Arsenic trioxide injection is an arsenical indicated: In combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. ( 1.1 ) For induction of remission and consolidation in patients with 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.
( 1.2 )
1.1Newly-Diagnosed Low-Risk APL
Arsenic trioxide injection is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
1.2Relapsed or Refractory APL
Arsenic trioxide injection is indicated for induction of remission and consolidation in patients with 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.
Contraindications
Arsenic trioxide is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )
Warnings and precautions
Hepatotoxicity: Elevated aspartate aminotransferase (AST), alkaline phosphatase and serum bilirubin have occurred in patients with newly-diagnosed low-risk APL treated with arsenic trioxide in combination with tretinoin. Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide for certain elevations in AST, alkaline phosphatase and bilirubin and resume at reduced dose upon resolution.
( 2.3 , 5.4 ) Carcinogenesis: Arsenic trioxide is a human carcinogen. Monitor patients for the development of second primary malignancies. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.6 , 8.1 , 8.3 )
Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide. In clinical trials, 16% to 23% of patients treated with arsenic trioxide for APL developed differentiation syndrome. Signs and symptoms include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction.
Differentiation syndrome has been observed with and without concomitant leukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When arsenic trioxide is used in combination with tretinoin, prophylaxis with prednisone is recommended during the induction cycle [see Dosage and Administration ( 2.1 )]. If differentiation syndrome is suspected, temporarily withhold arsenic trioxide and immediately initiate dexamethasone 10 mg intravenously every 12 hours and hemodynamic monitoring until resolution of signs and symptoms for a minimum of 3 days [see Dosage and Administration ( 2.3 )].
5.2Cardiac Conduction Abnormalities
Patients treated with arsenic trioxide can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trials of patients with newly diagnosed low-risk APL treated with arsenic trioxide in combination with tretinoin, 11% experienced QTc (Framingham formula) prolongation > 450 msec for men and > 460 msec for women throughout the treatment cycles. In the clinical trial of patients with relapsed or refractory APL treated with arsenic trioxide monotherapy, 40% had at least one ECG tracing with a QTc interval greater than 500 msec.
A prolonged QTc was observed between 1 and 5 weeks after start of arsenic trioxide infusion, and it usually resolved by 8 weeks after arsenic trioxide infusion. There are no data on the effect of arsenic trioxide on the QTc interval during the infusion of the drug. The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, a history of torsade de pointes, pre-existing QTc interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia.
The risk may be increased when arsenic trioxide is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) [see Drug Interactions ( 7 )] . Prior to initiating therapy with arsenic trioxide, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide to patients with a ventricular arrhythmia or prolonged QTc.
If possible, discontinue drugs that are known to prolong the QTc interval. If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see Drug Interactions ( 7 )]. During arsenic trioxide therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly, and more frequently for clinically unstable patients. For patients who develop a QTc Framingham greater than 450 msec for men or greater than 460 msec for women, withhold arsenic trioxide and any medication known to prolong the QTc interval.
Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume arsenic trioxide at a reduced dose [see Dosage and Administration ( 2.3 )] .
5.3Encephalopathy
Serious encephalopathies were reported in patients receiving arsenic trioxide. Monitor patients for neurological symptoms such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction. Advise patients and caregivers of the need for close observation. Wernicke's Encephalopathy Wernicke's encephalopathy occurred in patients receiving arsenic trioxide.
Wernicke's encephalopathy is a neurologic emergency that can be prevented and treated with thiamine. Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide). Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving arsenic trioxide.
If Wernicke's encephalopathy is suspected, immediately interrupt arsenic trioxide and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.
5.4 Hepatotoxicity In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with arsenic trioxide in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of arsenic trioxide and/or tretinoin. Long-term liver abnormalities can occur in patients with APL treated with arsenic trioxide in combination with tretinoin.
In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0 to 14 years) after treatment with arsenic trioxide in combination with tretinoin. During treatment with arsenic trioxide, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold arsenic trioxide and/or tretinoin if elevations in AST or alkaline phosphatase occur to greater than 5 times the upper limit of normal and/or elevation in serum total bilirubin occurs to greater than 3 times the upper limit of normal and resume at reduced dose upon resolution [see Dosage and Administration ( 2.3 )].
5.5Carcinogenesis
The active ingredient of arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.
5.6Embryo-Fetal Toxicity
Arsenic trioxide 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/m 2 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/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .
Interactions
Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and arsenic trioxide may increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions ( 5.1 )]. Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while the patient is using arsenic trioxide. Monitor ECGs more frequently in patients when it is not feasible to avoid concomitant use.
Drugs That Can Lead to Electrolyte Abnormalities Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation [see Warnings and Precautions ( 5.1 )]. Avoid concomitant use of drugs that can lead to electrolyte abnormalities. Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and arsenic trioxide. Drugs That Can Lead to Hepatotoxicity Concomitant use of these drugs and arsenic trioxide particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity [see Warnings and Precautions ( 5.4 )].
Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using arsenic trioxide. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.
Pregnancy and breastfeeding
8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology ( 12.1 )] and findings in animal studies, arsenic trioxide 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/m 2 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/m 2 basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m 2 basis.
There are no studies with the use of arsenic trioxide in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data One patient was reported to deliver a live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. A second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have a normal pregnancy outcome.
A third patient was a pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had a normal pregnancy outcome after treatment and monitoring. A fourth patient who became pregnant while receiving arsenic trioxide had a miscarriage. Animal Data 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/m 2 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/m 2 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/m 2 basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling.: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] Cardiac Conduction Abnormalities [see Warnings and Precautions ( 5.2 )] Encephalopathy [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Carcinogenesis [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (> 30%) are nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly-Diagnosed Low-Risk APL The safety of arsenic trioxide in combination with tretinoin was evaluated in Study APL0406, a randomized trial comparing arsenic trioxide plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL [see Clinical Studies (14.1)].
In the arsenic trioxide /tretinoin group, 98% of patients completed induction therapy and 89% completed at least three consolidation cycles. In the chemotherapy/tretinoin group, 96% completed induction therapy and 87% patients completed all three courses of consolidation therapy. Serious adverse reactions were reported in 25% of patients on the arsenic trioxide /tretinoin arm and 24% on the chemotherapy/tretinoin arm.
The serious adverse reactions reported in ≥ 2% of patients who received arsenic trioxide /tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections. Fatal adverse reactions were reported in 1 (1%) patient on the arsenic trioxide /tretinoin arm and 8 (6%) patients on the chemotherapy/tretinoin arm. Arsenic trioxide /tretinoin was discontinued due to toxicity in 1 patient during induction and in 4 patients during the first three consolidation courses, whereas chemotherapy/tretinoin was discontinued due to toxicity in 4 patients during induction and in 6 patients during consolidation.
Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4. Table 4Select Adverse Reactions of Arsenic trioxide in Combination with Tretinoin in Patients with Newly-Diagnosed APL in Study APL0406 *Mostly cases of reversible peripheral neuropathy Adverse Reaction Induction n (%) First Consolidation n (%) Second Consolidation n (%) Third Consolidation n (%) Thrombocytopenia > 15 days (Grade 3-4) arsenic trioxide /tretinoin Chemotherapy/tretinoin 74 (58%) 120 (88%) 6 (5%) 17 (14%) 6 (5%) 77 (63%) 8 (7%) 26 (22%) Neutropenia >15 days (Grade 3-4) arsenic trioxide /tretinoin Chemotherapy/tretinoin 61 (48%) 109 (80%) 8 (7%) 40 (32%) 7 (6%) 90 (73%) 5 (4%) 28 (24%) Hepatic toxicity (Grade 3-4) arsenic trioxide /tretinoin Chemotherapy/tretinoin 51 (40%) 4 (3%) 5 (4%) 1 (1%) 1 (1%) 0 (0%) 0 (0%) 0 (0%) Infection and fever of unknown origin arsenic trioxide /tretinoin Chemotherapy/tretinoin 30 (23%) 75 (55%) 10 (8%) 8 (6%) 4 (3%) 46 (38%) 2 (2%) 2 (2%) Hypertriglyceridemia arsenic trioxide /tretinoin Chemotherapy/tretinoin 29 (22%) 29 (22%) 22 (18%) 19 (15%) 17 (14%) 10 (8%) 16 (14%) 13 (11%) Hypercholesterolemia arsenic trioxide /tretinoin Chemotherapy/tretinoin 14 (10%) 12 (9%) 19 (16%) 12 (10%) 19 (16%) 12 (10%) 16 (14%) 11 (9%) QT prolongation arsenic trioxide /tretinoin Chemotherapy/tretinoin 11 (9%) 1 (1%) 3 (2%) 0 (0%) 3 (2%) 0 (0%) 2 (2%) 0 (0%) Gastrointestinal toxicity (Grade 3-4) arsenic trioxide /tretinoin Chemotherapy/tretinoin 3 (2%) 25 (18%) 0 (0%) 1 (1%) 0 (0%) 6 (5%) 0 (0%) 0 (0%) Neurotoxicity* arsenic trioxide /tretinoin Chemotherapy/tretinoin 1 (1%) 0 (0%) 5 (4%) 0 (0%) 6 (5%) 0 (0%) 7 (6%) 0 (0%) Cardiac function (Grade 3-4) arsenic trioxide /tretinoin Chemotherapy/tretinoin 0 (0%) 5 (4%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Relapsed or Refractory APL Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of arsenic trioxide.
Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included 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 most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus. Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received arsenic trioxide at the recommended dose.
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