). • 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 […]