairment Prior to initiating treatment, it is necessary to exclude or correct any electrolyte imbalances (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and Monitoring and Laboratory Tests).

The cytotoxic effect of ifosfamide occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue injury from accidental paravenous administration is low. In case of accidental paravenous administration of ifosfamide, the infusion should be stopped immediately, the extravascular ifosfamide solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate.

2 Recommended Dose and Dosage Adjustment The therapeutic administration of IFEX should invariably be accompanied by uroprotective treatment with mesna. For dosing instructions with mesna, please see the corresponding Product Monograph.

The recommended dosage is 2000-2400 mg/m2 per day over a period of a minimum of 30 minutes, on 5 consecutive days. If a lower daily dosage or the total dosage over a longer period is indicated, IFEX can be given every other day (days 1, 3, 5, 7 and 9) or on 10 consecutive days in lower doses.

The administration of high single dose infusions is feasible up to 5000-8000 mg/m2/24 h under protection of continuous mesna infusion to reduce the risk of urotoxicity. A treatment series should be repeated after an interval of not less than 3-4 weeks.

4 Drug-Drug Interactions). For information on use in patients with hepatic impairment, see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic. For monitoring and dose adjustment in elderly patients, see 7 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics.

Health Canada has not authorized an indication for pediatric use. Dose Adjustments for Adverse Drug Reactions If CNS toxicity develops, administration of ifosfamide should be discontinued, see 7 WARNINGS AND PRECAUTIONS, Neurologic.

3 Reconstitution Parenteral Products: Reconstitute with Sterile Water for Injection as follows: Table - Reconstitution Vial Size Volume of Diluent to be Added to Vial Approximate Available Volume Concentration per mL 1 g 20 mL 20 mL 50 mg/mL 3 g 60 mL 60 mL 50 mg/mL The pH of freshly reconstituted 5% w/v solutions usually range from 4 to 7.

V.

Infusion:

Shake well until dissolved. v. infusion listed below. V. 9% Sodium Chloride, USP Lactated Ringer’s Injection, USP NOTE: Product should be inspected visually for particulate matter and discoloration prior to administration. See 12 SPECIAL HANDLING INSTRUCTIONS.

See 11 STORAGE, STABILITY AND DISPOSAL. 4 Administration Prevention of Cystitis The concomitant administration of mesna helps to prevent the urotoxic side effects of IFEX which had previously limited the drug’s therapeutic use. Every IFEX regimen should be accompanied by uroprotective treatment with mesna.

Mesna is usually given by intravenous injection concurrently with IFEX and 4 and 8 hours afterwards, each dose being 20% of the IFEX dose (see mesna Product Monograph for dosage and administration). During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity (see 7 WARNINGS AND PRECAUTIONS).

If urinary excretion appears insufficient a fast-acting diuretic such as furosemide may be administered. 5 Missed Dose If a dose is delayed or missed, the patient should return to be assessed by the physician as soon as possible and continue treatment depending on physician’s discretion.

). • Fertility Animal data generated with cyclophosphamide, another oxazaphosphorine cytotoxic agent indicate that exposure of oocytes during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations (see 16 NON- CLINICAL TOXICOLOGY).

This effect should be considered in case of intended fertilization or pregnancy after discontinuation of ifosfamide therapy. The exact duration of follicular development IFEX (Ifosfamide for Injection) Page 14 of 39 Protected B / Protégé B in humans is not known, but may be longer than 12 months.

Sexually active women and men should use effective methods of contraception during these periods of time. Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility in both sexes have been reported.

Development of sterility appears to depend on the dose of ifosfamide, duration of therapy and the state of gonadal function at the time of treatment. Sterility may be irreversible in some patients. • Function Female Patients Amenorrhea has been reported in patients treated with ifosfamide.

In addition, with cyclophosphamide, another oxazaphosphorine cytotoxic agent, oligomenorrhea has been reported. The risk of permanent chemotherapy-induced amenorrhea is increased in older women. Girls treated with ifosfamide during prepubescence may develop secondary sexual characteristics normally and have regular menses.

Girls treated with ifosfamide during prepubescence subsequently have conceived. Girls who have retained ovarian function after completing treatment are at increased risk of developing premature menopause. Male Patients Men treated with ifosfamide may develop oligospermia or azoospermia.

Sexual function and libido generally are unimpaired in these patients. Boys treated with ifosfamide during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Some degree of testicular atrophy may occur.

Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Men treated with ifosfamide have subsequently fathered children. • Teratogenic Risk If ifosfamide is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus (see 16 NON- CLINICAL TOXICOLOGY).

Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. In addition, exposure to cyclophosphamide, another oxazaphosphorine cytotoxic agent, has been reported to cause miscarriage, malformations (following exposure during the first trimester), and neonatal effects, including leukopenia, pancytopenia, severe bone marrow hypoplasia, gastroenteritis and potential malignancies in offspring.

The following adverse reactions have been reported with another oxazaphosphorine cytostatic agent: intrauterine death, fetal malformation, fetal toxicity (including myelosuppression, gastroenteritis), premature labor, testicular atrophy, oligomenorrhea.

Respiratory Interstitial pneumonitis and pulmonary fibrosis have been reported with ifosfamide treatment. Other forms of pulmonary toxicity have also been reported. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has been reported.

IFEX (Ifosfamide for Injection) Page 15 of 39 Protected B / Protégé B Sensitivity/Resistance Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide. Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

Skin Alopecia is a very common, dose-dependent effect of ifosfamide administration. Chemotherapy- induced alopecia may progress to baldness. The hair can grow back, though it may be different in texture or color. 1 Pregnant Women IFEX (ifosfamide) can be teratogenic or cause fetal resorption in experimental animals.

The administration of ifosfamide during organogenesis has been shown to have a fetotoxic effect in mice, rats and rabbits and therefore may cause fetal damage when administered to pregnant women. It should not be used in pregnancy, particularly in early pregnancy, unless in the judgement of the physician the potential benefits outweigh the possible risk.

2 Breast-feeding As is the case with the oxazaphosphorine class of alkylating agents, IFEX is excreted in breast milk and breast feeding should be terminated prior to institution of IFEX therapy. Ifosfamide toxicity may occur in a breast-fed child.

These toxicities include neutropenia, thrombocytopenia, low hemoglobin, and diarrhea. 3 Pediatrics Pediatrics (<16 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

4 Geriatrics Geriatrics (> 65 years of age): In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.

A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age.

3 Pharmacokinetics, Geriatrics). 1 Adverse Reaction Overview The most common adverse reactions due to ifosfamide include alopecia; nausea and vomiting; hemorrhagic cystitis and hematuria; renal dysfunction and renal structural damage; and myelosuppression manifested by anemia, leukopenia, and thrombocytopenia.

In addition central IFEX (Ifosfamide for Injection) Page 16 of 39 Protected B / Protégé B nervous […]

, Hepatic/Biliary/Pancreatic 11/2024 7 WARNINGS AND PRECAUTIONS, Neurologic 11/2024 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential 11/2024 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2 TABLE OF CONTENTS ..............................................................................................................

2 PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4 1 INDICATIONS ...............................................................................................................

4 2 CONTRAINDICATIONS ................................................................................................. 4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5 4 DOSAGE AND ADMINISTRATION .................................................................................

7 5 OVERDOSAGE.............................................................................................................. 7 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8 7 WARNINGS AND PRECAUTIONS ..................................................................................

15 8 ADVERSE REACTIONS ................................................................................................ 19 9 DRUG INTERACTIONS ................................................................................................

26 10 CLINICAL PHARMACOLOGY ....................................................................................... 27 11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 27 12 SPECIAL HANDLING INSTRUCTIONS ...........................................................................

28 PART II: SCIENTIFIC INFORMATION ....................................................................................... 29 13 PHARMACEUTICAL INFORMATION ............................................................................

29 15 MICROBIOLOGY ........................................................................................................ 29 16 NON-CLINICAL TOXICOLOGY .....................................................................................

29 PATIENT MEDICATION INFORMATION .................................................................................. 32 IFEX (Ifosfamide for Injection) Page 4 of 39 Protected B / Protégé B PART I: HEALTH PROFESSIONAL INFORMATION 1 INDICATIONS IFEX (ifosfamide) is indicated for: • Soft Tissue Sarcoma • first-line single agent therapy • second-line single agent therapy in patients who have failed to respond or who have relapsed on other chemotherapeutic regimens.

• Pancreatic Carcinoma • second-line single agent therapy in patients who have failed to respond or who have relapsed on other chemotherapeutic regimens. • Cervical Carcinoma • […]

• IFEX is contraindicated in patients with: • a hypersensitivity to this drug or to any ingredient in the formulation, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING • severe myelosuppression • severe renal impairment • severe hepatic impairment • an active infection (bacterial, fungal, viral)/severe immunosuppression • urinary tract disease (cystitis, obstructions to the urine flow) • advanced cerebral arteriosclerosis See also 7 WARNINGS AND PRECAUTIONS.

IFEX (Ifosfamide for Injection) Page 5 of 39 Protected B / Protégé B