Cyclophosphamide for injection - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections.

Close hematological monitoring is required. • Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur.

Urotoxicity can be fatal.

Exclude or correct any urinary tract obstructions prior to treatment. • Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported.

Monitor patients, especially those with risk factors for cardiotoxicity or pre-existing cardiac disease. • Pulmonary Toxicity: Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur.

Monitor patients for signs and symptoms of pulmonary toxicity. • Secondary malignancies • Veno-occlusive Liver Disease: Fatal outcome can occur. • Embryo-Fetal Toxicity: Can cause fetal harm.

Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock.

Latent infections can be reactivated [ see Adverse Reactions ].

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician.

In case of neutropenic fever, antibiotic therapy is indicated.

Antimycotics and/or antivirals may also be indicated.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed.

Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3.

Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection.

G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use.

Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications.

The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment.

Peripheral blood cell counts are expected to normalize after approximately 20 days.

Bone marrow failure has been reported.

Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

5.2 Urinary Tract and Renal Toxicity Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide.

Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis.

Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis.

Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy.

Urotoxicity can be fatal.