Asadin

Asadin

arsenic trioxide

Manufacturer:

TTY Biopharm

Distributor:

American Taiwan Biopharma
Full Prescribing Info
Contents
Arsenic trioxide.
Description
Each mL contains arsenic trioxide 1 mg.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: 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.
Clinical Studies: Arsenic Trioxide (Asadin) 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 Arsenic Trioxide (Asadin) 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 Arsenic Trioxide (Asadin), 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 2of 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 receive Arsenic Trioxide (Asadin) doses generally similar to the recommended dose, had similar results with 9 of 12 (75%) patients attaining a CR.
Pharmacokinetics: The pharmacokinetics of trivalent arsenic, the active species of Arsenic Trioxide (Asadin), 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.
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 Arsenic Trioxide (Asadin) have not been studied.
Drug Interactions: No formal assessments of pharmacokinetic drug-drug interactions between Arsenic Trioxide (Asadin) and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes.
Indications/Uses
Arsenic Trioxide (Asadin) 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 (15;17) translocation or PML/RAR-alpha gene expression.
The response rate of other acute myelogenous leukemia subtypes to Arsenic Trioxide (Asadin) has not been examined.
Dosage/Direction for Use
Asadin (Arsenic trioxide) injection should be administered under the physician. Arsenic Trioxide (Asadin) should be diluted with 100 to 250 mL 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Arsenic Trioxide (Asadin) should be administered intravenously over 1-2 hours. The infusion duration may be extended up 4 hours if acute vasomotor reactions are observed.
Induction Treatment Schedule: Arsenic Trioxide (Asadin) 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. Arsenic Trioxide (Asadin) should be administered intravenously at a dose of 0.15 mg/kg daily.
Overdosage
If symptoms suggestive of serious acute arsenic toxicity appear, Arsenic trioxide (Asadin) 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.
Contraindications
Arsenic Trioxide (Asadin) is contraindicated in patients who are hypersensitive to arsenic.
Warnings
Arsenic Trioxide (Asadin) injection should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia.
APL Differentiation Syndrome: Nine of 40 patients with APL treated with Arsenic Trioxide (Asadin) at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome.
Some patients with APL treated with Arsenic Trioxide (Asadin) 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 that 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, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of Arsenic Trioxide (Asadin) 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 Arsenic Trioxide (Asadin) 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 Arsenic Trioxide (Asadin). During therapy with Arsenic Trioxide (Asadin), 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 Arsenic Trioxide (Asadin) therapy should be considered. If syncope, rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, Arsenic Trioxide (Asadin) 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 Arsenic Trioxide (Asadin) on the QTc interval during the infusion.
Hyperleukocytosis: Treatment with Arsenic Trioxide (Asadin) has been associated with the development of hyperleukocytosis (≥10 x 103/μL) in 20 of 40 patients. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts. Hyperleukocytosis was not treated with additional chemotherapy. WBC counts during consolidation were not as high as during induction treatment.
QT Prolongation: QT/QTc prolongation should be expected during treatment with arsenic trioxide and torsade de pointes as well as complete heart block has been reported. Over 460 ECG tracings from 40 patients with refractory or relapsed APL treated with Arsenic Trioxide (Asadin) were evaluated for QTc prolongation. Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after Arsenic Trioxide (Asadin) infusion, and then returned towards baseline by the end of 8 weeks after Arsenic Trioxide (Asadin) infusion. In these ECG evaluations, women did not experience more pronounced QT prolongation than men, and there was no correlation with age.
Complete AV block has been reported with arsenic trioxide in the published literature including a case of a patient with APL.
Physician use only.
Special Precautions
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Arsenic trioxide is a human carcinogen. 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.
Patients with Renal or Hepatic Impairment: Safety and effectiveness of Arsenic Trioxide (Asadin) in patients with renal and hepatic impairment have not been studied. Particular caution is needed in patients with renal failure receiving Arsenic Trioxide (Asadin), as renal excretion is the main route of elimination of arsenic.
Use in Pregnancy: Pregnancy Category D.
Women of childbearing potential should be advised to avoid becoming pregnant.
Arsenic Trioxide (Asadin) may cause fetal harm when administered to a pregnant woman. Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. The reproductive toxicity of arsenic trioxide has been studied in a limited manner. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia was observed in rats administered 10 mg/kg of arsenic trioxide on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m2 basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite, (approximately 5 times the projected human dose on a mg/m2 basis) on gestation days 6, 7, 8 or 9. Intravenous injection of 2 mg/kg sodium arsenic (approximately equivalent to the projected human daily dose on a mg/m2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
There are no studies in pregnant women using Arsenic Trioxide (Asadin). If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. One patient who became pregnant while receiving arsenic trioxide had a miscarriage.
Use in Lactation: Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Arsenic Trioxide (Asadin) 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.
Use in Children: There are limited clinical data on the pediatric use of Arsenic Trioxide (Asadin). Of 5 patients below the age 18 years (age range: 5 to 16 years) treated with Arsenic Trioxide (Asadin), at the recommended dose of 0.15mg/kg/day, 3 achieved a complete response.
Safety and effectiveness in pediatric patients below the age of 5 years have not been studied.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category D.
Women of childbearing potential should be advised to avoid becoming pregnant.
Arsenic Trioxide (Asadin) may cause fetal harm when administered to a pregnant woman. Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. The reproductive toxicity of arsenic trioxide has been studied in a limited manner. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia was observed in rats administered 10 mg/kg of arsenic trioxide on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m2 basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite, (approximately 5 times the projected human dose on a mg/m2 basis) on gestation days 6, 7, 8 or 9. Intravenous injection of 2 mg/kg sodium arsenic (approximately equivalent to the projected human daily dose on a mg/m2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
There are no studies in pregnant women using Arsenic Trioxide (Asadin). If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. One patient who became pregnant while receiving arsenic trioxide had a miscarriage.
Use in Lactation: Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Arsenic Trioxide (Asadin) 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.
Adverse Reactions
Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Arsenic Trioxide (Asadin). 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 Arsenic Trioxide (Asadin) on 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 that forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg. The adverse events that were observed in patients treated for APL with Arsenic Trioxide (Asadin) at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received Arsenic Trioxide (Asadin). (See Tables A and B.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image
Drug Interactions
Caution is advised when Arsenic Trioxide (Asadin) is co-administered 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).
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
L01XX27 - arsenic trioxide ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Soln for inj (vial) 1 mg/mL (sterile, clear, colorless) x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in