Ifosfamide

Bone marrow suppression may occur (may be severe and lead to fatal infections); monitor blood counts before and after each cycle. Leukopenia, neutropenia, thrombocytopenia, and anemia are associated with ifosfamide. Myelosuppression is dose dependent, increased with single high doses (compared to fractionated doses) and increased with decreased renal function. Severe myelosuppression may occur when administered in combination with other chemotherapy agents or radiation therapy. Use with caution in patients with compromised bone marrow reserve. Unless clinically necessary, avoid administering to patients with WBC 3 and platelets 3. Bleeding events due to thrombocytopenia may occur. Antimicrobial prophylaxis may be necessary in some neutropenic patients; administer antibiotics and/or antifungal agents for neutropenic fever.

Ifosfamide-induced cardiotoxicity has been reported; may be fatal. Arrhythmias (eg, atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia), ST-segment or T-wave changes, cardiomyopathy, pericardial effusion, pericarditis, and epicardial fibrosis have been observed. The risk for cardiotoxicity is dose-dependent; concomitant cardiotoxic agents (eg, anthracyclines), irradiation of the cardiac region, and renal impairment may also increase the risk. Use with caution in patients with cardiac risk factors or pre-existing cardiac disease. In a scientific statement from the American Heart Association, ifosfamide has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

May cause CNS toxicity which may be severe, resulting in encephalopathy and death; monitor for CNS toxicity; discontinue for encephalopathy. Symptoms of CNS toxicity (somnolence, confusion, dizziness, disorientation, hallucinations, cranial nerve dysfunction, psychotic behavior, extrapyramidal symptoms, seizures, coma, peripheral neuropathy, blurred vision, and/or urinary incontinence) have been observed within a few hours to a few days after initial dose, and generally resolve within 2 to 3 days of treatment discontinuation (although symptoms may persist longer); maintain supportive care until complete resolution. Recurrence of CNS toxicity (after several cycles with no CNS incidents) has been reported. Risk factors for CNS toxicity may include hypoalbuminemia, renal dysfunction, and high-dose antiemetic therapy. Concomitant centrally-acting medications may result in additive CNS effects. Peripheral neuropathy has been reported.

Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

Hemorrhagic cystitis may occur (may be severe); concomitant mesna reduces the risk of hemorrhagic cystitis. Hydration (at least 2 L/day in adults), dose fractionation, and/or mesna administration will reduce the incidence of hematuria and protect against hemorrhagic cystitis. Obtain urinalysis prior to each dose; if microscopic hematuria is detected, withhold until complete resolution. Exclude or correct urinary tract obstructions prior to treatment. Use with caution (if at all) in patients with active urinary tract infection. Hemorrhagic cystitis is dose-dependent and is increased with high single doses (compared with fractionated doses); past or concomitant bladder radiation or busulfan treatment may increase the risk for hemorrhagic cystitis.

Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive disease (VOD), has been reported with ifosfamide-containing regimens.

Anaphylactic/anaphylactoid reactions have been associated with ifosfamide. Cross sensitivity with similar agents may occur.

May cause significant suppression of the immune responses; may lead to serious infection, sepsis or septic shock. Reported infections have included bacterial, viral, fungal, and parasitic; latent viral infections may be reactivated. Use with caution with other immunosuppressants or in patients with infection.

Interstitial pneumonitis, pulmonary fibrosis, and pulmonary toxicity leading to respiratory failure (may be fatal) have been reported. Monitor for signs and symptoms of pulmonary toxicity.

May cause severe nephrotoxicity, resulting in renal failure. Nephrotoxicity may be fatal. Acute and chronic renal failure, as well as renal parenchymal and tubular necrosis (including acute), have been reported; tubular damage may be delayed (months to years) and may persist. Renal manifestations include decreased glomerular rate, increased creatinine, proteinuria, enzymuria, cylindruria, tubular acidosis, aminoaciduria, phosphaturia, and glycosuria. Syndrome of inappropriate antidiuretic hormone (SIADH), renal rickets, and Fanconi syndrome have been reported. Evaluate renal function prior to and during treatment; monitor urine for erythrocytes and signs of urotoxicity.

Secondary malignancies may occur (onset may be delayed); the risk for myelodysplastic syndrome (which may progress to acute leukemia) is increased with treatment.

May interfere with wound healing. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Use with caution in patients with prior radiation therapy.