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Vumon

Generic Name: Teniposide
Class: Antineoplastic Agents
VA Class: AN900
Molecular Formula: C32H32O13S
CAS Number: 29767-20-2

Warning(s)

  • Administer only under supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

  • Possible severe myelosuppression with resulting infection and bleeding.1 6 (See Myelosuppression under Cautions.)

  • Possible serious and potentially fatal hypersensitivity reactions.1 14 15 16 Epinephrine, with or without corticosteroids and antihistamines, has been used to alleviate signs and symptoms.1 14 15 16 (See Sensitivity Reactions under Cautions.)

Introduction

Antineoplastic agent; a semisynthetic podophyllotoxin-derivative that is structurally and pharmacologically related to etoposide.1 2 3 4 5 6

Uses for Vumon

Acute Lymphocytic Leukemia

Induction therapy (as a component of multiple-drug antineoplastic regimens) in childhood acute lymphocytic (lymphoblastic) leukemia (ALL) that is refractory to induction with other therapy or has relapsed despite such therapy1 6 26 (designated an orphan drug by FDA for this use).25

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May prolong remission;1 23 however, experience is limited, and only a minority of patients achieve long-term survival.1 2 5 21

Vumon Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1 (See IV Administration under Dosage and Administration.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer diluted solution by slow IV infusion.1 Do not administer by rapid IV injection.1 (See Cardiovascular Effects under Cautions.)

To prevent leaching of diethylhexyl phthalate (DEHP) plasticizer, use IV administration sets that do not contain DEHP (e.g., lipid sets, low DEHP-containing nitroglycerin sets).1

Ensure that IV catheter or needle is in proper position and functional prior to infusion to avoid extravasation.1 (See Local Effects under Cautions.)

Flush IV access site thoroughly with 5% dextrose or 0.9% sodium chloride injection prior to and following administration.1 Heparin should not be used due to potential for drug precipitation.1

Observe carefully for possible occlusion of the IV access site, including central venous catheters, particularly during prolonged (e.g., 24-hour) infusions.1 (See Compatibility under Stability.)

Observe closely for possible hypotensive or hypersensitivity reactions during administration (i.e., for ≥60 minutes after initiation of infusion) and frequently thereafter.1 (See Cardiovascular Effects and also see Sensitivity Reactions under Cautions.)

Handle cautiously.1 Skin reactions may occur following accidental exposure; use protective equipment (e.g., gloves).1 If accidental contact occurs, wash skin thoroughly with soap and water or flush mucosa thoroughly with water.1

Dilution

Must be diluted before IV infusion.1

Plastic equipment or devices may soften or crack and possibly leak when used with undiluted teniposide injection.1

To prevent leaching of DEHP plasticizer, prepare diluted solutions in containers that do not contain DEHP (e.g., glass or polyolefin plastic bags or containers).1 Use of PVC containers not recommended.1

For IV infusion, dilute concentrate in 5% dextrose or 0.9% sodium chloride injection to a final concentration of 0.1, 0.2, 0.4, or 1 mg/mL.1

Rate of Administration

Administer over at least 30–60 minutes to minimize risk of hypotension.1 6 (See Cardiovascular Effects under Cautions.) If hypotensive reaction occurs, use slower rate of infusion and monitor carefully if restarting after discontinuance and appropriate treatment.1

Dosage

Pediatric Patients

Acute Lymphocytic Leukemia
Patients Who Failed Induction Therapy with a Cytarabine-containing Regimen
IV

165 mg/m2 (in combination with cytarabine 300 mg/m2) twice weekly for 8 or 9 doses.1

Patients Who Failed Induction Therapy with Vincristine/Prednisone-containing Regimens
IV

250 mg/m2 (in combination with vincristine 1.5 mg/m2) weekly for 4–8 weeks with oral prednisone 40 mg/m2 daily for 28 days.1

Special Populations

Hepatic Impairment

Use with caution; dosage adjustments may be necessary.1

Renal Impairment

Dosage adjustments may be necessary.1

Patients with Down’s Syndrome

Initially, give half the usual dose; subsequent doses may be increased depending on degree of myelosuppression and mucositis encountered with previous doses.1

Cautions for Vumon

Contraindications

  • Known hypersensitivity to teniposide or polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil).1 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer only under supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Perform CBCs and renal and hepatic function tests prior to, during, and after completion of therapy.1 (See Myelosuppression under Cautions.)

Myelosuppression

Risk of dose-limiting myelosuppression (e.g., neutropenia, leukopenia, thrombocytopenia, anemia).1 2 5 6 8 9 Severe myelosuppression with resulting infection or bleeding may occur.1 6

Monitor for myelosuppression frequently during and after treatment.1 Perform CBCs (leukocyte count with differential, platelet count, hemoglobin) prior to initiation of therapy and before each subsequent dose.1 If severe myelosuppression occurs, consider supportive therapy, antibiotics for complicating infections, and blood product transfusions; repeat bone marrow examination before continuing therapy.1

Cardiovascular Effects

Transient hypotension reported following rapid IV administration, possibly resulting from direct effect of polyoxyl 35 castor oil contained in preparation.1

Administer over at least 30–60 minutes; observe patient closely during administration (i.e., for ≥60 minutes after initiation of infusion) and frequently thereafter.1

If clinically important hypotension occurs, discontinue infusion.1 BP usually normalizes within hours in response to infusion discontinuance and administration of IV fluids and other supportive therapy as necessary.1 Use slower rate of infusion and monitor carefully if restarting after discontinuance and appropriate treatment.1

Sudden death secondary to intractable hypotension and probable arrhythmia reported in at least 1 geriatric patient receiving teniposide in combination therapy for a nonleukemic malignancy.1 Hypertensive reactions, sometimes severe and accompanied by cardiac failure, reported rarely.12 13

Nervous System Effects

Acute CNS depression (manifested as somnolence and lethargy) and hypotension, accompanied by metabolic acidosis,11 reported in patients pretreated with antiemetics and receiving high-dose regimens of teniposide.1 11 CNS depression possibly resulting from depressant effects of antiemetic agents and high alcohol content of teniposide formulation.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 19 Teratogenicity and embryotoxicity demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if pregnancy occurs during therapy, apprise of potential fetal hazard.1

Sensitivity Reactions

Hypersensitivity Reactions

Risk of hypersensitivity reactions,1 14 15 16 including anaphylaxis-like manifestations (e.g., chills, fever, urticaria, tachycardia, flushing, bronchospasm, dyspnea, hypotension or hypertension).1 Reaction may occur with initial dose or with repeated exposure and may be life-threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, IV fluids, and other supportive measures as necessary.1 Etiology unknown, but reactions may result from polyoxyl 35 castor oil component or from teniposide itself.1 14 15 16 Frequency possibly increased in patients with neuroblastomas or brain tumors.1 14 15 Observe patients closely during administration (i.e., for ≥60 minutes after initiation of infusion) and frequently thereafter.1 If manifestations of anaphylaxis occur, discontinue infusion immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, antihistamines, pressor agents, IV fluids).1

Generally contraindicated in patients with known hypersensitivity to teniposide or polyoxyl 35 castor oil; however, may consider cautious administration when the antileukemic benefit already demonstrated clearly outweighs the possible risk.1 When reinitiating therapy in a patient who previously developed a hypersensitivity reaction, pretreat with a corticosteroid and antihistamine and observe patient carefully during and after infusion.1

Appropriate equipment and agents (e.g., epinephrine, antihistamines, corticosteroids, IV fluids, oxygen) should be readily available.1

No evidence of cross-sensitization between teniposide and etoposide.1

General Precautions

Toxicity

Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits outweigh the possible risks.1

Most adverse effects are reversible if detected early.1

Discontinue or reduce dosage and institute appropriate measures as necessary when severe adverse effects occur.1

Reinstitute therapy with caution, considering further need for the drug and possible toxicity recurrence.1

Local Effects

Extravasation may result in local tissue necrosis and/or thrombophlebitis.1

Dermatologic Effects

Alopecia reported; usually reversible but sometimes may progress to total baldness.1

Carcinogenicity

Secondary acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), with or without a preleukemic phase, reported in patients receiving maintenance therapy with teniposide in combination with other antineoplastic agents.1 10 Assess potential benefit versus risks of therapy.1 10

Animal studies to determine the carcinogenic potential of teniposide have not been performed to date; however, the drug should be considered a potential carcinogen.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether teniposide is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy established only for combination therapy of refractory childhood ALL.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.27 f

Each mL of teniposide concentrate for injection contains 30 mg of benzyl alcohol.1 Although a causal relationship has not been established, injections preserved with benzyl alcohol have been associated with toxicity in neonates.a b c d e

Hepatic Impairment

Use with caution.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Patients with Down’s Syndrome

Possible increased sensitivity to myelosuppressive chemotherapy.1 Dosage adjustments necessary.1 (See Down's Syndrome under Dosage and Administration.)

Patients with Hypoalbuminemia

Careful monitoring recommended.1 (See Distribution: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Neutropenia, leukopenia, anemia, thrombocytopenia, myelosuppression (nonspecified), mucositis, diarrhea, nausea, vomiting, infection, alopecia, bleeding, hypersensitivity reactions, rash, fever, hypotension.1

Interactions for Vumon

Specific Drugs

Drug

Interaction

Comments

Antiemetic agents

Possible CNS depression when used concomitantly with higher than recommended dosages of teniposide1

Methotrexate

Possible increased methotrexate clearance1

Sodium salicylate

Possibility of substantially increased plasma teniposide concentrations and potential for increased toxicity1

Use concomitantly with caution1

Sulfamethizole

Possibility of substantially increased plasma teniposide concentrations and potential for increased toxicity1

Use concomitantly with caution1

Tolbutamide

Possibility of substantially increased plasma teniposide concentrations and potential for increased toxicity1

Use concomitantly with caution1

Vumon Pharmacokinetics

Distribution

Extent

Limited distribution throughout the body because of extensive protein binding.1 Limited distribution into the brain; however, CSF concentrations are higher in patients with brain tumors.1

Concentrations in saliva, CSF, and malignant ascites fluid are low relative to those in plasma.1

Plasma Protein Binding

>99%.1

Special Populations

Volume of distribution increases with decreasing albumin concentrations.1 (See Patients with Hypoalbuminemia under Cautions.)

Elimination

Elimination Route

44% of dose is excreted in urine within 120 hours after dosing (with only 4–12% excreted as unchanged drug); 0–10% of dose is excreted in feces within 72 hours.1

Half-life

5 hours.1

Special Populations

Possible association between increased concentrations of serum alkaline phosphatase or γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) and a decrease in plasma teniposide clearance.1 (See Hepatic Impairment under Cautions.)

Stability

Storage

Parenteral

Injection

2–8°C; protect from light.1

Store diluted solutions at room temperature; do not refrigerate.1 Diluted solutions at concentrations of 0.1, 0.2, or 0.4 mg/mL are stable for up to 24 hours at room temperature.1 Diluted solutions at concentration of 1 mg/mL should be administered within 4 hours to reduce potential for precipitation.1 Stability and use times are identical for solutions prepared in glass or plastic containers.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Possible precipitation of diluted solutions.1 Precipitation reported during 24-hour infusions of teniposide diluted to concentrations of 0.1–0.2 mg/mL, resulting in occlusion of central venous access catheters.1 17 (See IV Administration under Dosage and Administration.) To minimize precipitation, avoid agitation, decrease storage time prior to administration, and avoid contact with other drugs or fluids.1

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Allopurinol

Amifostine

Amikacin sulfate

Aminophylline

Amphotericin B

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefazolin sodium

Cefotaxime sodium

Cefoxitin sodium

Ceftazidime

Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Chlorpromazine HCl

Cimetidine HCl

Ciprofloxacin

Cisplatin

Cladribine

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Dactinomycin

Daunorubicin HCl

Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Etoposide

Etoposide phosphate

Famotidine

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gallium nitrate

Ganciclovir sodium

Gemcitabine HCl

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Ifosfamide

Imipenem–cilastatin sodium

Leucovorin calcium

Lorazepam

Mannitol

Mechlorethamine HCl

Melphalan HCl

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Minocycline HCl

Mitomycin

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Netilmicin sulfate

Ondansetron HCl

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sargramostim

Sodium bicarbonate

Streptozocin

Thiotepa

Ticarcillin disodium

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Heparin1

Idarubicin HCl

Actions

  • Exact mechanism(s) of action not known; apparently produces cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis.1 6 7

  • Induces single- and double-stranded DNA breaks and also induces DNA-protein cross-links,1 2 5 possibly through inhibition of type II topoisomerase.1 6

  • Cell-cycle specific, inducing G2-phase arrest and preferentially killing cells in the G2 and late S phases.1 2 5

Advice to Patients

  • Importance of advising patients and/or their parents or guardians of adverse effects and associated manifestations.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Teniposide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion only

10 mg/mL

Vumon (with dehydrated alcohol 42.7% and benzyl alcohol 30 mg and polyoxyl 35 castor oil 500 mg per mL)

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb Oncology Division. Vumon (teniposide injection) prescribing information. Princeton, NJ: 1998 Oct.

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. [IDIS 178818] [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]

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. [IDIS 195977] [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. [IDIS 288970] [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. [IDIS 201327] [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. [IDIS 277532] [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. [IDIS 218989] [PubMed 3523250]

22. Childhood acute lymphoblastic leukemia. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

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.

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. [IDIS 276376] [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 ().

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 .

a. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-11. [PubMed 7188569]

b. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

c. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

d. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

e. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

f. Bristol-Myers Squibb Company. Vumon (teniposide injection) prescribing information. Princeton, NJ: 2004 Aug.

HID. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:1272-1280.

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