Leukopenia 2. Thrombocytopenia3. Tumor cell infiltration of bone marrow4. Previous X-ray therapy5. Previous therapy with other cytotoxic agents6. Impaired hepatic function7. Impaired renal function Laboratory Tests During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to d etermine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis. Drug Interactions The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of hi gh doses of phenobarbital. The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even thoughcyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride.If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted. Adrenalectomy Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient. Wound Healing Cyclophosphamide may interfere with normal wound healing. Carcinogenesis, Mutagenesis, and Impairment of Fertility See WARNINGS section for information on carcinogenesis, mutagenesis, and impairment of fertility. Pregnancy Pregnancy Category D—See WARNINGS section. Nursing Mothers Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for cyclophosphamide in humans, a decision should be made whether to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 125 page 4 of 9Pediatric Use The safety profile of cyclophosphamide in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS section). Geriatric Use Insufficient data from clinical studies of cyclophosphamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determin e whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared withpaclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients whoreceived cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, publishedreports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketingexperience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for anelderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patientresponse (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases). ADVERSE REACTIONS Information on adverse reactions associated with the use of cyclophosphamide is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are describe d in the WARNINGS section. Reproductive System See WARNINGS section for information on impairment of fertility. Digestive System Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring durin g therapy. These adverse drug effects generally remit when cyclophosphamide treatment is stopped. Skin and Its Structures Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event repor ting, a definitive causal relationship to cyclophosphamide has not been established. Hematopoietic System Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and lessfrequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with areduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.Thrombocytopenia or anemia develop occasionally in patients treated with cyclophosphamide. These hematologic effects usually ca n be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days aftercessation of therapy. Urinary System See WARNINGS section for information on cystitis and urinary bladder fibrosis. Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclophosphamide. Such lesionsusually resolve following cessation of therapy. Infections See WARNINGS section for information on reduced host resistance to infections. Carcinogenesis See WARNINGS section for information on carcinogenesis. Respiratory System Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 126 page 5 of 9Other Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitiv ity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience. OVERDOSAGE No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur. DOSAGE AND ADMINISTRATION Treatment of Malignant Diseases Adults and Children When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficienc y usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly.Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord withevidence of antitumor activity and/or leukopenia.