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 injection) 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, rash, 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® EL (polyoxyethylated castor oil) component of the vehicle or to teniposide itself. 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.) 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® EL. 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, hypotension, and metabolic acidosis 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

In animal studies, Vumon caused a decrease in sperm count and genetic damage to sperm. No studies have been done to demonstrate the effect of these changes on human sperm and male fertility. Young men of reproductive age should be advised of the possibility that Vumon treatment may compromise their ability to father a child and that there is some possibility for birth defects if they do. They should be counseled on the possibility of storing sperm for future artificial insemination.

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.

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.

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 intravenously 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

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.

Pediatric Use

Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received Vumon as a single agent (see ADVERSE REACTIONS). No association between any particular age group and adverse effects was reported in any of these investigations.

Patients with Down Syndrome

Patients with both Down 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

Hematologic Toxicity

Vumon, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Sepsis, sometimes fatal, may be a consequence of 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: Carcinogenesis, Mutagenesis, Impairment of Fertility.)

Gastrointestinal Toxicity

Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% 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% 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, rash, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% 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 neuroblastoma.

Central Nervous System

Neurotoxicity has been reported, including severe cases of neuropathy, in patients receiving vincristine sulfate and Vumon concomitantly.

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% of evaluable pediatric patients who received Vumon as single-agent therapy. It was usually reversible.

Other Adverse Reactions

The following adverse reactions have been reported: headache, confusion, and asthenia. Headache and confusion were associated with hypersensitivity reactions.

Overdosage

Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of Vumon, and who were also pretreated with antiemetic drugs.

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.

Vumon Dosage and Administration