WARNING Teniposide injection 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 teniposide injection. Epinephrine, with or without corticosteroids and antihistamines, has been employed to alleviate hypersensitivity reaction symptoms.
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WARNINGS Teniposide 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 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 teniposide therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of teniposide: 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 teniposide 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 polyoxyl 35 castor oil component of the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to teniposide are at risk for recurrence of symptoms and should only be retreated reactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between teniposide and etoposide. 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 nonleukemic malignancy (see ADVERSE REACTIONS). Patients receiving teniposide 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, teniposide 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 polyoxyl 35 castor oil. If clinically significant hypotension develops, the teniposide 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 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 a risk for central nervous system depression. Pregnancy 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 admin- istration of teniposide 0.1 to 3 mg/kg (0.6-18 mg/m 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 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. 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.
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 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 VUMON Summary of Toxicity for All Evaluable Pediatric Patients Toxicity Incidence in Evaluable Patients (%) Hematologic Toxicity Myelosuppression, nonspecified 75 Leukopenia (<3,000 WBC/mcL) 89 Neutropenia (<2,000 ANC/mcL) 95 Thrombocytopenia (<100,000 plt/mcL) 85 Anemia 88 Non-Hematologic Toxicity Mucositis 76 Diarrhea 33 Nausea/vomiting 29 Infection 12 Alopecia 9 Bleeding 5 Hypersensitivity reactions 5 Rash 3 Fever 3 Hypotension/Cardiovascular 2 Neurotoxicity <1 Hepatic dysfunction <1 Renal dysfunction <1 Metabolic abnormalities <1 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. (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 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. To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.