freedrug levels in plasma which could result in potentiation of drug toxicity.Therefore, caution should be used in administering VUMON to patients receivingthese other agents. There was no change in the plasma kinetics of teniposidewhen coadministered with methotrexate. However, the plasma clearance of methotrexatewas slightly increased. An increase in intracellular levels of methotrexatewas observed in vitro in the presence of teniposide.
Childrenat SJCRH with ALL in remission who received maintenance therapy with VUMONat weekly or twice weekly doses (plus other chemotherapeutic agents), hada relative risk of developing secondary acute nonlymphocytic leukemia (ANLL)approximately 12 times that of patients treated according to other less intensiveschedules.
A short course of VUMON for remission-inductionand/or consolidation therapy was not associated with an increased risk ofsecondary ANLL, but the number of patients assessed was small. The potentialbenefit from VUMON must be weighed on a case by case basis against the potentialrisk of the induction of a secondary leukemia. The carcinogenicity of teniposidehas not been studied in laboratory animals. Compounds with similar mechanismsof action and mutagenicity profiles have been reported to be carcinogenicand teniposide should be considered a potential carcinogen in humans. Teniposidehas been shown to be mutagenic in various bacterial and mammalian genetictoxicity tests. These include positive mutagenic effects in the Ames/Salmonellaand B. subtilis bacterial mutagenicity assays. Teniposidecaused gene mutations in both Chinese hamster ovary cells and mouse lymphomacells and DNA damage as measured by alkaline elution in human lung carcinomaderived cell lines. In addition, teniposide induced aberrations in chromosomestructure in primary cultures of human lymphocytes in vitro andin L5178y/TK +/- mouse lymphoma cells in vitro. Chromosomeaberrations were observed in vivo in the embryonic tissueof pregnant Swiss albino mice treated with teniposide. Teniposide also causeda dose-related increase in sister chromatid exchanges in Chinese hamster ovarycells, and it has been shown to be embryotoxic and teratogenic in rats receivingteniposide during organogenesis. Treatment of pregnant rats intravenouslywith doses between 1.0 and 3.0 mg/kg/day on alternate days from day 6 to 16post coitum caused retardation of embryonic development, prenatal mortality,and fetal abnormalities.
See WARNINGS .
It is not known whether this drug is excreted in human milk. Becausemany drugs are excreted in human milk and because of the potential for seriousadverse reactions in nursing infants, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking into account the importanceof VUMON therapy to the mother.
Adverse events were eva luated 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 particularage group and adverse effects was reported in any of these investigations.
Patients with both Down syndrome andleukemia may be especially sensitive to myelosuppressive chemotherapy, therefore,initial dosing with VUMON should be reduced in these patients. It is suggestedthat the first course of VUMON should be given at half the usual dose. Subsequentcourses may be administered at higher dosages depending on the degree of myelosuppressionand mucosit
