Teniposide

Pregnancy Category D.

Teniposide may cause fetal harm when administered to a pregnant woman. Teniposide has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous administration of teniposide, 0.1 to 3 mg/kg (0.6-18 mg/m²), 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 teniposide 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 teniposide.

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 teniposide therapy to the mother.

Children at SJCRH with ALL in remission who received maintenance therapy with teniposide 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 teniposide 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 teniposide 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.

Male Fertility

In animal studies, teniposide 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 teniposide 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.

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 teniposide 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 7 studies assessed teniposide activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with teniposide and were expected to develop significant myelosuppression as an endpoint of treatment.

Single-Agent Teniposide Summary of Toxicity for All Evaluable Pediatric Patients:

Hematologic Toxicity

Teniposide, 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 teniposide 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 teniposide in combination with other antineoplastic agents.

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 teniposide 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 teniposide. The incidence of hypersensitivity reactions to teniposide 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 teniposide concomitantly.

Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose teniposide who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the teniposide formulation may place patients receiving higher than recommended doses of teniposide at risk for central nervous system depression.

Alopecia

Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received teniposide 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.