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Ifex (Ifosfamide) - Warnings and Precautions

 
 



WARNING: MYELOSUPPRESSION, NEUROTOXICITY, and UROTOXICITY

Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle. CNS toxicities can be severe and result in encephalopathy and death. Monitor for CNS toxicity and discontinue treatment for encephalopathy. 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 (5.1-5.3)]

 

WARNINGS AND PRECAUTIONS

Myelosuppression, Immunosuppression, and Infections

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When IFEX is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.

Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, IFEX should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.

IFEX should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Central Nervous System Toxicity, Neurotoxicity

Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following IFEX therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.

Ifosfamide neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation. Symptoms may persist for longer periods of time. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued.

Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy.

Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery.

Renal and Urothelial Toxicity and Effects

Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.

Monitor serum and urine chemistries, including phosphorus and potassium regularly. Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.

Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide.

Tubular damage may become apparent during therapy, months or even years after cessation of treatment. Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of ifosfamide treatment.

The risk and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.

Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of IFEX. These urotoxic effects can be reduced by prophylactic use of mesna.

Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after a single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis.

Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions [see  Contraindications (4) ].

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force dieresis in order to reduce the risk of urinary tract toxicity. Obtain a urinalysis prior to each dose of IFEX. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of IFEX should be given with vigorous oral or parenteral hydration.

Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.

Cardiotoxicity

Manifestations of cardiotoxicity reported with ifosfamide treatment include:

  • •Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia
  • •Decreased QRS voltage and ST-segment or T-wave changes
  • •Toxic cardiomyopathy leading to heart failure with congestion and hypotension
  • •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.

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.

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.

Veno-occlusive Liver Disease

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

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].

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.

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.

Impairment of Wound Healing

Ifosfamide may interfere with normal wound healing.

Nursing

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

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D.

[See Warnings and Precautions].

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.

Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.

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.

Nursing Mothers

Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women must not breastfeed during treatment with ifosfamide.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics]. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.

Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Use in Patients with Renal Impairment

No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable.

Use in Patients with Hepatic Impairment

No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. IFEX should be given cautiously to patients with impaired hepatic function.

Page last updated: 2014-08-28

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