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BRISTOL-MYERS SQUIBB INTRODUCES VUMON(R) FOR CHILDHOOD LEUKEMIA

 BRISTOL-MYERS SQUIBB INTRODUCES VUMON(R) FOR CHILDHOOD LEUKEMIA
 PRINCETON, N.J., Oct. 7 /PRNewswire/ -- Bristol-Myers Squibb Company (NYSE: BMY) today announced the introduction of VUMON(R) (teniposide), in combination with other approved anticancer drugs, for induction treatment of refractory childhood acute lymphoblastic leukemia (ALL).
 The Food and Drug Administration has granted Orphan Drug Status to VUMON based on the limited patient population for this drug. VUMON is available in 50 mg/5 ml sterile ampules individually and in trays of 10 ampules each.
 ALL is a disease that affects people of all ages, but there is a clear peak of incidence in early childhood. The overall incidence of ALL is greatest between the ages of two and four years, dropping off to its lowest point between the second and third decade but then rising again somewhat after the age of 65. Approximately 2,000 new cases of ALL are diagnosed in children up to the age of 15 years in the U.S. annually. Nearly 80 percent of childhood leukemias are ALL, making it the most common form of childhood cancer diagnosed in the U.S.
 "While there are 2,000 new cases of ALL diagnosed each year, approximately 500 patients will have refractory ALL," said Isadore M. Pike, M.D., director, Medical Affairs, Bristol-Myers Oncology Division. "These children have a particularly poor prognosis. Treatment with available therapy generally does not produce long-term remissions, and patients become less likely to achieve remission with each relapse."
 "We have been working with the National Cancer Institute since the late 1970's to develop VUMON for this small but important patient population. Clinical studies with VUMON indicate that it can prolong complete remission and survival duration when used in combination chemotherapy regimens for pediatric patients with refractory ALL," added Pike.
 In a clinical study conducted at St. Jude Children's Research Hospital in Memphis, Tenn., nine children with ALL who had failed induction therapy with a regimen containing cytarabine (an anticancer drug) were given VUMON and cytarabine. Three of the patients experienced complete remissions for periods of 30 weeks, 59 weeks and 13 years. In another clinical study conducted at the same research center, 16 children with ALL refractory to regimens containing vincristine (an anticancer drug) and prednisone (a corticosteroid drug) were given VUMON along with vincristine and prednisone. Three of the patients experienced complete remissions for periods of 5.5, 37 and 73 weeks.
 The major dose-limiting toxicity with VUMON is bone marrow suppression, which increases with drug dose in a gradual fashion. Hypersensitivity reactions, including anaphylaxis-like symptoms such as blood pressure changes, bronchospasm and flushing, may occur with initial dosing or at repeated exposure to VUMON. Patients receiving VUMON therapy should be closely monitored for at least the first sixty minutes following the start of the infusion. Other important information about adverse reactions is included in the product labelling.
 The company also announced it will continue to provide VUMON at no cost to those patients who are currently enrolled in clinical trials being conducted by the National Cancer Institute (NCI). VUMON has been available under investigational new drug protocols with the NCI since 1988 for the treatment of relapsed or refractory acute lymphoblastic leukemia.
 Bristol-Myers Squibb Company is a diversified health care company whose principal businesses are pharmaceuticals, consumer products, nutritionals and medical devices. It is among the world's leading makers of cardiovascular, anticancer, anti-infective, central nervous system and dermatological drug therapies, diagnostic agents and over- the-counter medications.
 Full prescribing information for VUMON follows.
 PACKAGE INSERT
 VumonR (teniposide) for Injection Concentrate
 WARNING
 Vumon (teniposide) for Injection Concentrate is a cytotoxic drug, which should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.
 Severe myelosuppression with resulting infection or bleeding may occur. Hypersensitivity reactions, including anaphylaxis-like symptoms, may occur with initial dosing or at repeated exposure to Vumon. Epinephrine, with or without corticosteroids and antihistamines has been employed to alleviate hypersensitivity reaction symptoms.
 DESCRIPTION
 Vumon (teniposide) for Injection Concentrate (also commonly known as VM-26), is supplied as a sterile nonpyrogenic solution in a nonaqueous medium intended for dilution with a suitable parenteral vehicle prior to intravenous infusion. Vumon is available in 50 mg (5 mL) ampules. Each mL contains 10 mg teniposide, 30 mg benzyl alcohol, 60 mg N,N- dimethylacetamide, 500 mg Cremophor(R)EL (polyoxyethylated castor oil)(A) and 42.7 percent (V/V) dehydrated alcohol. The pH of the clear solution is adjusted to approximately 5 with maleic acid.
 (A) Cremophor EL is the registered trademark of BASF Aktiengesellschaft. Teniposide is a semisynthetic derivative of podophyllotoxin. The chemical name for teniposide is 4'- demethylepipodophyllotoxin 9-|4,6-0-(R)-2-thenylidene-beta-D- glucopyranoside~. Teniposide differs from etoposide, another podophyllotoxin derivative, by the substitution of a thenylidene group on the glucopyranoside ring.
 Teniposide has the following structural formula:
 Teniposide is a white to off-white crystalline powder with the empirical formula C(subscript 32)H(subscript 32)O(subscript 13)S and a molecular weight of 656.66. It is a lipophilic compound with a partition coefficient value (octanol/water) of approximately 100. Teniposide is insoluble in water and ether. It is slightly soluble in methanol and very soluble in acetone and dimethylformamide.
 CLINICAL PHARMACOLOGY
 Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis.


Teniposide causes dose-dependent single- and double- stranded breaks in DNA and DNA:protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate.
 Teniposide has a broad spectrum of in vivo antitumor activity against murine tumors, including hematologic malignancies and various solid tumors.


Notably, teniposide is active against sublines of certain murine leukemias with acquired resistance to cisplatin, doxorubicin, amsacrine, daunorubicin, mitoxantrone or vincristine.
 Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m(superscript 2) over 1 to 2.5 hours) of Vumon given to eight children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV percent) based on a two- compartmental model analysis of the data are as follows:
 Parameter Mean CV percent
 Total body clearance (mL/min/m(superscript 2)) 10.3 25
 Volume at steady-state (L/m(superscript 2)) 3.1 30
 Terminal half-life (hours) 5.0 44
 Volume of central compartment (L/m(superscript 2) 1.5 36
 Rate constant, central to peripheral (1/hours) 0.47 62
 Rate constant, peripheral to central (1/hours) 0.42 37
 There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if Vumon is to be administered to patients with hepatic dysfunction.
 In adults, at doses of 100 to 333 mg/m(superscript 2)/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of Vumon for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m(superscript 2) over a period of one to two hours exceeded 40 (mu)g/mL; by 20 to 24 hours after infusion plasma levels were generally < 2 (mu)g/mL.
 Renal clearance of parent teniposide accounts for about 10 percent of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m(superscript 2) of tritium-labeled teniposide, 44 percent of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4 to 12 percent of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0 to 10 percent of the dose.
 Mean steady-state volumes of distribution range from 8 to 44 L/m(superscript 2) for adults and 3 to 11 L/m(superscript 2) for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors.
 Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99 percent. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF and malignant ascites fluid are low relative to simultaneously measured plasma levels.
 The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins, and its cellular uptake is greater. Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide.
 In a study at St. Jude Children's Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with Vumon plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL refractory to vincristine/prednisone-containing regimens were treated with Vumon plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these two studies patients served as their own control based on the premise that long term complete remissions could not be achieved by re- treatment with drugs to which they had previously failed to respond.
 INDICATION AND USAGE
 Vumon, in combination with other approved anticancer agents, is indicated for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.
 CONTRAINDICATIONS
 Vumon is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or CremophorREL (polyoxyethylated castor oil).
 WARNINGS
 Vumon is a potent drug and should be used only by physicians experienced in the administration of cancer chemotherapeutic drugs. Blood counts as well as renal and hepatic function tests should be carefully monitored prior to and during therapy.
 Patients being treated with Vumon (teniposide) should be observed frequently for myelosuppression both during and after therapy. Dose- limiting bone marrow suppression is the most significant toxicity associated with Vumon therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of Vumon: hemoglobin, white blood cell count and differential and platelet count. If necessary, repeat bone marrow examination should be performed prior to the decision to continue therapy in the setting of severe myelosuppression.
 Physicians should be aware of the possible occurrence of a hypersensitivity reaction variably manifested by chills, fever, urticaria, tachycardia, bronchospasm, dyspnea, hypertension or hypotension and facial flushing. This reaction may occur with the first dose of Vumon and may be life threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, intravenous fluids and other supportive measures as clinically indicated. The exact cause of these reactions is unknown. They may be due to the Cremophor(R)EL (polyoxyethylated castor oil) component of the vehicle or to teniposide itself(1). Patients who have experienced prior hypersensitivity reactions to Vumon are at risk for recurrence of symptoms and should only be re-treated with Vumon if the antileukemic benefit already demonstrated clearly outweighs the risk of a probable hypersensitivity reaction for that patient. When a decision is made to re-treat a patient with Vumon in spite of an earlier hypersensitivity reaction, the patient should be pretreated with corticosteroids and antihistamines and receive careful clinical observation during and after Vumon infusion. In the clinical experience with Vumon at SJCRH and the National Cancer Institute (NCI), re-treatment of patients with prior hypersensitivity reactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between Vumon and VePesid.
 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. (See "ADVERSE REACTIONS" section.) Patients receiving Vumon treatment should be under continuous observation for at least the first 60 minutes following the start of the infusion and at frequent intervals thereafter. If symptoms or signs of anaphylaxis occur, the infusion should be stopped immediately, followed by the administration of epinephrine, corticosteroids, antihistamines, pressor agents, or volume expanders at the discretion of the physician. An aqueous solution of epinephrine 1:1000 and a source of oxygen should be available at the bedside.
 For parenteral administration, Vumon should be given only by slow intravenous infusion (lasting at least 30- to 60-minutes) since hypotension has been reported as a possible side effect of rapid intravenous injection, perhaps due to a direct effect of Cremophor(R)EL(2, 3). If clinically significant hypotension develops, the Vumon infusion should be discontinued. The blood pressure usually normalizes within hours in response to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. If the infusion is restarted, a slower administration rate should be used and the patient should be carefully monitored.
 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.
 Pregnancy: Pregnancy "Category D."
 Vumon may cause fetal harm when administered to a pregnant woman. Vumon has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats intravenous administration of Vumon, 0.1-3 mg/kg (0.6-18 mg/m(superscript 2)), every second day from day 6 to day 16 post coitum caused dose-related embryotoxicity and teratogenicity. Major anomalies included spinal and rib defects, deformed extremities, anophthalmia and celosomia.
 There are no adequate and well-controlled studies in pregnant women. If Vumon is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Vumon.
 PRECAUTIONS
 General: In all instances where the use of Vumon is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Vumon therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.
 Vumon must be administered as an intravenous infusion. Care should be taken to ensure that the intravenous catheter or needle is in the proper
position and functional prior to infusion. Improper administration of Vumon may result in extravasation causing local tissue necrosis and/or thrombophlebitis. In some instances, occlusion of central venous access devices has occurred during 24-hour infusion of Vumon at a concentration of 0.1 to 0.2 mg/mL. Frequent observation during these infusions is necessary to minimize this risk(4, 5).
 Laboratory Tests: Periodic complete blood counts and assessments of renal and hepatic function should be done during the course of Vumon treatment.


They should be performed prior to therapy and at clinically appropriate intervals during and after therapy. There should be at least one determination of hematologic status prior to therapy with Vumon.
 Drug Interactions: In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering Vumon to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide.
 Carcinogenesis, Mutagenesis, Impairment of fertility: Children at SJCRH with ALL in remission who received maintenance therapy with Vumon at weekly or twice weekly doses (plus other chemotherapeutic agents), had a relative risk of developing secondary acute nonlymphocytic leukemia (ANLL) approximately 12 times that of patients treated according to other less intensive schedules(6). A short course of Vumon for remission-induction and/or consolidation therapy was not associated with an increased risk of secondary ANLL, but the number of patients assessed was small. The potential benefit from Vumon must be weighed on a case by case basis against the potential risk of the induction of a secondary leukemia. The carcinogenicity of teniposide has not been studied in laboratory animals. Compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic and teniposide should be considered a potential carcinogen in humans. Teniposide has been shown to be mutagenic in various bacterial and mammalian genetic toxicity tests. These include positive mutagenic effects in the Ames/Salmonella and B. subtilis bacterial mutagenicity assays. Teniposide caused gene mutations in both Chinese hamster ovary cells and mouse lymphoma cells and DNA damage as measured by alkaline elution in human lung carcinoma derived cell lines. In addition, teniposide induced aberrations in chromosome structure in primary cultures of human lymphocytes in vitro and in L5178y/TK +/- mouse lymphoma cells in vitro. Chromosome aberrations were observed in vivo in the embryonic tissue of pregnant Swiss albino mice treated with teniposide. Teniposide also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells and it has been shown to be embryotoxic and teratogenic in rats receiving teniposide during organogenesis. Treatment of pregnant rats IV with doses between 1.0 and 3.0 mg/kg/day on alternate days from day 6 to 16 post coitum caused retardation of embryonic development, prenatal mortality and fetal abnormalities.
 Pregnancy: Pregnancy "Category D." (See "WARNINGS" section.)
 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Vumon therapy to the mother.
 Patients with Down's Syndrome: Patients with both Down's Syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with Vumon should be reduced in these patients. It is suggested that the first course of Vumon should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient.
 ADVERSE REACTIONS
 The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which Vumon was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these seven studies assessed Vumon activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with Vumon and were expected to develop significant myelosuppression as an endpoint of treatment.
 /delval/
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 /CONTACT: Robert F. Laverty of Bristol-Myers Squibb, 609-252-5551/
 /FIRST AND FINAL ADD -- PACKAGE INSERT, CONTINUED -- TO FOLLOW/
 (BMY) CO: Bristol-Myers Squibb ST: New Jersey IN: MTC SU: PDT


KD-MK -- PH010 -- 7447 10/07/92 12:14 EDT
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