"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
APL Differentiation Syndrome
Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome. 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), 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. [see ADVERSE REACTIONS].
Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, And QT Prolongation
Torsade de pointes and complete heart block have been reported. QT/QTc prolongation can occur. 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 TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion.
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. If it's not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see DRUG INTERACTIONS].
Monitor ECG weekly, and more frequently for clinically unstable patients.
For QTc greater than 500 msec, complete corrective measures and reassess the QTc with serial ECGs prior to initiating TRISENOX. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute QT interval value > 500 msec and immediately correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. There are no data on the effect of TRISENOX on the QTc interval during the infusion.
The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see DRUG INTERACTIONS].
TRISENOX can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/mē basis. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/mē basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/mē basis. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with TRISENOX [see Use in Specific Populations ].
The patient's electrolyte and glucose levels, as well as hepatic, renal, 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been conducted with TRISENOX by intravenous administration [see WARNINGS AND PRECAUTIONS].
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.
Use In Specific Populations
TRISENOX can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/mē basis [see Data]. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/mē basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/mē basis. There are no studies in pregnant women using TRISENOX. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
One patient who became pregnant while receiving arsenic trioxide had a miscarriage.
Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were 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/mē 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/mē basis), on gestation days 6, 7, 8 or 9. Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/mē basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, discontinue breastfeeding during treatment with TRISENOX.
Females And Males Of Reproductive Potential
TRISENOX can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during and after treatment with TRISENOX.
Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with TRISENOX.
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. In an additional study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving TRISENOX at 0.15 mg/kg/day was similar to that observed in adult patients [see ADVERSE REACTIONS]. No children less than 4 years of age were enrolled in the trial due to the rarity of APL in this age group.
Clinical trials of TRISENOX (arsenic trioxide) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Monitor elderly patients closely, reflecting the greater frequency of decreased hepatic and renal function, concomitant disease or other drug therapy in this population.
Patients With Renal Impairment
Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see CLINICAL PHARMACOLOGY]. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.
Patients With Hepatic Impairment
Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/6/2015
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