Clinical Information
Gen. Code and Des.
53975 arsenic trioxide INTRAVEN VIAL 10 MG/10ML
Strength
10 mg/10 mL (1 mg/mL)
Dose Form
VIAL (ML)
Product Category
RX Pharmaceuticals
Fine Line Class
850085008510 All Rx Products
DEA Class
NC
OMP Family
AHFS Class
10000000 ANTINEOPLASTIC AGENTS
Active Ingredients
7172 arsenic trioxide 1327533
TRISENOX- arsenic trioxide injection, solution
Cephalon, Inc.
WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING
APL Differentiation Syndrome: 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. High-dose steroids have been administered 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), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously BID) , irrespective of the leukocyte count, and continue 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 [see Warnings and Precautions (5.1)].
Cardiac Conduction Abnormalities: Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. 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 [see Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
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.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Induction Treatment Schedule: Administer TRISENOX intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Do not exceed 60 doses for induction.
Consolidation Treatment Schedule: Begin consolidation treatment 3 to 6 weeks after completion of induction therapy. Administer TRISENOX intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks.
2.2 Dose Adjustment for Non-Hematologic Adverse Reactions
If a severe non-hematologic adverse reaction occurs (such as neurologic or dermatologic toxicity), consider delaying TRISENOX infusion until the event has resolved (≤ Grade 1).
2.3 Instructions for Preparation and Intravenous Administration
Administration
Administer TRISENOX 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.
The TRISENOX ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not mix TRISENOX with other medications.
Reconstitution
Dilute TRISENOX 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. Do not save any unused portions for later administration.
Safe Handling Procedures
TRISENOX is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
2.4 Stability
After dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.
3 DOSAGE FORMS AND STRENGTHS
TRISENOX is an injectable solution for intravenous administration supplied as 10 mg /10 mL of arsenic trioxide in single-use ampules.
4 CONTRAINDICATIONS
TRISENOX is contraindicated in patients who are hypersensitive to arsenic.
OVERDOSAGE
10.1 Manifestations
Manifestations of TRISENOX (arsenic trioxide) overdosage include convulsions, muscle weakness and confusion.
10.2 Management
If symptoms of TRISENOX (arsenic trioxide) overdosage develop, the injection should be immediately discontinued and chelation therapy should be considered.
A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided. Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.
11 DESCRIPTION
TRISENOX is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is As2 O3 , with a molecular weight of 197.8
TRISENOX is available in 10 mL, single-use ampules containing 10 mg of arsenic trioxide. TRISENOX is formulated as a sterile, nonpyrogenic, clear solution of arsenic trioxide in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. TRISENOX is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 1.0 mg/mL. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) and hydrochloric acid, which is used to adjust the pH to 7.5 - 8.5.
12 CLINICAL PHARMACOLOGY
12.1 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 promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha.
HOW SUPPLIED/STORAGE AND HANDLING
16.1 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.
16.2 Storage and Handling
Store at 25�C (77�F); excursions permitted to 15 - 30�C (59 - 86�F). Do not freeze.
TRISENOX is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
17 PATIENT COUNSELING INFORMATION
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APL Differentiation Syndrome
Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high dose corticosteroids. Advise patients to immediately report any of these symptoms.
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ECG Abnormalities � QT Prolongation
Advise patients that TRISENOX may cause ECG abnormalities, including QT prolongation. QT prolongation is an increase in the time it takes the heart to relax between beats. If extreme, this prolongation has the potential to cause fainting, irregular heart beat, or more serious side effects. Advise patients to immediately report any of these symptoms. Advise patients to provide a complete list of current medications as caution should be taken when TRISENOX is coadministered with other medications that can cause QT prolongation or lead to electrolyte abnormalities.
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Other Side Effects
Advise patients of the expected adverse reactions of TRISENOX. Most patients in clinical trials experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse reactions have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy. Advise patients to call their physician at the onset of any treatment-related adverse reactions.
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Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions 5.4 and Use in Specific Populations 8.1)].
Advise females and males of reproductive potential to use effective contraception during and after treatment with TRISENOX [see Use in Specific Populations ( 8.3)].
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Lactation
Advise females to discontinue breastfeeding during treatment with TRISENOX [see Use in Specific Populations ( 8.2)].
