IFOSFAMIDE Drug Interactions: What You Need to Know

INTERACTIONS Ifosfamide is a substrate for both CYP3A4 and CYP2B6.

• 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 (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St.

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Wort) 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.

7.2 Inhibitors of CYP3A4 CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

7.1 Inducers of CYP3A4 CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St.

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Wort) 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.

7.2 Inhibitors of CYP3A4 CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

CONTRAINDICATIONS Continued use of Ifosfamide for Injection is contraindicated in patients with severely depressed bone marrow function (see WARNINGS and PRECAUTIONS sections). Ifosfamide for Injection is also contraindicated in patients who have demonstrated a previous hypersensitivity to it.

AND PRECAUTIONS

• Myelosuppression: Can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after treatment. (5.1)
• Neurotoxicity: Severe and fatal neurotoxicity can occur. Carefully monitor the patient for CNS toxicity and other neurotoxic effects. Discontinue therapy should encephalopathy develop. (5.2)
• Urotoxicity: Severe nephrotoxicity with renal failure and death can occur. Monitor for nephrotoxicity with serum and urine chemistries. Mesna should be used to reduce hemorrhagic cystitis. (5.3)
• Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Use with caution in patients with cardiac risk factors and in patients with preexisting cardiac disease. The risk of cardiotoxicity is dose dependent. (5.4)
• Pulmonary toxicity: Interstitial pneumonitis, pulmonary fi brosis, and other forms of pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated (5.5)
• Secondary malignancies as late sequelae have occurred. (5.6)
• Pregnancy: Can cause fetal harm. Women should not become pregnant and men should not father a child during therapy. (5.8)
• Anaphylactic/anaphylactoid reactions have been reported. (5.10)

5.1 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 ifosfamide 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, ifosfamide should not be given to patients with a WBC count below 2000/μL and/or a platelet count below 50,000/μL. Ifosfamide 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.

5.2 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 ifosfamide therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use. Ifosfamide neurotoxicity may manifest within a few hours to a few days after fi rst 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.

5.3 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 ifosfamide. 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 <span class="opacity-50 text-xs">[see Contraindications (4)]</span> . 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 ifosfamide. 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 ifosfamide 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.

5.4 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.

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 Ifosfamide 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> .

5.1 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 ifosfamide 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, ifosfamide should not be given to patients with a WBC count below 2000/μL and/or a platelet count below 50,000/μL. Ifosfamide 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.

5.2 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 ifosfamide therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use. Ifosfamide neurotoxicity may manifest within a few hours to a few days after fi rst 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.

5.3 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 ifosfamide. 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 <span class="opacity-50 text-xs">[see Contraindications (4)]</span> . 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 ifosfamide. 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 ifosfamide 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.

5.4 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.

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 Ifosfamide 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> .