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 of 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.

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 , 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 neuroblastoma. ¹

Central Nervous System:   Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose VUMON (teniposide injection) 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.

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 (teniposide injection) 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.

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