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TENIPOSIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Teniposide, a podophyllotoxin derivative, is a cell cycle phase-specific antineoplastic agent.

Specific Substances

    1) Epipodophyllotoxin, 4'-demethyl-,9-(4,6-O-2-thenylidene-beta-D-glucopyranoside)
    2) 4'-Demethyl-epipodophyllotoxin-beta-D-thenylidene-glucoside
    3) VM-26
    4) NSC-122819
    5) CAS 29767-20-2
    1.2.1) MOLECULAR FORMULA
    1) C32H32O13S (Prod Info teniposide intravenous injection, 2015)

Available Forms Sources

    A) FORMS
    1) Teniposide is available in 50 mg/5 mL (10 mg/mL) ampules for injection. Each mL contains 10 mg teniposide, 30 mg benzyl alcohol, 60 mg N,N-dimethylacetamide, 500 mg purified polyoxyl 35 castor oil and 42.7% (v/v) dehydrated alcohol (Prod Info teniposide intravenous injection, 2015).
    B) USES
    1) In combination with other antineoplastic agents, teniposide is used for induction therapy in patients with refractory childhood acute lymphoblastic leukemia (Prod Info teniposide intravenous injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Teniposide, a phase-specific cytotoxic agent, is used in combination with other antineoplastic agents for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.
    B) PHARMACOLOGY: Teniposide acts at the premitotic stage of cell division to prevent cells from entering mitosis by causing dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. It does not intercalate into or bind strongly to DNA. It is cell phase–specific, acting in the late S or early G2 phase of cell division.
    C) TOXICOLOGY: Teniposide is a semi-synthetic derivative of podophyllotoxin. Overdose effects are likely to occur in rapidly dividing cells (ie, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Teniposide is intended for children only; limited reports of exposure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: FREQUENT: Myelosuppression is the dose-limiting toxicity. Other adverse effects that may commonly occur include nausea, vomiting, mucositis, and diarrhea. RARE: Hypersensitivity reactions, consisting of chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and blood pressure changes (hypotension or hypertension). Transient hypotension following rapid intravenous administration have been infrequently reported in pediatric patients and may be due to the ethanol content of the formulation.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Severe myelosuppression is anticipated following overdose. Hypotension, metabolic acidosis and somnolence have been reported after 3 to 5 times the usual therapeutic dose.
    2) MILD TO MODERATE TOXICITY: Events are anticipated to be similar to adverse effects reported with therapy. Hematologic toxicity includes: myelosuppression, leukopenia, neutropenia, thrombocytopenia and anemia. Gastrointestinal effects include: mucositis, diarrhea and nausea/vomiting.
    3) SEVERE TOXICITY: Severe myelosuppression may produce bleeding and infection. Hypersensitivity reactions including anaphylaxis-like symptoms may develop.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Transient hypotension has been reported infrequently in pediatric patients following rapid intravenous administration of teniposide. It has been suggested that the ethanol content in the formulation may produce hypotensive symptoms.
    2) Severe hypertension was reported in two 6-week-old female infants, with congenital leukemia, who received intravenous teniposide therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Acute CNS depression has been reported in patients following administration of high-dose intravenous infusions of teniposide who were pretreated with antiemetic agents.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal effects including mild to moderate nausea and vomiting, diarrhea and mucositis are frequently reported during therapy.
    0.2.11) ACID-BASE
    A) WITH THERAPEUTIC USE
    1) Metabolic acidosis has been rarely reported following teniposide administration.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) The dose-limiting toxic effect of teniposide is myelosuppression, specifically, neutropenia and thrombocytopenia have occurred in up to 95% of patients.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Allergic reactions, including anaphylaxis, have occurred during teniposide administration, and may occur more frequently in patients with brain tumors or neuroblastoma.
    0.2.20) REPRODUCTIVE
    A) Teniposide is classified as FDA pregnancy category D. There are no adequate and well-controlled studies of teniposide use in pregnant women. In a single case, a normal infant was delivered to a mother who received teniposide during the second and third trimesters. Embryotoxicity and teratogenicity, including spinal and rib defects, deformed extremities, anophthalmia, and celosomia, have been reported following teniposide administration in animals. There was evidence of decreased sperm count and genetic damage to sperm in animal studies.
    0.2.21) CARCINOGENICITY
    A) The relative risk of developing secondary acute non-lymphogenic leukemia (ANLL) was approximately 12 times greater in patients who received weekly or twice weekly teniposide in combination with other chemotherapeutic agents compared to patients who were treated with less intensive treatment schedules.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor renal and hepatic function in patients with significant exposure.
    C) Monitor fluid and electrolytes and acid-base status in patients with prolonged vomiting or diarrhea or with high dose teniposide.
    D) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor vital signs with rapid intravenous administration of teniposide.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Teniposide is administered by the intravenous route. See PARENTERAL overview for further treatment information.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes and IV fluids as needed. Treat significant diarrhea with antidiarrheal agents. Monitor vital signs for clinically significant hypotension. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe myelosuppression (ie, neutropenia).
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. MYELOSUPPRESSION: Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. HYPOTENSION: IV 0.9% NaCl, dopamine, norepinephrine. Central venous pressure monitoring may be indicated to guide fluid therapy. ANAPHYLAXIS: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    C) DECONTAMINATION
    1) Decontamination is not necessary in most situations as teniposide is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if unstable due to an infusion reaction (hypersensitivity reaction) or unstable hypotension.
    E) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day subQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    F) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    G) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    H) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    I) EXTRAVASATION INJURY
    1) Teniposide is classified as a neutral agent by one source and an irritant by another. If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer hyaluronidase (see dosing below). Elevate the affected area. Apply warm packs for 15 to 20 minutes for at least 4 times daily. Administer analgesics for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. HYALURONIDASE: 150 Units (1 mL) given as five 0.2 mL injections into the extravasation site at the leading edge; use a solution of 150 Units/1 mL vial and do not dilute further. Use a 25-gauge needle or smaller to inject subQ or intradermally into the extravasation site. Change needle after each injection. Other sources recommend the following hyaluronidase dose: 150 to 900 Units subQ or intradermally.
    J) INTRATHECAL INJECTION
    1) Intrathecal overdose with teniposide has not been reported, however, acute CNS depression has been observed in patients receiving higher than recommended doses of teniposide. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as teniposide is highly protein bound. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    K) ENHANCED ELIMINATION
    1) It is unlikely that hemodialysis would be useful because teniposide is highly protein bound. Plasmapheresis or plasma exchange might be useful if performed early after large overdose, but use of these modalities has not been reported.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PHARMACOKINETICS
    1) Teniposide is highly protein bound (greater than 99%) with a mean steady-state volume of distribution range from 8 to 44 L/m(2) for adults and 3 to 11 L/m(2) for children. In addition, steady-state volume of distribution increases with a decrease in plasma albumin levels (ie, hypoalbuminemia). Terminal half-life is 5 hours. Renal clearance of the parent compound accounts for about 10% of total body clearance.
    N) PITFALLS
    1) Symptoms of overdose are likely similar to reported side effects of teniposide. Overdose can result in an early onset of myelosuppression with a delay in recovery (ie, patients being treated for refractory ALL), so reliable and ongoing follow-up is imperative.
    O) DIFFERENTIAL DIAGNOSIS
    1) Underlying disease process. Other antineoplastic agents may contribute to or worsen hematologic toxicity.

Range Of Toxicity

    A) TOXIC DOSE: A specific toxic dose of teniposide has not been established. Doses of 567 to 893 mg/m(2) have caused somnolence, hypotension and metabolic acidosis in children.
    B) THERAPEUTIC DOSE: ADULT: Not indicated for adult use. PEDIATRIC: The recommended dose ranges from 165 mg/m(2) IV twice weekly for 8-9 doses to 250 mg/m(2) IV weekly for 4-8 weeks.

Clinical Effects

Summary Of Exposure

    A) USES: Teniposide, a phase-specific cytotoxic agent, is used in combination with other antineoplastic agents for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.
    B) PHARMACOLOGY: Teniposide acts at the premitotic stage of cell division to prevent cells from entering mitosis by causing dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. It does not intercalate into or bind strongly to DNA. It is cell phase–specific, acting in the late S or early G2 phase of cell division.
    C) TOXICOLOGY: Teniposide is a semi-synthetic derivative of podophyllotoxin. Overdose effects are likely to occur in rapidly dividing cells (ie, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Teniposide is intended for children only; limited reports of exposure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: FREQUENT: Myelosuppression is the dose-limiting toxicity. Other adverse effects that may commonly occur include nausea, vomiting, mucositis, and diarrhea. RARE: Hypersensitivity reactions, consisting of chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and blood pressure changes (hypotension or hypertension). Transient hypotension following rapid intravenous administration have been infrequently reported in pediatric patients and may be due to the ethanol content of the formulation.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Severe myelosuppression is anticipated following overdose. Hypotension, metabolic acidosis and somnolence have been reported after 3 to 5 times the usual therapeutic dose.
    2) MILD TO MODERATE TOXICITY: Events are anticipated to be similar to adverse effects reported with therapy. Hematologic toxicity includes: myelosuppression, leukopenia, neutropenia, thrombocytopenia and anemia. Gastrointestinal effects include: mucositis, diarrhea and nausea/vomiting.
    3) SEVERE TOXICITY: Severe myelosuppression may produce bleeding and infection. Hypersensitivity reactions including anaphylaxis-like symptoms may develop.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Transient hypotension has been reported infrequently in pediatric patients following rapid intravenous administration of teniposide. It has been suggested that the ethanol content in the formulation may produce hypotensive symptoms.
    2) Severe hypertension was reported in two 6-week-old female infants, with congenital leukemia, who received intravenous teniposide therapy.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Transient hypotension has been reported in 2% of evaluable pediatric patients following rapid intravenous administration of teniposide (Prod Info teniposide intravenous injection, 2015).
    b) Hypotension, somnolence, and metabolic acidosis were reported in three pediatric cases with high-dose teniposide plus cytarabine for the treatment of leukemia. Teniposide was given in doses or 567 mg/m(2), 614 mg/m(2), and 893 mg/m(2) (3 to 5 times the conventional dose of 200 mg/m(2)). These effects occurred during or shortly after the end of the infusion and were thought to be related to the ethanol content in the formulation (McLeod et al, 1991).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Severe hypertension was reported in 2 6-week old female infants, with congenital leukemia, who received intravenous teniposide therapy. The first patient developed an increase of 50 mmHg of her systolic pressure (baseline was 80 mmHg) after receiving the second dose of teniposide, 1 mg/mL (a total volume of 18 mL) given over 30 minutes. Following the third teniposide dose, the patient's systolic blood pressure increased to 150 mmHg. Despite management with hydralazine, the patient's blood pressure continued to fluctuate and, following the fifth dose, the patient experienced a hypertensive crisis (systolic BP greater than 200 mg) followed by a seizure. The patient's blood pressure gradually normalized with supportive therapy. The second patient also experienced a hypertensive crisis (systolic blood pressure of 200 mmHg) 2 hours after completion of teniposide infusion, 5 mg/kg administered over 45 minutes. Although the patient's blood pressure began to normalize following intravenous administration of diphenhydramine, approximately 5 days later her blood pressure peaked at 300 mmHg and was uncontrollable. Although a renovascular origin was suggested, an abdominal ultrasound ruled out any renal abnormalities as the cause of severe hypertension. The patient died of severe hypertension combined with myelosuppression (Shimizu et al, 1987).

Reproductive

    3.20.1) SUMMARY
    A) Teniposide is classified as FDA pregnancy category D. There are no adequate and well-controlled studies of teniposide use in pregnant women. In a single case, a normal infant was delivered to a mother who received teniposide during the second and third trimesters. Embryotoxicity and teratogenicity, including spinal and rib defects, deformed extremities, anophthalmia, and celosomia, have been reported following teniposide administration in animals. There was evidence of decreased sperm count and genetic damage to sperm in animal studies.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In a case report, teniposide used in combination with other chemotherapy during the second and third trimester of pregnancy did not have an adverse effect on the infant born at 37 weeks gestation. A normal infant was delivered to a woman with Burkitt lymphoma who had received teniposide 75 to 100 mg/m(2) every 2.5 to 3 weeks beginning in the 22nd gestational week and continuing for 6 courses (Lowenthal et al, 1982).
    B) ANIMAL STUDIES
    1) Intravenous administration of teniposide to pregnant animals, at doses of 0.1 to 3 mg/kg (0.6 to 18 mg/m(2)) every second day from day 6 to day 16 following mating, resulted in dose-related embryotoxicity and teratogenicity, including spinal and rib defects, deformed extremities, anophthalmia, and celosomia (Prod Info teniposide intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Teniposide is classified as FDA pregnancy category D (Prod Info teniposide intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) Retardation of embryonic development, prenatal mortality, and fetal abnormalities were noted as a result of treatment of pregnant animals with IV teniposide doses between 0.1 and 3 mg/kg/day on alternate days from day 6 to 16 post-coitum (Prod Info teniposide intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known if teniposide is excreted in human milk (Prod Info teniposide intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) There was evidence of decreased sperm count and genetic damage to sperm in animal studies (Prod Info teniposide intravenous injection, 2015).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS29767-20-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Teniposide
    b) Carcinogen Rating: 2A
    1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    3.21.2) SUMMARY/HUMAN
    A) The relative risk of developing secondary acute non-lymphogenic leukemia (ANLL) was approximately 12 times greater in patients who received weekly or twice weekly teniposide in combination with other chemotherapeutic agents compared to patients who were treated with less intensive treatment schedules.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) The relative risk of developing secondary acute non-lymphogenic leukemia (ANLL) was approximately 12 times greater in patients who received weekly or twice weekly teniposide in combination with other chemotherapeutic agents compared to patients who were treated with less intensive treatment schedules (Prod Info teniposide intravenous injection, 2015).
    2) In a small number of patients, short course treatment for remission-induced and/or consolidation therapy with teniposide was not shown to increase the risk of developing secondary ANLL. However, only a small number of patients were assessed and larger studies are needed to determine the true risk of developing secondary ANLL (Prod Info teniposide intravenous injection, 2015).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenicity studies with teniposide have not been conducted in animals. However, teniposide should be considered a potential carcinogen in humans as compounds with similar mechanisms of action have been reported to be carcinogenic (Prod Info teniposide intravenous injection, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY DISTRESS
    1) WITH THERAPEUTIC USE
    a) Pulmonary hyaline membrane disease was reported in a 16-year-old boy following 10 weeks of treatment with teniposide for medulloblastoma. The patient developed dyspnea and worsening of obtundation. Biopsy revealed alveoli lining with a thick hyaline-like fibrinous material and marked interstitial infiltration with lymphocytes. Histiocytes and giant cells were also present (Commers & Foley, 1979).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Acute CNS depression has been reported in patients following administration of high-dose intravenous infusions of teniposide who were pretreated with antiemetic agents.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEPRESSION
    1) WITH THERAPEUTIC USE
    a) Acute CNS depression occurred in patients following administration of high-dose intravenous infusions of teniposide and who were pretreated with antiemetic agents. It is believed that the depressant effects of the antiemetics as well as the alcohol content of the teniposide formulation may have been contributing factors (Prod Info teniposide intravenous injection, 2015).
    b) Somnolence, hypotension, and metabolic acidosis were reported in three pediatric cases with high-dose teniposide plus cytarabine for the treatment of leukemia. Teniposide was given in doses of 567 mg/m(2), 614 mg/m(2), and 893 mg/m(2) (3 to 5 times the conventional dose of 200 mg/m(2)). These symptoms occurred during or shortly after the end of the infusion and were thought to be related to the ethanol content in the formulation (McLeod et al, 1991)

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal effects including mild to moderate nausea and vomiting, diarrhea and mucositis are frequently reported during therapy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported in 29% of pediatric patients (n=303) who received teniposide as single-agent therapy (Prod Info teniposide intravenous injection, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 33% of pediatric patients (n=303) who received teniposide as single-agent therapy (Prod Info teniposide intravenous injection, 2015).
    C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Mucositis was reported in 76% of pediatric patients (n=303) who received teniposide as single-agent therapy (Prod Info teniposide intravenous injection, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure associated with immune hemolytic anemia was reported in a 47-year-old man receiving teniposide and lomustine. Following the 34th infusion of teniposide (total dose of 3000 mg), malaise, chills, nausea, fever, myalgia and lumbar pain were observed with a significant drop in systolic pressure. Urine output decreased to 200 mL per 24 hours and hematocrit increased significantly. Hemoglobinuria was present and jaundice developed. Following diuretic treatment, BUN, urine output and creatinine returned to normal after 2 weeks and the patient was well during 21-month follow up. A direct Coomb's test was strongly positive with 4 anti-serums to IgG, and antibody to teniposide (Habibi et al, 1982; Habibi et al, 1981).

Acid-Base

    3.11.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Metabolic acidosis has been rarely reported following teniposide administration.
    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Hypotension, somnolence, and metabolic acidosis were reported in three pediatric cases with high-dose teniposide plus cytarabine for the treatment of leukemia. Teniposide was given in doses of 567 mg/m(2), 614 mg/m(2), and 893 mg/m(2) (3 to 5 times the conventional dose). These effects occurred during or shortly after the end of the infusion and were thought to be related in part to the ethanol content in the formulation. In the first case, a 2-year-old-girl, a serum bicarbonate was measured at 13 mEq/L one hour after the end of infusion. A plasma ethanol concentration taken during the teniposide infusion was 80 mg/dL. In the second case, a 10-year-old girl experienced symptoms 2 hours into the infusion. The serum bicarbonate obtained one hour after the onset of symptoms was 20 mEq/L. The whole blood ethanol concentration during the infusion was 130 mg/dL. In the third case, a 3-year-old-girl, venous blood gas results obtained 1 hour after the infusion was stopped were pH 7.07, pCO2 32 mmHg, pO2 44 mmHg, and bicarbonate of 9.3 mEq/L. A whole blood ethanol concentration of 60 mg/dL was obtained just 10 minutes prior to the start of symptoms (McLeod et al, 1991).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) The dose-limiting toxic effect of teniposide is myelosuppression, specifically, neutropenia and thrombocytopenia have occurred in up to 95% of patients.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) The dose-limiting toxic effect of teniposide is myelosuppression. Anemia, leukopenia, neutropenia, and thrombocytopenia are common and can be expected when using the doses and schedules of teniposide necessary for the treatment of acute nonlymphocytic leukemia. Specifically, neutropenia (less than 2000 ANC/mcL) and thrombocytopenia (less 100,000 plt/mcl) have occurred in up to 95% of patients (Prod Info teniposide intravenous injection, 2015).
    b) Death secondary to bone marrow aplasia and septicemia has been reported (Pouillart et al, 1979; Cerny et al, 1988).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported in 88% of pediatric patients (n=303) who received teniposide as single-agent therapy (Prod Info teniposide intravenous injection, 2015).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia (less than 3000 WBC/mcL) was reported in 89% of pediatric patients (n=303) who received teniposide as single-agent therapy (Prod Info teniposide intravenous injection, 2015).
    D) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Teniposide-induced hemolytic anemia concomitant with renal failure has been reported in the presence of anti-teniposide antibody (Habibi et al, 1982; Habibi et al, 1981).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia, sometimes progressing to complete baldness, was reported in 9% of pediatric patients (n=303) who received teniposide as single-agent therapy. The alopecia was typically reversible (Prod Info teniposide intravenous injection, 2015).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Allergic reactions, including anaphylaxis, have occurred during teniposide administration, and may occur more frequently in patients with brain tumors or neuroblastoma.
    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions, including anaphylaxis, have occurred during teniposide administration (Prod Info teniposide intravenous injection, 2015; Kellie et al, 1991; Anon, 1979; Seiler et al, 1979; Chiuten et al, 1979; Dombernowsky et al, 1972). These reactions are characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and hypo- or hypertension. The incidence is approximately 5% in pediatric patients. This incidence may be greater in patients with brain tumors or neuroblastoma (Prod Info teniposide intravenous injection, 2015).

Genotoxicity

    A) Chromosome structure aberrations were induced from teniposide in primary cultures of human lymphocytes in vitro and in L5178y/TK +/- mouse lymphoma cells in vitro, as well as in the embryonic tissue (in vivo) of pregnant Swiss albino mice. Dose-related increases in sister chromatid exchanges in Chinese hamster ovary cells were also observed (Prod Info teniposide intravenous injection, 2015).
    B) Mutagenicity from teniposide has been demonstrated in bacterial and mammalian genetic toxicity tests. Both the Ames/Salmonella and B. subtilis bacterial mutagenicity assays demonstrated positive mutagenic effects. Gene mutations and DNA damage (alkaline elution in human lung carcinoma derived cell lines) were noted in both Chinese hamster ovary cells and mouse lymphoma cells (Prod Info teniposide intravenous injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor renal and hepatic function in patients with significant exposure.
    C) Monitor fluid and electrolytes and acid-base status in patients with prolonged vomiting or diarrhea or with high dose teniposide.
    D) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor vital signs with rapid intravenous administration of teniposide.
    4.1.2) SERUM/BLOOD
    A) Complete blood counts should be monitored in all patients.
    B) Monitor renal and hepatic function in patients with significant exposure.
    C) Monitor fluid and electrolytes in patients with prolonged vomiting or diarrhea or with high dose teniposide.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor renal and hepatic function in patients with significant exposure.
    C) Monitor fluid and electrolytes and acid-base status in patients with prolonged vomiting or diarrhea or with high dose teniposide.
    D) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Monitor vital signs with rapid intravenous administration of teniposide.

Oral Exposure

    6.5.3) TREATMENT
    A) SUPPORT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) Hemodialysis is unlikely to be beneficial because teniposide is highly protein bound.
    2) The effectiveness of plasma exchange has not been reported. Removal of plasma proteins might be an effective method of reducing the body burden following overdose.

Range Of Toxicity

Summary

    A) TOXIC DOSE: A specific toxic dose of teniposide has not been established. Doses of 567 to 893 mg/m(2) have caused somnolence, hypotension and metabolic acidosis in children.
    B) THERAPEUTIC DOSE: ADULT: Not indicated for adult use. PEDIATRIC: The recommended dose ranges from 165 mg/m(2) IV twice weekly for 8-9 doses to 250 mg/m(2) IV weekly for 4-8 weeks.

Therapeutic Dose

    7.2.1) ADULT
    A) Teniposide is not currently FDA approved for use in adult patients.
    7.2.2) PEDIATRIC
    A) INDUCTION THERAPY: The suggested dose is 165 mg/m(2) IV, with 300 mg/m(2) IV cytarabine, twice weekly for 8 to 9 doses (Prod Info teniposide intravenous injection, 2015).
    B) REFRACTORY THERAPY to vincristine/prednisone regimens: The suggested dose is 250 mg/m(2) IV, with 1.5 mg/m(2) IV vincristine, weekly for 4 to 8 weeks with 40 mg/m(2) prednisone orally for 28 days (Prod Info teniposide intravenous injection, 2015).

Maximum Tolerated Exposure

    A) Three children who received doses of 567 mg/m(2), 614 mg/m(2), and 893 mg/m(2) developed hypotension, somnolence and metabolic acidosis, but recovered (McLeod et al, 1991). Effects were believed to be related, at least in part, to the ethanol content of the formulation.
    B) Based on therapeutic use, dose-limiting bone marrow suppression is the most significant toxicity associated with teniposide (Prod Info teniposide intravenous injection, 2015).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Peak plasma concentrations ranging from 77 to 116 mcg/mL, mean 93 mcg/mL, were noted in patients (n=3) receiving greater than 500 mg/square meter of body surface area. These patients experienced somnolence, hypotension and metabolic acidosis (McLeod et al, 1991).
    2) A decreased clearance of teniposide has been observed with an increase in alkaline phosphatase or gamma glutamyl-transpeptidase (Prod Info teniposide intravenous injection, 2015) which may lead to toxic concentrations.

Workplace Standards

    A) ACGIH TLV Values for CAS29767-20-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS29767-20-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS29767-20-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Teniposide
    a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS29767-20-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SYSTEMIC: Teniposide is a topoisomerase II inhibitor. Topoisomerase II creates and reseals double-stranded DNA breaks and is therefore likely to be involved in DNA replication and repair. Teniposide is able to induce the stabilization of a DNA-topoisomerase II complex such that the strand-rejoining activity of the enzyme is impaired (Clark & Slevin, 1987).
    B) Teniposide acts at the premitotic stage of cell division to prevent cells from entering mitosis by causing dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. It does not intercalate into or bind strongly to DNA. It is cell phase–specific, acting in the late S or early G2 phase of cell division (Prod Info teniposide intravenous injection, 2015; Clark & Slevin, 1987).

Toxicologic Mechanism

    A) Teniposide is a semi-synthetic derivative of podophyllotoxin that is similar to etoposide (VP 16-213) in mechanism of action, efficacy and toxicity (Issell, 1982). It is derived from the root of Podophyllum peltatum (the May apple or mandrake) and is a crystalline derivative of alpha peltatin.

Physicochemical

Physical Characteristics

    A) Teniposide is a white to off-white crystalline powder that is insoluble in water and ether, slightly soluble in methanol, and very soluble in acetone and dimethylformamide (Prod Info teniposide intravenous injection, 2015).

Ph

    A) Adjusted to approximately 5 (Prod Info teniposide intravenous injection, 2015)

Molecular Weight

    A) 656.66 (Prod Info teniposide intravenous injection, 2015)

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    161) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    162) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    163) Product Information: KEPIVANCE(TM) IV injection, palifermin IV injection. Amgen Inc, Thousand Oaks, CA, 2005.
    164) Product Information: LEUKINE(R) subcutaneous, IV injection, sargramostim subcutaneous, IV injection. Bayer Healthcare, Seattle, WA, 2008.
    165) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    166) Product Information: VUMON(R) injection intravenous solution, teniposide injection intravenous solution. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2011.
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