Carcinoma of the breast. Nonmalignant Disease Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children: Cyclophosphamide is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid thera py or in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects, cyclophosphamide may induce a remission. Cyclophosphamide is not indicated for the nephrotic syndrome in adults or for any other renal disease.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 123 page 2 of 9CONTRAINDICATIONS Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it. See WARNINGS and PRECAUTIONSsections. WARNINGS Carcinogenesis, Mutagenesis, and Impairment of Fertility Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoprolifera tive malignancies. Second malignancies most frequently were detected in patients treated for primary myeloproliferative orlymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. In a singlebreast cancer trial utilizing two to four times the standard dose of cyclophosphamide in conjunction with doxorubicin a small n umber of cases of secondary acute myeloid leukemia occurred within two years of treatment initiation. Urinary bladder malignanciesgenerally have occurred in patients who previously had hemorrhagic cystitis. In patients treated with cyclophosphamide-containingregimens for a variety of solid tumors, isolated case reports of secondary malignancies have been published. One case of carcin oma of the renal pelvis was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility ofcyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have been reportedfollowing cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants and a six-month old fetus bornto women treated with cyclophosphamide. Ectrodactylia was found in two of the three cases. Normal infants have also been born towomen treated with cyclophosphamide during pregnancy, including the first trimester. If this drug is used during pregnancy, or if thepatient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetu s. Women of childbearing potential should be advised to avoid becoming pregnant.Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterilityappears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatm ent. Cyclophosphamide-induced sterility may be irreversible in some patients.Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of womentreated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy.Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and haveregular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in lateprepubescence has been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived.Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normaltestosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with cyclophosphamide duringprepubescence develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increasedgonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in somepatients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile bycyclophosphamide have subsequently fathered normal children. Urinary System Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. Rarely, this condition can be severe and even fatal . Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without accompanying cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These adverse effects appear to depend on the dose of cyclophosphamide and th e duration of therapy. Such bladder injury is thought to be due to cyclophosphamide metabolites excreted in the urine. Forced fluidintake helps to assure an ample output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder.This helps to prevent cystitis. Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it maypersist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually necessary to discontinue cyclophosphamide therapy in instances of severe hemorrhagic cystitis. Cardiac Toxicity Although a few instances of cardiac dysfunction have been reported following use of recommended doses of cyclophosphamide, no causal relationship has been established. Acute cardiac toxicity has been reported with doses as low as 2.4 g/m 2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few instances with high doses of cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the first cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis.