Dilution:
[Prescribed dose] [100-250 ml] [1-2 hours]*
*[Possibly over 4 hours if acute vasomotor reactions observed]
TRISENOX should be diluted with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the ampule. The TRISENOX ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not save any unused portions for later administration. Do not mix TRISENOX with other medications.
TRISENOX should be administered intravenously over 1-2 hours.. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.
Stability
AAfter dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.
Dosing Regimen
TRISENOX is recommended to be given according to the following schedule:
Induction Treatment Schedule: TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Total induction dose should not exceed 60 doses.
Consolidation Treatment Schedule: Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy. TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks. |
WARNING
Experienced Physician and Institution: TRISENOX (arsenic trioxide) injection should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia.
APL Differentiation Syndrome: Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously BID) should be immediately initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome.
ECG Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.
ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed; preexisting electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations should be kept above 4 mEq/L and magnesium concentrations should be kept above 1.8 mg/dL. Patients who reach an absolute QT interval value > 500 msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. If syncope, rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, TRISENOX therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion. |
INDICATIONS
TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
The response rate of other acute myelogenous leukemia subtypes to TRISENOX has not been examined.
CONTRAINDICATIONS
TRISENOX is contraindicated in patients who are hypersensitive to arsenic.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha.
Pharmacokinetics
The pharmacokinetics of trivalent arsenic, the active species of TRISENOX, have not been characterized.
Metabolism
The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails.
In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11.
Excretion
Disposition of arsenic following intravenous administration has not been studied. Trivalent arsenic is mostly methylated in humans and excreted in urine.
Special Populations
The effects of renal or hepatic impairment or gender, age and race on the pharmacokinetics of TRISENOX have not been studied
DOSAGE AND ADMINISTRATION
TRISENOX should be diluted with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the ampule. The TRISENOX ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not save any unused portions for later administration. Do not mix TRISENOX with other medications.
TRISENOX should be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.
Stability
After dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.
Dosing Regimen
TRISENOX is recommended to be given according to the following schedule:
Induction Treatment Schedule: TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Total induction dose should not exceed 60 doses.
Consolidation Treatment Schedule: Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy. TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks.
HANDLING AND DISPOSAL
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
HOW SUPPLIED
TRISENOX (arsenic trioxide) injection is supplied as a sterile, clear, colorless solution in 10 mL glass, single-use ampules.
NDC 63459-600-10 10 mg/10 mL (1 mg/mL) ampule in packages of ten ampules.
Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). Do not freeze.
Do not use beyond expiration date printed on the label.
TRISENOX is a trademark of Cephalon, Inc., or its affiliates. |
PRIMARY:
1) [PACKAGE INSERT DATA] : Cephalon, Inc. Frazer, PA 19355. TRISENOX (arsenic trioxide) injection, solution Package insert. November 2008.
Other:
Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication NIH 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. Jones RB, et al. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA J Clin. 1983;33:258-263. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990;47:1033-1049. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm. 1996;53:1669-1685. |
