Vumon

Teniposide is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Teniposide is used to treat acute lymphoblastic leukemia (a type of blood cancer) in children.

Teniposide is usually given after other cancer medications have been tried without successful treatment.

Teniposide may also be used for purposes not listed in this medication guide.

Do not receive teniposide if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are receiving teniposide, whether you are a man or a woman. Teniposide use by either parent may cause birth defects.

Before receiving teniposide, tell your doctor if you have kidney or liver disease, Down syndrome, bone marrow suppression, low albumin levels, or a weak immune system.

Teniposide can lower blood cells that help your body fight infections. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

Using teniposide may increase your risk of developing other types of cancer, such as leukemia. Talk with your doctor about your specific risk.

Call your doctor at once if you have a serious side effect such as fever, chills, flu symptoms, mouth sores, easy bruising, unusual bleeding, pale skin, fast heart rate, trouble breathing, severe headache, severe nausea and vomiting, or feeling like you might pass out.

You should not receive this medication if you are allergic to teniposide or to a medication ingredient called Cremophor (synthetic castor oil).

To make sure you can safely receive teniposide, tell your doctor if you have any of these other conditions:

• Down Syndrome;
• bone marrow suppression;
• liver or kidney disease;
• low albumin levels; or
• a weak immune system (from disease or from taking certain medicines).

Do not receive teniposide if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are receiving teniposide, whether you are a man or a woman. Teniposide use by either parent may cause birth defects.

This medication can decrease sperm count and may affect fertility in men (your ability to have children).

It is not known whether teniposide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using teniposide.

Using teniposide may increase your risk of developing other types of leukemia. Talk with your doctor about your specific risk.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

• fever, chills, itching, body aches, flu symptoms, sores in your mouth and throat;
• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
• fast or pounding heartbeats, wheezing, chest tightness, trouble breathing;
• severe headache, buzzing in your ears, anxiety, confusion, chest pain, uneven heartbeats;
• pain, burning, irritation, or skin changes where the injection was given;
• feeling like you might pass out; or
• severe nausea and vomiting.

Less serious side effects may include:

• mild headache;
• drowsiness, dizziness, feeling tired or weak;
• mild nausea, stomach pain, loss of appetite;
• constipation, diarrhea;
• temporary hair loss; or
• mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You should not receive this medication if you are allergic to teniposide or to a medication ingredient called Cremophor (synthetic castor oil).

To make sure you can safely receive teniposide, tell your doctor if you have any of these other conditions:

• Down Syndrome;
• bone marrow suppression;
• liver or kidney disease;
• low albumin levels; or
• a weak immune system (from disease or from taking certain medicines).

FDA pregnancy category D. Do not receive teniposide if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are receiving teniposide, whether you are a man or a woman. Teniposide use by either parent may cause birth defects.

This medication can decrease sperm count and may affect fertility in men (your ability to have children).

It is not known whether teniposide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using teniposide.

Using teniposide may increase your risk of developing other types of leukemia. Talk with your doctor about your specific risk.

Vumon is a prescription medication used to treat acute lymphocytic leukemia (ALL) in children. ALL is a type of cancer of the white blood cells. Vumon belongs to a group of drugs known as podophyllotoxin derivatives. These work by slowing or stopping the growth of cancer cells in your body.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects include low blood counts, inflammation and sores in the mouth, and diarrhea.

Vumon is part of the drug class:

• Podophyllotoxin derivatives

Common side effects of Vumon include the following:

• low blood cell counts
• sores and inflammation of the mouth
• diarrhea
• nausea
• vomiting
• infection
• hair loss
• bleeding
• rash
• fever

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Contraindications

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

Warnings/Precautions

Warnings

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.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.)

Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis.

Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. 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. 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.

Teniposide has a broad spectrum of in vivo antitumor activity against murine tumors, including hematologic malignancies and various solid tumors. Notably, teniposide is active against sublines of certain murine leukemias with acquired resistance to cisplatin, doxorubicin, amsacrine, daunorubicin, mitoxantrone, or vincristine.

Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m2 over 1 to 2.5 hours) of Vumon given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows:

There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if Vumon is to be administered to patients with hepatic dysfunction.

In adults, at doses of 100 to 333 mg/m2/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of Vumon for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m2 over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL.

Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m2 of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. 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.

Mean steady-state volumes of distribution range from 8 to 44 L/m2 for adults and 3 to 11 L/m2 for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors.

Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels.

The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide.

In a study at St. Jude Children’s Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with Vumon plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL refractory to vincristine/prednisone-containing regimens were treated with Vumon plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these 2 studies, patients served as their own control based on the premise that long-term complete remissions could not be achieved by re-treatment with drugs to which they had previously failed to respond.

Vumon 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 Vumon (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 Vumon therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of Vumon: 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 Vumon 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 Cremophor® EL (polyoxyethylated castor oil) component of the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to Vumon are at risk for recurrence of symptoms and should only be re-treated with Vumon if the antileukemic benefit already demonstrated clearly outweighs the risk of a probable hypersensitivity reaction for that patient. When a decision is made to re-treat a patient with Vumon in spite of an earlier hypersensitivity reaction, the patient should be pretreated with corticosteroids and antihistamines and receive careful clinical observation during and after Vumon infusion. In the clinical experience with Vumon at SJCRH and the National Cancer Institute (NCI), re-treatment of patients with prior hypersensitivity reactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between Vumon and VePesid®.

One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving Vumon combination therapy for a non-leukemic malignancy. (See ADVERSE REACTIONS.) Patients receiving Vumon 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, Vumon 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 Cremophor® EL. If clinically significant hypotension develops, the Vumon 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 Vumon who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the Vumon formulation may place patients receiving higher than recommended doses of Vumon at risk for central nervous system depression.

Pregnancy

Vumon may cause fetal harm when administered to a pregnant woman. Vumon has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous administration of Vumon, 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 Vumon 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 Vumon.

Male Fertility

In animal studies, Vumon 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 Vumon 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.