Teniposide

656.65

656.65

249-831-2

957E6438QA

DTXSID8023638

C857

Crystals from absolute ethanol

L - Antineoplastic and immunomodulating agents

29349990

189 Ų

1.24 (LogP)

white to beige

1.6±0.1 g/cm3

242-246 °C

864.3°C at 760 mmHg

476.5±34.3 °C

1.697

DMSO: soluble 10mg/mL, clear

-20°C Freezer

6.8X10-26 mm Hg at 25 °C /Estimated/

LD50 intraperitoneal in mouse: 29570ug/kg

D20 -107° (9:1 chloroform/methanol)

Henry's Law constant = 5.8X10-32 atm-cu m/mol at 25 °C /Estimated/

pKa = 10.13

266.1 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Teniposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent, which is structurally and pharmacologically related to etoposide. Teniposide differs structurally from etoposide by addition of a thenylidine ring on the glucopyranoside ring.|Hydroxyl radical reaction rate constant = 3.0X10-10 cu cm/molecule-sec at 25 °C /Estimated/

UN 2811 6.1 / PGIII

3

36/37/38-45

26-36-45-53

KC0180000

Xi,T

P201-P308 + P313

H350

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.|PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for TENIPOSIDE (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl teniposide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H350 (100%): May cause cancer [Danger Carcinogenicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 42 companies from 4 notifications to the ECHA C&L Inventory.|H341: Suspected of causing genetic defects [Warning Germ cell mutagenicity]|P201, P202, P260, P264, P270, P281, P308+P313, P309+P311, P314, P405, and P501

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for TENIPOSIDE (10 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

Chemotherapy with etoposide or teniposide in combination with other agents is associated with serum enzyme elevations in 5% to more than 50% of patients, depending upon the dose and other agents used. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to etoposide or teniposide because of the exposure to other potentially hepatotoxic agents. Rare instances of clinically apparent liver injury have been reported in patients receiving etoposide, but the time to onset and pattern of injury has varied greatly. Onset can be as short as 1 to as long as 5 months after initiation of therapy. Some published cases of liver injury after regimens of chemotherapy that have included etoposide appear to represent sinusoidal obstruction syndrome. These cases have usually followed etoposide therapy in combination with an alkylating agent or total body irradiation. In addition, etoposide has been linked to cases of acute hepatitis arising after 1 to 5 months of treatment, which have generally been self-limiting, but occasionally severe. The role of etoposide in causing injury was not always clear. The pattern of serum enzyme elevation in reported cases has been hepatocellular. Immunoallergic features (rash, fever, eosinophilia) and autoantibodies were absent. The liver histology of etoposide hepatotoxicity has not been well characterized. The hepatotoxicity of teniposide has been less well defined than that of etoposide, probably because it has had limited use.

Concurrent administration of ciclosporin at 5 mg/kg bw over 2 h, followed by 30 mg/kg bw over 48 h intravenously, increased the AUC for teniposide by 50%, due to a reduction in clearance. Conversely, concurrent administration of phenytoin increased the clearance rate of teniposide to 32 mL/min per m2 from 13 mL/min per m2 for control patients.

Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia

Etoposide and teniposide are semisynthetic analogues of podophyllotoxin that are used as antineoplastic agents in the therapy of several forms of solid tumors, leukemia and lymphoma, usually in combination with other agents. Both etoposide and teniposide are associated with an appreciable rate of serum enzyme elevations during therapy, and high doses have been implicated in causing clinically apparent acute liver injury including sinusoidal obstruction syndrome.

Antineoplastic Agents

Antineoplastic Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors|Teniposide is indicated, in combination with other approved anticancer agents, for induction therapy of refractory childhood acute lymphocytic (lymphoblastic) leukemia. /Included in US product labeling/|Teniposide is indicated as a single agent or in combination for therapy of refractory non-Hodgkin's lymphoma. /NOT included in US product labeling/|Teniposide is indicated as a single agent or in combination for therapy of refractory neuroblastoma. /NOT included in US product labeling/

Since patients with Down's syndrome and leukemia may be particularly sensitive to myelosuppressive chemotherapy, initial dosage of teniposide should be reduced in such patients.|There currently is insufficient experience with teniposide therapy in patients with impaired renal and/or hepatic function to make specific recommendations for dosage adjustment. However, the possibility that adjustment in teniposide dosage may be necessary in such patients should be considered.|The major and dose-limiting adverse effect of teniposide is hematologic toxicity. Myelosuppression, which is dose related, can be severe when teniposide is used in combination with other chemotherapeutic agents for the treatment of acute lymphocytic leukemia (ALL). Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of teniposide necessary for the treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. Severe myelosuppression with resulting infection and bleeding may occur in patients receiving the drug. Infection and bleeding have occurred in about 12 and 5%, respectively, of pediatric patients receiving teniposide monotherapy.|Pregnancy risk category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|For more Drug Warnings (Complete) data for TENIPOSIDE (18 total), please visit the HSDB record page.

Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II. (See all compounds classified as Topoisomerase II Inhibitors.)

From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose.|10.3 mL/min/m2|Teniposide was detected in intracerebral tumors at concentrations of 0.05-1.12 ug/g tissue in 11 patients given 100-150 mg/sq m teniposide 1.5-3 hr before tumor resection. The concentrations in adjacent normal brain tissue were low (< 0.9 ug/g tissue) in three patients and undetectable (< 0.05 ug/g tissue) in the others|Teniposide was detected in one patient who died three days after a cumulative intravenous dose of 576 mg, the highest concentrations occurring in the spleen, prostate, heart, large bowel, liver and pancreas.|It is not known whether teniposide is distributed into breast milk.|Elimination: Renal: 4 to 12% of a dose as unchanged teniposide. In a study of tritium-labeled teniposide in adults, 44% of the radiolabel (parent compound and metabolites) was recovered in urine within 120 hours after dosing. Fecal: 0 to 10% of a dose.|For more Absorption, Distribution and Excretion (Complete) data for TENIPOSIDE (6 total), please visit the HSDB record page.

In isolated human liver preparations, cytochrome P450 mixed-function isozymes catalysed metabolism of the (pendant) E-ring to O-demethylated and catechol metabolites. This metabolism was subsequently attributed primarily to CYP3A4 activity and to a lesser degree to CYP3A5. Peroxidase-mediated O-demethylation of teniposide has also been reported.|In children given teniposide, the main metabolite in serum and urine was reported to be the hydroxy acid, formed by opening of the lactone ring; the cis-isomer, which may be a degradation product formed during storage, was also detected. The aglycone, formed by loss of the glucopyranoside moiety, was not detected (Evans et al., 1982). The hydroxy acid has not been found in plasma or urine in other studies with high doses of teniposide, and no changes in the measured concentration of teniposide in these samples was found after incubation with glucuronidase, indicating formation of little or none of the proposed glucuronide metabolites (Holthuis et al., 1987). In another study, however, 6% of the administered dose of teniposide was excreted in the urine as parent drug over 24 h, and a further 8% as a proposed aglycone glucuronide, which was not formally identified.|In general, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation. Various metabolic species of teniposide have been identified, but their mutagenic properties have not been studied.|Teniposide has known human metabolites that include Teniposide catechol.

5 hours|Terminal half life: 5 hours. NOTE: Plasma teniposide concentrations decline biexponentially following intravenous infusion.|It has a multiphasic pattern of clearance from plasma. After distribution, half lives of 4 hours and 10 to 40 hours are observed.

The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate.|It is an inhibitor of DNA topoisomerase II enzymes: Teniposide is a DNA topoisomerase II poison that has been shown to promote DNA cleavage, with a strong preference for a C or T at position -1. Most of the mutational events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Teniposide does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. Unlike many other DNA topoisomerase II poisons, teniposide does not bind to DNA, either covalently or by intercalation. Instead, it appears to interact directly with the DNA topoisomerase II enzyme.|... The drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. Teniposide has been shown to induce single-stranded DNA breaks; the drug also induces double-stranded DNA breaks and DNA-protein cross links. ... Teniposide appears to be cell cycle specific, inducing G2-phase arrest and preferentially killing cells in the G2 and late S phases.

... The 50-mg intravenous preparation typically also contains benzyl alcohol (0.15 g), N,N-dimethylacetamide (0.3 g), polyethoxylated castor oil (2.5 g), maleic acid to a pH of 5.1 and absolute ethanol to 5 mL.

Treatment of overdose: Supportive blood product and antibiotic therapy, as indicated, is recommended. There is no known antidote.|Emergency and supportive measures; 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur.3. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. 4. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. 5. Extravasation. Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment. ... Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase ... may be beneficial. Do not use ice pack. /Antineoplastic Agents/.|Decontamination; 1. Prehospital. Administer activated charcoal, if available. IF a delay of more than 60 minutes is expected before charcoal can be given, ... if it can be administered within a few minutes of exposure and there are no contraindications. 2. Hospital. Administer activated charcoal. Gastric emptying is not necessary after a small ingestion if activated charcoal can be given promptly /Antineoplastic Agents/.|Enhanced elimination; Because of the rapid intracellular incorporation of most agents, dialysis and other extracorporeal removal procedures are generally not effective /Antineoplastic Agents/.

/SIGNS AND SYMPTOMS/ When teniposide was given at a high total dose of 300-1000 mg/sq m over three days, hematological toxic effects were dose-limiting, with leukocyte counts of < 0.5-109/L in all three patients at 1000 mg/sq m. These patients also developed an intensely pruritic erythematous rash with purpura four to seven days after the start of chemotherapy, which involved the upper part of the chest and the upper part of the legs. In two of these patients, ulceration was also seen. The rash cleared spontaneously within one week and, in two patients who were treated again at 500 mg/sq m, no rash occurred. In the one patient who received a second dose of 1000 mg/sq m, paraesthesia and an abnormal electromyography were seen.|/SIGNS AND SYMPTOMS/ Clinical effects of overdose. ... Acute and chronic: Bone marrow suppression (fever; chills; cough or hoarseness; lower back or side pain; painful or difficult urination; unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin.|/CASE REPORTS/ Acute myeloid leukemia developed in 20 out of 580 children treated with teniposide with or without etoposide for acute lymphoblastic leukemia; one case was found in a patient treated with neither etoposide nor teniposide. The overall cumulative risk was 3.8% at six years. The median interval between the diagnoses of acute lymphoblastic leukemia and acute myeloid leukemia was 40 months. Six cases were acute myelomonocytic leukemia, eight were acute monoblastic leukemia, three were acute myeloblastic leukemia, one was acute megakaryoblastic leukemia, one was acute myeloid leukemia and two were acute undifferentiated leukemia. In four patients, acute myeloid leukemia developed after relapse had occurred, and these were not included in the analysis. In the analysis of leukemia risk, the doses of teniposide and etoposide were weighted equally since the potency of teniposide in vitro 10 times that of etoposide is offset in vitro by extensive protein binding, resulting in 10 times less unbound active drug. The analyses indicated the importance of the schedule and frequency of epipodophyllotoxin treatment in determining the risk for acute myeloid leukemia|/CASE REPORTS/ During treatment with VM-26 a 20-year-old patient with metastatic medulloblastoma developed an acute, fulminating pulmonary illness. Open lung biopsy revealed advanced alveolar hyaline membrane formation with interstitial round cell infiltrate.|/EPIDEMIOLOGY STUDIES/ Sixty-two children in Spain in whom acute lymphoblastic leukemia was newly diagnosed between 1985 and 1988 were initially treated with teniposide (165 mg/sq m), cytarabine, vincristine, L-asparaginase and prednisone and subsequently with teniposide (165 mg/sq m), cytarabine, vincristine, cranial irradiation, mercaptopurine, methotrexate and prednisone. Of 60 patients in whom complete remission was achieved, 14 suffered a bone-marrow relapse. During treatment, acute myeloid leukemia developed in three of these patients (two cases of acute monoblastic leukemia, one of acute myelomonocytic leukemia). Thus, the frequency of conversion from acute lymphoblastic leukemia to acute myeloid leukemia was 3/60. The time from diagnosis to conversion was 17, 23 and 29 months. /It was/ noted that 45 children with non-T-cell acute lymphoblastic leukemia were treated between 1981 and 1984 with a regimen that did not include teniposide and cytarabine, and no cases of acute myeloid leukemia were observed at relapse.

Demethyl Epipodophyllotoxin Thenylidine Glucoside

Trade names for teniposide include Vehem, Vehem-Sandoz, Vumon and Vumon Parenteral.

Semi-synthetic derivative of podophyllotoxin

The methods for the analysis of teniposide in various matrices include high-performance liquid chromatography, thin-layer and paper chromatography and radioimmunoassay.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients