Acute Lymphocytic Leukemia
Teniposide is used as a component of multiple-drug antineoplastic regimens for induction therapy in childhood acute lymphocytic (lymphoblastic) leukemia (ALL) that is refractory to induction with other therapy or has relapsed despite such therapy.1,6,26
Since almost all children with ALL achieve an initial remission with primary regimens (e.g., vincristine and prednisone combined with asparaginase with or without daunorubicin), the principal obstacle to cure is hematologic and/or extramedullary relapse.22,23 The prognosis for children whose ALL relapses depends on the time to relapse and the site of relapse; early relapse and isolated bone marrow relapse or combined bone marrow and extramedullary relapse are associated with poorer prognosis.22 Thus, while a substantial proportion of patients whose ALL relapses following initial induction with vincristine, prednisone, and asparaginase subsequently can be reinduced into remission with the addition of daunorubicin to the regimen, the duration of second remission in children whose disease has relapsed during or within 6 months after chemotherapy is short (e.g., less than 1 year) and long-term survival is low.2,5,20 Some patients may achieve long-term, disease-free survival with intensive combination therapy or other aggressive approaches including bone marrow transplantation or hematopoietic stem cell transplantation.22 Consolidation therapy with teniposide and cytarabine in children whose disease was successfully reinduced into a second remission with daunorubicin-containing regimens appears to prolong remission; however, experience is limited, and only a minority of patients appear to achieve long-term survival.1,2,5,21 In a study in a small number of children whose ALL relapsed with a cytarabine-containing regimen, reinduction into complete remission with teniposide and cytarabine was achieved in approximately 30% of patients with a duration ranging from 30 weeks to 13 years.1 In another study in a small number of children whose ALL was refractory to regimens containing vincristine and prednisone, reinduction into complete remission with the addition of teniposide to the regimen was achieved in approximately 20% of patients with a duration ranging from 5.5 to 73 weeks.1 In a limited number of children whose ALL relapsed beyond 6 months after completion of initial chemotherapy that included vincristine, prednisone, and doxorubicin, reinduction into prolonged complete remission was achieved in more than one-third of such children with the addition of teniposide, cytarabine, and CNS prophylaxis as well as maintenance cycles of chemotherapy and late intensification cycles with teniposide and cytarabine.23 There also is evidence that the likelihood of prolonged remission may be improved, particularly in high-risk patients, by use of extended intensified chemotherapy in which teniposide, cytarabine, and other drugs are initiated for remission reinforcement prior to the development of relapse.24,25
Children with ALL should be referred to physicians who are actively engaged in the treatment of this disease and therefore are familiar with the latest and most advantageous regimens.1,22
Administration 
Teniposide is administered by slow IV infusion.1 The drug should not be administered by rapid IV injection .1 (See Cautions: Cardiovascular Effects.)
To minimize the risk of hypotensive reactions, IV infusions of teniposide should be administered over a period of at least 30-60 minutes.1,6 Patients should be observed closely for possible hypotensive or hypersensitivity reactions during administration of the drug.1 (See Cautions: Precautions and Contraindications.) When a hypotensive reaction occurs and the infusion is discontinued and then restarted after appropriate treatment of the reaction, a slower rate of infusion should be employed and the patient should be monitored carefully.1
Teniposide for injection concentrate must be diluted prior to IV infusion .1 For IV infusion, the manufacturer recommends diluting the concentrate in 5% dextrose or 0.9% sodium chloride injection to a final teniposide concentration of 0.1, 0.2, 0.4, or 1 mg/mL.1
Careful placement of the IV catheter is important so that extravasation of teniposide, which may result in local tissue necrosis and/or thrombophlebitis, is avoided.1 Patients should be observed carefully for possible occlusion of the IV access site, including central venous catheters, particularly during prolonged (e.g., 24-hour) infusions at concentrations of 0.1 or 0.2 mg/mL.1 The manufacturer's labeling should be consulted for additional information on proper techniques for dilution, storage, and administration of teniposide as well as measures to avoid precipitation of the drug.1
Dosage
Acute Lymphocytic Leukemia
Optimum dosage of teniposide for the treatment of acute lymphocytic leukemia (ALL) in children has not been established.1 The manufacturer states that a limited number of children with ALL that failed induction therapy with a cytarabine-containing regimen received combined therapy with teniposide 165 mg/m2 and cytarabine 300 mg/m2 IV twice weekly for 8 or 9 doses.1 The manufacturer also states that a limited number of children with ALL that was refractory to vincristine/prednisone-containing regimens received combined therapy with teniposide 250 mg/m2 and vincristine 1.5 mg/m2 IV weekly for 4-8 weeks and oral prednisone 40 mg/m2 daily for 28 days.1
Patients with Down syndrome may be particularly sensitive to myelosuppressive chemotherapy; therefore, the manufacturer recommends that initial doses of teniposide be reduced in such patients and suggests using half the usual dose for the first course of therapy.1 Depending on the degree of myelosuppression and mucositis encountered with initial doses in patients with Down syndrome, it may be possible subsequently to increase the dose.1
Dosage in Renal and Hepatic Impairment
There currently is insufficient experience with teniposide therapy in patients with impaired renal and/or hepatic function to make specific recommendations for dosage adjustment.1 However, the possibility that adjustment in teniposide dosage may be necessary in such patients should be considered.1
Hematologic Effects
The major and dose-limiting adverse effect of teniposide is hematologic toxicity.1,2,5,6,8,9 Myelosuppression, which is dose related,8 can be severe when teniposide is used in combination with other chemotherapeutic agents for the treatment of acute lymphocytic leukemia (ALL).1 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.1,9,22 Severe myelosuppression with resulting infection and bleeding may occur in patients receiving the drug.1,6 Infection and bleeding have occurred in about 12 and 5%, respectively, of pediatric patients receiving teniposide monotherapy.1
Myelosuppression with teniposide is manifested mainly by neutropenia (neutrophil count less than 2000/mm3), which has been reported in about 95% of pediatric patients receiving the drug as monotherapy.1 In most clinical studies evaluating teniposide, many of the patients had abnormal hematologic status at the beginning of therapy with the drug and were expected to develop substantial myelosuppression as an endpoint of treatment.1 Leukopenia (leukocyte count less than 3000/mm3) has occurred in 89% and thrombocytopenia (platelet count less than 100,000/mm3) in 85% of pediatric patients receiving teniposide monotherapy.1 Anemia has been reported in 88% of pediatric patients receiving monotherapy with the drug.1
The occurrence of secondary acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), with or without a preleukemic phase, has been reported in patients receiving teniposide in combination with other antineoplastic agents,1,10 and the potential benefit of teniposide therapy must be weighed on an individual basis against the risk of induction of a secondary leukemia.1,10 (See Cautions: Mutagenicity and Carcinogenicity.)
GI Effects
Diarrhea, nausea, and vomiting are the most frequent adverse GI effects of teniposide, occurring in about 20-30% of pediatric patients receiving the drug as monotherapy.1,9 Teniposide-induced nausea and vomiting generally are mild to moderate in severity,1,9 but have required discontinuance of the drug in about 5% of pediatric patients.9 Mucositis has occurred in about 75% of pediatric patients receiving teniposide monotherapy.1
Cardiovascular Effects
The frequency of adverse cardiovascular effects in pediatric patients receiving teniposide monotherapy is about 2%.1 Transient hypotension has occurred in about 2% of pediatric patients following rapid IV administration of the drug,1 possibly resulting from a direct effect of the polyoxyl 35 castor oil contained in the concentrate for injection.1 Hypotension occurs infrequently when teniposide is administered over at least 30-60 minutes.1,8 If clinically important hypotension occurs during administration of teniposide, infusion of the drug should be discontinued.1 Blood pressure usually normalizes within hours in response to discontinuance of the infusion and administration of IV fluids and other supportive therapy as necessary.1 One episode of sudden death attributed to intractable hypotension and probable arrhythmia was reported in a geriatric patient receiving teniposide in combination therapy for a nonleukemic malignancy.1 Hypotension also has been reported in association with somnolence and metabolic acidosis in a few pediatric patients receiving IV infusions of high-dose† teniposide and pretreatment with antiemetics.1,11 (See Cautions: Nervous System Effects.) Blood pressure changes (hypotension or hypertension), tachycardia, and flushing may occur in patients experiencing sensitivity reactions to teniposide.1,14,15,16 (See Cautions: Sensitivity Reactions.) Rarely, hypertensive reactions, sometimes severe and accompanied by cardiac failure, have been reported following teniposide administration to infants or children.12,13 Delayed hypotension, ECG changes, or other cardiac toxicity has not been documented to date with teniposide.1
Sensitivity Reactions
Hypersensitivity reactions,1,14,15,16 characterized by anaphylaxis-like signs and symptoms of chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and blood pressure changes (hypotension or hypertension), have occurred in about 5% of pediatric patients receiving teniposide monotherapy.1 (See Cautions: Precautions and Contraindications.) The reaction may occur with the initial dose of teniposide or on repeated exposure to the drug and may be life-threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, IV fluids, and other supportive measures as necessary.1 Epinephrine, with or without corticosteroids and antihistamines, has been used to alleviate the signs and symptoms of hypersensitivity reactions.1,14,15,16 The frequency of hypersensitivity reactions appears to be increased in patients with neuroblastomas or brain tumors.1,14,15 Some data suggest that the overall frequency of hypersensitivity reactions to teniposide may be as high as 50% but only rarely are they a dose-limiting adverse effect.16 The exact cause of these reactions is not known,1 but they may result from the polyoxyl 35 castor oil (Cremophor® EL, polyethoxylated castor oil) in the teniposide concentrate for injection or from teniposide itself.1,14,15,16 (For information on hypersensitivity reactions associated with this vehicle, see Cautions: Sensitivity Reactions, in Cyclosporine 92:44.) Patients who have experienced previous hypersensitivity reactions to teniposide are at risk for recurrence of the reaction1,14,15,16 and should be retreated with the drug only if the antileukemic benefit already demonstrated clearly outweighs the risk of a probable hypersensitivity reaction.1 (See Cautions: Precautions and Contraindications.) There is no evidence to date to suggest cross-sensitization between teniposide and etoposide.1
Dermatologic Effects
Alopecia, sometimes progressing to total baldness, was observed in 9% of pediatric patients who received teniposide monotherapy.1 Teniposide-induced alopecia usually is reversible.1 Rash has occurred in about 3% of patients receiving teniposide monotherapy.1
Nervous System Effects
Neurotoxicity has occurred in less than 1% of pediatric patients receiving various doses and schedules of teniposide monotherapy for a variety of hematologic malignancies and solid tumors.1 Acute CNS depression (manifested as somnolence and lethargy) and hypotension,1,11 accompanied by metabolic acidosis,11 have been observed in patients pretreated with antiemetics and receiving high-dose† regimens of teniposide.1,11 (See Cautions: Precautions and Contraindications.) These adverse effects were associated with elevated plasma teniposide concentrations and clinically important blood alcohol concentrations, apparently from the teniposide formulation.11 The alcohol content of the teniposide formulation and the depressant effects of antiemetics may place patients at risk for CNS depression when higher than recommended doses of teniposide are administered.1
Other Adverse Effects
Fever has occurred in about 3% of pediatric patients receiving teniposide monotherapy.1 Other adverse effects, which have occurred in less than 1% of pediatric patients receiving the drug as monotherapy, include hepatic or renal dysfunction and metabolic abnormalities.1
In some cases, precipitation of teniposide resulting in occlusion of central venous access devices has occurred during 24-hour infusions of solutions of the drug at a concentration of 0.1-0.2 mg/mL.1,17 Frequent observation during such infusions is necessary to minimize this risk.1 (See Dosage and Administration: Administration.)
Precautions and Contraindications
Teniposide is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without evidence of toxicity.1,2,5,6,8,9 The drug must be used only under constant supervision by physicians experienced in therapy with cytotoxic agents and only when the potential benefits of teniposide therapy are thought to outweigh the possible risks.1 Most adverse effects of teniposide are reversible if detected early.1 When severe adverse effects occur during teniposide therapy, the drug should be discontinued or dosage reduced and appropriate measures instituted as necessary.1 Teniposide therapy should be reinstituted with caution, with adequate consideration of further need for the drug and awareness of possible recurrence of toxicity.1
Patients receiving teniposide should be observed closely for at least 60 minutes after initiation of the infusion and at frequent intervals thereafter for possible hypotensive or hypersensitivity reactions, and appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of these reactions should be readily available whenever teniposide is administered.1 If clinically important hypotension occurs during administration of teniposide, infusion of the drug should be discontinued and IV fluids and other supportive therapy should be administered as necessary.1 If signs or symptoms of anaphylaxis occur during administration of the drug, the infusion should be discontinued immediately and appropriate therapy (e.g., antihistamines, epinephrine, oxygen, corticosteroids) instituted as necessary.1 Teniposide for injection concentrate generally is contraindicated in patients with known hypersensitivity to the drug or polyoxyl 35 castor oil, since such patients are at risk for recurrence of a reaction, which can be life-threatening; however, cautious administration of the drug can be considered when the antileukemic benefit already demonstrated clearly outweighs the possible risk.1 If a decision is made to treat a patient with teniposide despite a previous hypersensitivity reaction, the manufacturer recommends that the patient be pretreated with a corticosteroid and antihistamine and observed carefully during and after infusion of teniposide.1 In addition, appropriate equipment and agents (e.g., epinephrine, antihistamines, corticosteroids, IV fluids) for the management of anaphylaxis or other severe systemic reactions (e.g., hypotension) should be readily available.1
Hematologic function must be monitored frequently and carefully during and after teniposide therapy.1 Complete blood counts should be performed and renal and hepatic function evaluated before teniposide therapy is initiated and at appropriate intervals during and after therapy.1 The manufacturer states that hemoglobin, leukocyte count with differential, and platelet counts should be performed at the initiation of teniposide therapy and before each subsequent dose of the drug.1 At least one determination of hematologic status should be made before teniposide therapy is initiated.1 If necessary, repeat bone marrow examination should be performed before a decision is made to continue teniposide therapy in patients with severe myelosuppression.1Severe myelosuppression with resulting infection or bleeding may occur in patients receiving the drug.1 Treatment of severe hematologic toxicity may consist of supportive therapy, anti-infectives for complicating infections, and blood product transfusions.1
Since patients with Down syndrome and leukemia may be particularly sensitive to myelosuppressive chemotherapy, initial dosage of teniposide should be reduced in such patients.1 (See Dosage and Administration: Dosage.)
Since there appears to be an association between increased serum alkaline phosphatase or γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) concentrations and a decrease in plasma teniposide clearance, the drug should be administered with caution in patients with hepatic dysfunction.1
The alcohol content of the teniposide formulation and the depressant effects of antiemetics may place patients at risk for CNS depression when higher than recommended doses of the drug are administered.1 (See Cautions: Nervous System Effects.)
Pediatric Precautions
Safety and efficacy of teniposide have been established for combination therapy of refractory childhood acute lymphocytic leukemia.1,6 In an analysis of data from 7 studies involving 303 patients ranging in age from 0.5 months to 20 years who received teniposide as a single agent for a variety of hematologic malignancies and solid tumors, no age-related difference in tolerance was reported.1,27
Mutagenicity and Carcinogenicity
Teniposide has been shown to be mutagenic in various bacterial and mammalian genotoxicity tests.1 The drug was mutagenic in the Ames Salmonella and Bacteroides subtilis bacterial mutagenicity assays.1 Teniposide also caused DNA damage as measured by alkaline elution in human lung carcinoma-derived cell lines and gene mutations in mouse lymphoma and Chinese hamster ovary cells.1 In addition, the drug has induced chromosomal aberrations in primary human cultures of lymphocytes in vitro,1 in L5178Y/TK± mouse lymphoma cells in vitro,1,18 and in the embryonic tissue of pregnant Swiss albino mice in vivo.1 Teniposide also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells.1
Studies in animals to determine the carcinogenic potential of teniposide have not been performed to date;1 however, because compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic, the drug should be considered a potential carcinogen.1 In one study, children with ALL in remission who received maintenance therapy with teniposide once or twice weekly in combination with other antineoplastic agents were reported to have a relative risk of developing secondary acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) approximately 12 times that of patients treated with less intensive schedules.1,10 A short course of teniposide for remission-induction and/or consolidation therapy was not associated with an increased risk of secondary AML, but the number of patients assessed was small.1,10 The potential benefit of teniposide therapy must be weighed on an individual basis against the possible risk of induction of a secondary leukemia.1
Pregnancy and Lactation
Pregnancy
Teniposide may cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.1,19 The drug has been shown to be teratogenic and embryotoxic in animals.1 In pregnant rats, dose-related embryotoxicity and teratogenicity occurred following IV teniposide dosages of 0.1-3 mg/kg daily given on alternate days from day 6 to 16 postcoitum; major anomalies included rib and spinal defects, deformed extremities, anophthalmia, and celosomia, and at dosages of 1-3 mg/kg daily retardation of embryonic development, fetal abnormalities, and prenatal mortality occurred.1 There are no adequate and well-controlled studies to date using teniposide in pregnant women.1 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.1 Teniposide should be used during pregnancy only in life-threatening situations or for severe disease for which safer drugs cannot be used or are ineffective.19 When teniposide is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1
Lactation
It is not known whether teniposide is distributed into human milk.1 Because of the potential for serious adverse reactions to teniposide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Description
Teniposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent that is structurally and pharmacologically related to etoposide.1,2,3,4,5,6 Teniposide differs structurally from etoposide by addition of a thenylidene ring on the glucopyranoside ring.1
The exact mechanism(s) of action of teniposide is not known, but the drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis.1,6,7 Teniposide has been shown to induce single-stranded DNA breaks; the drug also induces double-stranded DNA breaks and DNA-protein cross-links.1,2,5 The drug's effects on DNA appear to involve inhibition of type II topoisomerase since teniposide does not intercalate into nor bind strongly to DNA.1,6 Teniposide appears to be cell-cycle specific, inducing G2-phase arrest and preferentially killing cells in the G2and late S phases.1,2,5
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.
1. Bristol-Myers Squibb. Vumon® (teniposide injection) prescribing information. Princeton, NJ: 2006 Jun.
2. National Cancer Institute Cancer Therapy Evaluation Program. Group C treatment protocol: VM-26 in combination with Ara-C for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia. NCI protocol No. 188-16. Bethesda, MD: National Cancer Institute; 1988 Aug 15.
3. Strife J, Jardine I. Analysis of the anticancer drugs VP 16-213 and VM 26 and their metabolites by high-performance liquid chromatography. J Chromatogr . 1980; 182:211-20. [PubMed 7380913]
4. Grem JL, Hoth DF, Leyland-Jones B et al. Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases. J Clin Oncol . 1988; 6:351-79. [PubMed 3276827]
5. National Cancer Institute Therapy Evaluation Program. Group C treatment protocol: VM-26 in combination with Ara-C for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia. NCI protocol No. 188-0016. Bethesda, MD: National Cancer Institute; 1989 Jan 25.
6. Anon. Teniposide for acute lymphoblastic leukemia. Med Lett Drugs Ther . 1992; 34:105-6. [PubMed 1435505]
7. Krishan A, Paika K, Frei E III. Cytofluorometric studies on the action of podophyllotoxin and epipodophyllotoxins (VM-26, VP-16-213) on the cell cycle traverse on human lymphoblasts. J Cell Biol . 1975; 66:521-30. [PubMed 1057547][PubMedCentral]
8. O'Dwyer PJ, Alonso MT, Leyland-Jones B et al. Teniposide: a review of 12 years of experience. Cancer Treat Rep . 1984; 68:1455-66. [PubMed 6391663]
9. Bristol-Myers Squibb Oncology Division. Vumon® (teniposide) concentrate for injection formulary guide. Princeton, NJ; 1992.
10. Pui CH, Ribeiro RC, Hancock ML et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med . 1991; 325:1682-7. [PubMed 1944468]
11. McLeod HL, Baker DK Jr, Pui CH et al. Somnolence, hypotension, and metabolic acidosis following high-dose teniposide treatment in children with leukemia. Cancer Chemother Pharmacol . 1991; 29:150-4. [PubMed 1760858]
12. Razon-Veronesi S. Cardiovascular toxic effects of VM26 in the treatment of acute lymphatic leukemia: presentation of two cases. Tumori . 1982; 68:253-5. [PubMed 6958114]
13. Shimizu H, Frankel LS, Culbert SJ. Severe hypertensive reactions to teniposide (VM-26) in infants with congenital leukemia. Am J Pediatr Hematol/Oncol . 1987; 9:239-41.
14. O'Dwyer PJ, King SA, Fortner CL et al. Hypersensitivity reactions to teniposide (VM-26): an analysis. J Clin Oncol . 1986; 4:1262-9. [PubMed 3525769]
15. Hayes FA, Abromowitch M, Green AA. Allergic reactions to teniposide in patients with neuroblastoma and lymphoid malignancies. Cancer Treat Rep . 1985; 69:439-41. [PubMed 3857970]
16. Kellie SJ, Crist WM, Pui CH et al. Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia. Cancer . 1991; 67:1070-5. [PubMed 1991254]
17. Strong DK, Morris LA. Precipitation of teniposide during infusion. Am J Hosp Pharm . 1990; 47:512,518. [PubMed 2316530]
18. DeMarini DM, Brock KH, Doerr CL et al. Mutagenicity and clastogenicity of teniposide (VM-26) in L5178Y/JK±-3.7.2C mouse lymphoma cells. Mutat Res . 1987; 187:141-9. [PubMed 3821767]
19. Food and Drug Administration. Prescription drug advertising; content and format for labeling of human prescription drugs. Fed Regist . 1979; 44:37434-67.
20. Bleyer WA, Sather H, Hammond GD. Prognosis and treatment after relapse of acute lymphoblastic leukemia and non-Hodgkins lymphoma: 1985. Cancer . 1986; 58:590-4. [PubMed 3459571]
21. Rivera GK, Buchanan G, Boyett JM et al. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group study. N Engl J Med . 1986; 315:273-8. [PubMed 3523250]
22. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Jul 20.
23. Sadowitz PD, Smith SD, Shuster J et al. Treatment of late bone marrow relapse in children with acute lymphocytic leukemia: a Pediatric Oncology Group study. Blood . 1993; 81: 602-9. [PubMedCentral]
24. Rivera GK, Raimondi SC, Hancock ML et al. Improved outcome in childhood acute lymphoblastic leukemia with reinforced early treatment and rotational combination chemotherapy. Lancet . 1991; 337:61-6. [PubMed 1670723]
25. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 1998 Aug 13. From FDA web site. [Web]
26. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]
27. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Vumon (teniposide) [October 1, 2002]. From FDA web site. [Web]