5 . 7 Food and Drug Administration (FDA) All reporting to the FDA will be completed by the IND Sponsor. 7. 5 . 7 .1 Expedited IND Safety Reports 7 Calendar - Day Telephone or Fax Report : The IND Sponsor is required to notify the FDA of any fatal or life - threatening adverse event that is unexpected and assessed by the investigator to be possibly related to the investigational agent. Such reports are to be telephoned or faxed to the FDA within 7 calendar days of first learning of the event. Follow - up information will be submitted to the FDA as soon as relevant information is available. 15 Calendar - Day Written Report : The IND Sponsor is required to notify the FDA of any SAE that is unexpected and related to the investigational agent in a written IND Safety Report. Written IND Safety Reports should include an Analysis of Similar Events in accordance with regulation 21 CFR § 312.32. All safety reports previously filed with the IND concerning similar events should be analyzed. The new report should contain comments on the significance of the new event in light of the previous, similar reports. J1790 / Version 7.0/ December 10, 2020 44 Written IND safety reports with Analys is of Similar Events are to be submitted to the FDA within 15 calendar days of first learning of the event. Follow -up information will be submitted to the FDA as soon as relevant information is available. 7.5.7.2 IND Annual Reports In accordance with the regulation 21 CFR § 312. 33, the IND Sponsor shall within 60 days of the anniversary date that the IND went into effect submit a brief report of the adverse events and progress of the investigation. Please refer to Code of Federal Regulations, 21 CFR § 31 2.33 for a list of the elements required for the annual report. All IND annual reports will be submitted to the FDA by the IND Sponsor. 7.5.8 Recombinant DNA Advisory Committee (RAC) Unexpected SAEs believed to be related to the investigational product( s) will be reported by the Protocol Chair to RAC by email if fatal or life -threatening within 7 calendar days or by written report if related and unexpected to the investigational product(s) within 15 calendar days. SAEs that are unrelated or related and e xpected with the investigational product (s) will be reported to RAC in the Annual Report. Follow -up information will be submitted to the RAC as soon as relevant information is available. 8. PHARMACEUTICAL INFORMATION 8.1 Cyclophosphamide (Cytoxan®, CY) 8.1.1 Agent Accountability The IND S ponsor or the IND Sponsor’s representative shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigati onal product in accordance with the protocol and any applicable laws and regulations. 8.1.2 Mode of Action CY is a synthetic antineoplastic drug chemically related to the nitrogen mustards. CY is biotransformed principally in the liver to active alkylati ng metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross - linking of tumor cell DNA. 8.1.3 Descriptio n CY ( CYTOXAN® ; cyclophosphamide for injection, USP) is a sterile , white powder containing cyclophosphamide monohydrate and is supplied in vials for single -dose use. J1790 / Version 7.0/ December 10, 2020 45 8.1.4 Packaging and Labeling Information CY is commercially available. 8.1.5 Preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Add the diluent to the vial and shake it vigorously to dissolve. If the powder fail s to dissolve immediately and completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity of diluent shown below to constitute the product: Dosage Strength CYTOXAN Contains Cyclophosphamide Monohydrate Quantity of Diluent 500 mg 534.5 mg 25 mL 1 g 1069.0 mg 50 mL 2 g 2138.0 mg 100 mL CY may be prepared for parenteral use by infusion using any of the following methods: 1. CY constituted with 0.9% sterile sodium chloride may be infused without further dilution. 2. CY constituted with 0.9% sterile sodium chloride may be infused following further dilution in the following: • Dextrose Injection, USP (5% dextrose) • Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride) • 5% Dextrose and Ringer’s Injection • Lactated Ringer’s Injection, USP • Sodium Chloride Injection, USP (0.45% sterile sodium chloride) • Sodium Lactate Injection, USP (1/6 molar sodium lactate) 8.1.6 Storage Store vials at or below 77° F (25° C). 8.1.7 Stability CY (prepared for either direct injection or infusion) is chemically and physically stable for 24 hours at room temperature or for 6 days in the refrigerator; it does not contain any antimicrobial preservative and thus care must be taken to assure the sterilit y of prepared solutions. J1790 / Version 7.0 / December 10, 2020 46 8. 1 .8 Route of Administration CY is administered by IV injection over 30 minutes. 8. 1 .9 Subject Care Implications During treatment, the subject ’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. The rate of metabolism and the leukopenic activity of CY reportedly are increased by chronic administration of high doses of phenobarbital. The physician should be alert for possible combine d drug actions, desirable or undesirable, involving CY even though CY has been used successfully concurrently with other drugs, including other cytotoxic drugs. CY treatment, which causes a marked and persistent inhibition of cholinesterase activity, poten tiates the effect of succinylcholine chloride. If a subject has been treated with CY within 10 days of general anesthesia, the anesthesiologist should be alerted. CY may interfere with normal wound healing. 8.