IFEX (Page 2 of 6)

5.4 Cardiotoxicity

Manifestations of cardiotoxicity reported with ifosfamide treatment include:

1.

Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia

2.

Decreased QRS voltage and ST-segment or T-wave changes

3.

Toxic cardiomyopathy leading to heart failure with congestion and hypotension

4.

Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis

Fatal outcome of ifosfamide-associated cardiotoxicity has been reported.

The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.

5.5 Pulmonary Toxicity

Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.

5.6 Secondary Malignancies

Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.

The secondary malignancy may develop several years after chemotherapy has been discontinued.

5.7 Veno-occlusive Liver Disease

Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide.

5.8 Pregnancy

IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells. Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose.

Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug 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 Use in Specific Populations (8.1)].

5.9 Effects on Fertility

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 state of gonadal function at the time of treatment. Sterility may be irreversible in some patients.

Female Patients

Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.

Male Patients

Men treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children.

5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity

Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide.

Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

5.11 Impairment of Wound Healing

Ifosfamide may interfere with normal wound healing.

5.12 Nursing

Ifosfamide is excreted in breast milk. Women must not breastfeed during treatment with ifosfamide [ see Use in Specific Populations (8.3)].

6 ADVERSE REACTIONS

6.1 Adverse Reactions from Clinical Trials

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 practice. The adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m² per course.

* The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below. † Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported. ‡ Includes cases reported as anemia and decrease in hemoglobin/hematocrit. § Encephalopathy with coma and death has been reported. ¶ Central nervous system toxicity was reported to be manifested by the following signs and symptoms: Abnormal behavior, Affect lability Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar syndrome, Cerebral function deficiency, Cognitive disorder, Coma, Confusional state, Convulsions, Cranial nerve dysfunction, Depressed state of consciousness, Depression, Disorientation, Dizziness, Electroencephalogram abnormal, Encephalopathy, Flat affect. Hallucinations, Headache, Ideation, Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms, Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction, Restlessness, Somnolence, Tremor, Urinary incontinence. # Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported. Þ Hypotension leading to shock and fatal outcome has been reported. ß Hepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome. à Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria. See also Post-marketing Adverse Reactions (6.2). è Renal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria. ð Includes cases reported as phlebitis and irritation of the venous walls. ø Includes cases reported as granulocytopenic fever.
System Organ Class (SOC)		Adverse Reaction	Percentage (Ratio)
INFECTIONS AND INFESTATIONS		Infection	9.9% (112/1128)
BLOOD AND LYMPHATIC SYSTEM DISORDERS		Leukopenia * (any)	—
		Leukopenia <1 x 103 /µL	43.5% (267/614)
		Thrombocytopenia † (any)	—
		Thrombocytopenia, 50 x 103 /µL	4.8% (35/729)
		Anemia ‡	37.9% (202/533)
METABOLISM AND NUTRITION DISORDERS		Anorexia	1.1% (15/1317)
NERVOUS SYSTEM DISORDERS		Central nervous system toxicity §, ¶	15.4% (154/1001)
		Peripheral neuropathy	0.4% (5/1317)
CARDIAC DISORDERS		Cardiotoxicity #	0.5% (7/1317)
VASCULAR DISORDERS		Hypotention Þ	0.3% (4/1317)
GASTROINTESTINAL DISORDERS		Nausea/Vomiting	46.8% (443/964)
		Diarrhea	0.7% (9/1317)
		Stomatitis	0.3% (4/1317)
HEPATOBILIARY DISORDERS		Hepatotoxicity ß	1.8% (22/1190)
SKIN AND SUBCUTANEOUS TISSUES DISORDERS		Alopecia	89.6% (540/603)
		Dermatitis	0.08% (1/1317)
		Papular rash	0.08% (1/1317)
RENAL AND URINARY DISORDERS		Hemorrhagic cystitis à	—
		Hematuria
		— without mesna	44.1% (282/640)
		— with mesna	21.3% (33/155)
	Macrohematuria
	— without mesna		11.1% (66/594)
	— with mesna		5.2% (5/97)
	Renal dysfunction è		—
	Renal structural damage		—
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS	Phlebitis ð		2.8% (37/1317)
	Neutropenic fever ø		1.0% (13/1317)
	Fatigue		0.3% (4/1317)
	Malaise		Unable to calculate