Bang Lai

Bang Lai (teniposide injection), in combination with other approved anticancer agents, is indicated for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.

NOTE: Contact of undiluted Bang Lai with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of Bang Lai.

In order to prevent extraction of the plasticizer DEHP [di(2-ethylhexyl) phthalate], solutions of Bang Lai should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers.

Bang Lai solutions should be administered with non-DEHP containing intravenous administration sets.

In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of Bang Lai 165 mg/m² and cytarabine 300 mg/m² intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of Bang Lai 250 mg/m² and vincristine 1.5 mg/m² intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m² orally for 28 days.

Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment.

Preparation and Administration Precautions

Caution should be exercised in handling and preparing the solution of Bang Lai. Several guidelines on proper handling and disposal of anticancer drugs have been published.^1–4 Skin reactions associated with accidental exposure to Bang Lai may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing Bang Lai. If Bang Lai solution contacts the skin, immediately wash the skin thoroughly with soap and water. If Bang Lai contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Preparation for Intravenous Administration

Bang Lai must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. Bang Lai solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of Bang Lai solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers.

Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of Bang Lai diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of Bang Lai.

Hypotension has been reported following rapid intravenous administration; it is recommended that the Bang Lai solution be administered over at least a 30- to 60-minute period. Bang Lai should not be given by rapid intravenous injection.

In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended.

Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient's exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured.

Stability

Unopened ampules of Bang Lai are stable until the date indicated on the package when stored under refrigeration (2°-8°C) in the original package. Freezing does not adversely affect the product.

Bang Lai is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or Cremophor® EL (polyoxyethylated castor oil).

WARNINGS

Bang Lai 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 Bang Lai (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 Bang Lai therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of Bang Lai: 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 Bang Lai 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 Bang Lai are at risk for recurrence of symptoms and should only be re-treated with Bang Lai 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 Bang Lai in spite of an earlier hypersensitivity reaction, the patient should be pretreated with corticosteroids and antihistamines and receive careful clinical observation during and after Bang Lai infusion. In the clinical experience with Bang Lai 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 Bang Lai and VePesid®.

For parenteral administration, Bang Lai 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 Bang Lai 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 Bang Lai who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the Bang Lai formulation may place patients receiving higher than recommended doses of Bang Lai at risk for central nervous system depression.

Pregnancy

Pregnancy Category D

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

Male Fertility

In animal studies, Bang Lai 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 Bang Lai 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.

PRECAUTIONS

General

In all instances where the use of Bang Lai is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Bang Lai therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Bang Lai must be administered as an intravenous infusion. Care should be taken to ensure that the intravenous catheter or needle is in the proper position and functional prior to infusion. Improper administration of Bang Lai may result in extravasation causing local tissue necrosis and/or thrombophlebitis. In some instances, occlusion of central venous access devices has occurred during 24-hour infusion of Bang Lai at a concentration of 0.1 to 0.2 mg/mL. Frequent observation during these infusions is necessary to minimize this risk.

Laboratory Tests

Periodic complete blood counts and assessments of renal and hepatic function should be done during the course of Bang Lai treatment. They should be performed prior to therapy and at clinically appropriate intervals during and after therapy. There should be at least one determination of hematologic status prior to therapy with Bang Lai.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Children at SJCRH with ALL in remission who received maintenance therapy with Bang Lai at weekly or twice weekly doses (plus other chemotherapeutic agents), had a relative risk of developing secondary acute nonlymphocytic leukemia (ANLL) approximately 12 times that of patients treated according to other less intensive schedules.

A short course of Bang Lai for remission-induction and/or consolidation therapy was not associated with an increased risk of secondary ANLL, but the number of patients assessed was small. The potential benefit from Bang Lai must be weighed on a case by case basis against the potential risk of the induction of a secondary leukemia. The carcinogenicity of teniposide has not been studied in laboratory animals. Compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic and teniposide should be considered a potential carcinogen in humans. Teniposide has been shown to be mutagenic in various bacterial and mammalian genetic toxicity tests. These include positive mutagenic effects in the Ames/Salmonella and B. subtilis bacterial mutagenicity assays. Teniposide caused gene mutations in both Chinese hamster ovary cells and mouse lymphoma cells and DNA damage as measured by alkaline elution in human lung carcinoma derived cell lines. In addition, teniposide induced aberrations in chromosome structure in primary cultures of human lymphocytes in vitro and in L5178y/TK +/- mouse lymphoma cells in vitro . Chromosome aberrations were observed in vivo in the embryonic tissue of pregnant Swiss albino mice treated with teniposide. Teniposide also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells, and it has been shown to be embryotoxic and teratogenic in rats receiving teniposide during organogenesis. Treatment of pregnant rats intravenously with doses between 1.0 and 3.0 mg/kg/day on alternate days from day 6 to 16 post coitum caused retardation of embryonic development, prenatal mortality, and fetal abnormalities.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Bang Lai therapy to the mother.

Pediatric Use

Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received Bang Lai as a single agent (see ADVERSE REACTIONS). No association between any particular age group and adverse effects was reported in any of these investigations.

Patients with Down Syndrome

Patients with both Down syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with Bang Lai should be reduced in these patients. It is suggested that the first course of Bang Lai should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient.

The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which Bang Lai was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number of patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these 7 studies assessed Bang Lai activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with Bang Lai and were expected to develop significant myelosuppression as an endpoint of treatment.

Single-Agent Bang Lai Summary of Toxicity for All Evaluable Pediatric Patients

Hematologic Toxicity

Bang Lai, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Sepsis, sometimes fatal, may be a consequence of severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of Bang Lai necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with Bang Lai in combination with other antineoplastic agents. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.)

Gastrointestinal Toxicity

Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate.

Hypotension

Transient hypotension following rapid intravenous administration has been reported in 2% of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving Bang Lai combination therapy for a non-leukemic malignancy.

No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted.

Allergic Reactions

Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, rash, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% of evaluable pediatric patients receiving intravenous Bang Lai. The incidence of hypersensitivity reactions to Bang Lai appears to be increased in patients with brain tumors and in patients with neuroblastoma.

Central Nervous System

Neurotoxicity has been reported, including severe cases of neuropathy, in patients receiving vincristine sulfate and Bang Lai concomitantly.

Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose Bang Lai who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the Bang Lai formulation may place patients receiving higher than recommended doses of Bang Lai at risk for central nervous system depression.

Alopecia

Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received Bang Lai as single-agent therapy. It was usually reversible.

Other Adverse Reactions

The following adverse reactions have been reported: headache, confusion, and asthenia. Headache and confusion were associated with hypersensitivity reactions.

Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of Bang Lai, and who were also pretreated with antiemetic drugs.

There is no known antidote for Bang Lai overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care, including blood products and antibiotics as indicated.