Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3795
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Trisenox (Injection, Solution)
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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.<br/>Stability: After dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.<br/>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.
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TRISENOX is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is AsO, with a molecular weight of 197.8 g. 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 toadjust the pH to 7.5 - 8.
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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.<br/>Pharmacokinetics: The pharmacokinetics of trivalent arsenic, the active species of TRISENOX, have not been characterized.<br/>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.<br/>Excretion: Disposition of arsenic following intravenous administration has not been studied. Trivalent arsenic is mostly methylated in humans and excreted in urine.<br/>Special Populations: The effects of renal or hepatic impairment or gender, age and race on the pharmacokinetics of TRISENOX have not been studied .<br/>Drug Interactions: No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes .<br/>Clinical Studies: TRISENOX has been investigated in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen, in an open-label, single-arm, non-comparative study. Patients received 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or up to a maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with a confirmatory bone marrow���30 days later) rate in this population of previously treated patients was 28 of 40 (70%). Among the 22 patients who had relapsed less than one year after treatment with ATRA, there were 18 complete responders (82%). Of the 18 patients receiving TRISENOX���one year from ATRA treatment, there were 10 complete responders (55%). The median time to bone marrow remission was 44 days and to onset of CR was 53 days. Three of 5 children, 5 years or older, achieved CR. No children less than 5 years old were treated. Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with TRISENOX, at the same dose, for 25 additional days over a period up to 5 weeks. In follow-up treatment, 18 patients received further arsenic trioxide as a maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with a median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with a median follow-up time of 483 days (range 280 to 755). Cytogenetic conversion to no detection of the APL chromosome rearrangement was observed in 24 of 28 (86%) patients who met the response criteria defined above, in 5 of 5 (100%) patients who met some but not all of the response criteria, and 3 of 7 (43%) of patients who did not respond. Reverse Transcriptase���Polymerase Chain Reaction conversions to no detection of the APL gene rearrangement were demonstrated in 22 of 28 (79%) of patients who met the response criteria, in 3 of 5 (60%) of patients who met some but not all of the response criteria, and in 2 of 7 (29%) of patients who did not respond. Responses were seen across all age groups tested, ranging from 6 to 72 years. The ability to achieve a CR was similar for both genders. There were insufficient patients of Black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in members of each group. Another single center study in 12 patients with relapsed or refractory APL, where patients received TRISENOX (arsenic trioxide) injection doses generally similar to the recommended dose, had similar results with 9 of 12 (75%) patients attaining a CR.
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TRISENOX is contraindicated in patients who are hypersensitive to arsenic.
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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.
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Laboratory Tests: The patient's electrolyte, hematologic and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase. ECGs should be obtained weekly, and more frequently for clinically unstable patients, during induction and consolidation. Drug Interactions: No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other agents have been conducted. Caution is advised when TRISENOX is coadministered with other medications that can prolong the QT interval (e.g. certain antiarrhythmics or thioridazine) or lead to electrolyte abnormalities (such as diuretics or amphotericin B). Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for information on carcinogenesis. Arsenic trioxide and trivalent arsenite salts have not been demonstrated to be mutagenic to bacteria, yeast or mammalian cells. Arsenite salts are clastogenic in vitro (human fibroblast, human lymphocytes, Chinese hamster ovary cells, Chinese hamster V79 lung cells). Trivalent arsenic produced an increase in the incidence of chromosome aberrations and micronuclei in bone marrow cells of mice. The effect of arsenic on fertility has not been adequately studied. Pregnancy: Pregnancy Category D. See WARNINGS section. Nursing Mothers: Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: There are limited clinical data on the pediatric use of TRISENOX. Of 5 patients below the age of 18 years (age range: 5 to 16 years) treated with TRISENOX, at the recommended dose of 0.15 mg/kg/day, 3 achieved a complete response. Safety and effectiveness in pediatric patients below the age of 5 years have not been studied. Patients with Renal or Hepatic Impairment: Safety and effectiveness of TRISENOX in patients with renal and hepatic impairment have not been studied. Particular caution is needed in patients with renal failure receiving TRISENOX, as renal excretion is the main route of elimination of arsenic.
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If symptoms suggestive of serious acute arsenic toxicity (e.g., convulsions, muscle weakness and confusion) appear, TRISENOX (arsenic trioxide) 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.
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arsenic trioxide
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Trisenox (Injection, Solution)
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Clinical Studies Experience: Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of TRISENOX. Forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg of which 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy. Serious adverse events (SAEs), grade 3 or 4 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to TRISENOX in the Phase 2 study of 40 patients with refractory or relapsed APL included APL differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval���500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2). The following table describes the adverse events that were observed in patients treated for APL with TRISENOX at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received TRISENOX.<br/>Post-Marketing Experience: The following reactions have been reported from clinical trials and/or world-wide post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. Cardiac disorders: ventricular extrasystoles in association with QT prolongation, and ventricular tachycardia in association with QT prolongation Nervous system disorders: peripheral neuropathy Hematologic disorders: pancytopenia Respiratory, thoracic, and mediastinal disorders: A differentiation syndrome, like retinoic acid syndrome, has been reported with the use of TRISENOX for the treatment of malignancies other than APL.
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Trisenox
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