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/FIRST AND FINAL ADD -- PH010 --- BRISTOL-MYERS SQUIBB/

 /FIRST AND FINAL ADD -- PH010 --- BRISTOL-MYERS SQUIBB/
 SINGLE-AGENT (VUMON) TENIPOSIDE
 SUMMARY OF TOXICITY FOR ALL EVALUABLE PEDIATRIC PATIENTS
 Toxicity Incidence in
 Evaluable
 Patients (Pct.)
 Hematologic Toxicity
 Myelosuppression, nonspecified 75
 Leukopenia (< 3000 WBC/(mu)L) 89
 Neutropenia (< 2000 ANC/(mu)L) 95
 Thrombocytopenia (<100,000 plt/(mu)L) 85
 Anemia 88
 Non-Hematologic Toxicity
 Mucositis 76
 Diarrhea 33
 Nausea/vomiting 29
 Infection 12
 Alopecia 9
 Bleeding 5
 Hypersensitivity reactions 5
 Rash 3
 Fever 3
 Hypotension/Cardiovascular 2
 Neurotoxicity <1
 Hepatic dysfunction <1
 Renal dysfunction <1
 Metabolic abnormalities <1
 Hematologic Toxicity: Vumon, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of Vumon necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with Vumon in combination with other antineoplastic agents. See "PRECAUTIONS" subsection "Carcinogenesis, Mutagenesis, Impairment of fertility".
 Gastrointestinal Toxicity: Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29 percent of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate.
 Hypotension: Transient hypotension following rapid intravenous administration has been reported in 2 percent of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving Vumon combination therapy for a non-leukemic malignancy.
 No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted.
 Allergic Reactions: Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5 percent of evaluable pediatric patients receiving intravenous Vumon. The incidence of hypersensitivity reactions to Vumon appears to be increased in patients with brain tumors, and in patients with neuroblastoma1.
 Central Nervous System: Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose Vumon who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the Vumon formulation may place patients receiving higher than recommended doses of Vumon at risk for central nervous system depression.
 Alopecia: Alopecia, sometimes progressing to total baldness, was observed in 9 percent of evaluable pediatric patients who received Vumon as single agent therapy. It was usually reversible.
 OVERDOSAGE
 There is no known antidote for Vumon overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care including blood products and antibiotics as indicated.
 DOSAGE AND ADMINISTRATION
 NOTE: Contact of undiluted Vumon (teniposide) for Injection
 Concentrate with plastic equipment or devices used to
 prepare solutions for infusion may result in softening or
 cracking and possible drug product leakage. This effect
 has not been reported with diluted solutions of Vumon.
 In order to prevent extraction of the plasticizer DEHP
 |di(2-ethylhexyl)phtalate~, solutions of Vumon for
 Injection Concentrate should be prepared in non-DEHP
 containing LVP containers such as glass or polyolefin
 plastic bags or containers.
 Vumon solutions should be administered with non-DEHP
 containing IV administration sets.
 In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of Vumon 165mg/m(superscript)2 and cytarabine 300 mg/m(superscript)2 intravenously, twice weekly for 8-9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of Vumon 250 mg/m(superscript)2 and vincristine 1.5 mg/m(superscript)2 intravenously, weekly for 4-8 weeks and prednisone 40 mg/m(superscript)2 orally x 28 days.
 Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment.
 Preparation and Administration Precautions: Vumon is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of Vumon. Skin reactions associated with accidental exposure to Vumon may occur. The use of gloves is recommended. If Vumon solution contacts the skin, immediately wash the skin thoroughly with soap and water. If Vumon contacts mucous membranes, the membranes should be flushed thoroughly with water.
 Preparation for Intravenous Administration: Vumon must be diluted with either 5 percent Dextrose Injection, USP or 0.9 percent Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL or 1.0 mg/mL. Solutions prepared in 5 percent Dextrose Injection, USP or 0.9 percent Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. Vumon solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of Vumon solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers.
 Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration(7). In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and
container permit. Precipitation has been reported during 24-hour infusions of


Vumon diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients(4)(5). Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5 percent Dextrose Injection or 0.9 percent Sodium Chloride Injection, USP before and after administration of Vumon(5).
 Hypotension has been reported following rapid intravenous administration; it is recommended that the Vumon solution be administered over at least a 30 to 60-minute period. Vumon should not be given by rapid intravenous injection.
 In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP |di(2- ethylhexyl)phtalate~ from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9 percent Sodium Chloride Injection, USP, and 5 percent Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended.
 Similarly, the use of non-DEHP IV administration sets is recommended. Lipid administration sets or low DEHP containing nitroglycerin sets will keep patients' exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended IV administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials or IV pumps cannot be assured.
 Stability: Unopened ampules of Vumon (teniposide) for Injection Concentrate are stable until the date indicated on the package when stored under refrigeration (2 degrees-8 degrees C) in the original package. Freezing does not adversely affect the product.
 HOW SUPPLIED
 NDC 0015-3075-19 50 mg/5 mL sterile clear, colorless glass
 ampules individually packaged in a carton.
 NDC 0015-3075-97 50 mg/5 mL sterile clear, colorless glass
 ampules individually nested in a carton tray of
 10 ampules per tray.
 Storage: Store the unopened ampules under refrigeration (2 degrees- 8 degrees C). Retain in original package to protect from light.
 Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (8-14). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. References:
 1. O'Dwyer PJ, King SA, Fortner CL and Leyland-Jones B:


Hypersensitivity reactions to teniposide (VM-26): an analysis. J Clin Oncol 1986; 4(8):1262-1269.
 2. Lorenz W, Reimann H-J, Schmall A et al: Histamine release in dogs by CremophorREL and its derivatives. Agents and Actions 1977; 7(1):63-67.
 3. Lassus M, Scott D, and Leyland-Jones B: Allergic reactions associated with cremophor containing antineoplastics. Proc. Am Soc Clin Oncol 1985; 4:268 (Abstract C-1042).
 4. Strong D, Morris L: Precipitation of teniposide during infusion. Am J Hosp Pharm; Mar 1990: Letter, 47:512,518.
 5. Bogardus J, Kaplan M, Carpenter J: Precipitation of teniposide during infusion. Am J Hosp Pharm; Mar 1990: Letter, 47:518-519.
 6. Pui C-H, et al: Acute Myeloid Leukemia in Children Treated with Epipodophyllotoxins for Acute Lymphoblastic Leukemia. N Engl J Med 1991; 325: 1682-1687.
 7. Deardoff D, Schmidt C: Mixing additives in plastic LVPs. Am J


Hosp Pharm; Dec 1980: Letter, 37:1610,1613.
 8. Recommendations for the safe handling of parenteral antineoplastic drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing office, Washington, DC 20402.
 9. AMA Council Report. Guidelines for handling parenteral antineoplasics. JAMA 1985; 253 (11): 1590-1592.
 10. National Study Commission on Cytotoxic Exposure - Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts, 02115.
 11. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426-428.
 12. Jones RB, et al: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians 1983; Sept./Oct 258-263.
 13. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am J Hosp Pharm 1990; 47:1033-1049.
 14. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
 U.S. Patent No. 3,524,844
 MANUFACTURED BY:
 Bristol Laboratories Oncology Products
 A Bristol-Myers Squibb Company
 Princeton, New Jersey 08543
 U.S.A.
 /delval/
 -0- 10/7/92 AA PH010
 /END FIRST AND FINAL ADD/
 (BMY) CO: Bristol-Myers Squibb ST: New Jersey IN: MTC SU: PDT


JS-MK -- PH010A -- 7426 10/07/92 11:42 EDT
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