Arsenic trioxide

1 INDICATIONS AND USAGE 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 ) 1.1 Newly-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. 1.2 Relapsed 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.

2 DOSAGE AND ADMINISTRATION Newly-diagnosed low-risk APL: Induction : Administer 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission. Do not exceed 60 days. ( 2.1 ) Consolidation: Administer 0.15 mg/kg/day intravenously daily for 5 days per week during weeks 1 to 4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin. ( 2.1 ) Relapsed or refractory APL: Induction: Administer 0.15 mg/kg/day intravenously daily until bone marrow remission. Do not exceed 60 days. ( 2.2 ) Consolidation: Administer 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. ( 2.2 ) 2.1 Recommended Dosage for Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia (APL) A treatment course for patients with newly-diagnosed low-risk APL consists of 1 induction cycle and 4 consolidation cycles. For the induction cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily in combination with tretinoin until bone marrow remission but not to exceed 60 days (see Table 1). For the consolidation cycles, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily 5 days per week during weeks 1 to 4 of each 8-week cycle for a total of 4 cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5 to 6 of the fourth cycle of consolidation. Table 1: Recommended Dosage of Arsenic Trioxide Injection in Combination with Tretinoin Induction (1 cycle) Arsenic trioxide injection 0.15 mg/kg once daily intravenously until marrow remission but not to exceed 60 days Tretinoin a 22.5 mg/m 2 twice daily orally until marrow remission but not to exceed 60 days Consolidation (4 cycles) Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Arsenic trioxide injection 0.15 mg/kg once daily intravenously Days 1 to 5 Days 1 to 5 Days 1 to 5 Days 1 to 5 -- -- -- -- Tretinoin a 22.5 mg/m 2 twice daily orally Days 1 to 7 Days 1 to 7 -- -- Days b 1 to 7 Days b 1 to 7 -- -- a Rounded to the nearest 10 mg increment b Omitted during the 4th cycle of consolidation Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day 1 until the end of induction cycle with arsenic trioxide injection and tretinoin is recommended. 2.2 Recommended Dosage for Relapsed or Refractory APL A treatment course for patients with relapsed or refractory APL consists of 1 induction cycle and 1 consolidation cycle [see Clinical Studies (14.2) ] . For the induction cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dosage of arsenic trioxide injection is 0.15 mg/kg/day intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction cycle. 2.3 Monitoring and Dosage Modifications for Adverse Reactions During induction, monitor coagulation studies, blood counts, and chemistries at least 2 to 3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly. Table 2 shows the dosage modifications for adverse reactions due to arsenic trioxide injection when used alone or in combination with tretinoin. Table 2: Dosage Modifications for Adverse Reactions of Arsenic Trioxide Injection Adverse Reaction Dosage Modification Differentiation syndrome, defined by the presence of 2 or more of the following: - Unexplained fever - Dyspnea - Pleural and/or pericardial effusion - Pulmonary infiltrates - Renal failure - Hypotension - Weight gain greater than 5 kg [see Warnings and Precautions (5.1) ] Temporarily withhold arsenic trioxide injection. Consider holding tretinoin if symptoms are severe. Administer dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for a minimum of 3 days. Resume treatment when the clinical condi …

3 DOSAGE FORMS AND STRENGTHS Injection: 10 mg/10 mL (1 mg/mL) arsenic trioxide clear solution in a single-dose vial. Injection: 12 mg/6 mL (2 mg/mL) arsenic trioxide clear solution in a single-dose vial. Injection: 10 mg/10 mL (1 mg/mL) and 12 mg/6 mL (2 mg/mL) arsenic trioxide in single-dose vials. ( 3 )

4. CONTRAINDICATIONS Arsenic Trioxide Injection is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic. ( 4 )

6 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 . 6.1 Clinical 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 4 Select 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 (Gr …

7 DRUG 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with arsenic trioxide; dose reduction may be warranted. ( 8.6 ) Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with arsenic trioxide. ( 8.7 ) 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. 8.2 Lactation Risk Summary Arsenic trioxide is excreted in human milk. There are no data on the effects of arsenic trioxide on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with arsenic trioxide and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Arsenic trioxide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Conduct pregnancy testing in females of reproductive potential prior to initiation of arsenic trioxide. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with arsenic trioxide and for 6 months …

12.1 Mechanism of Action The mechanism of action of Arsenic Trioxide Injection 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.

11 DESCRIPTION Arsenic trioxide injection is a sterile injectable solution of arsenic trioxide. The molecular formula of arsenic trioxide in the solid state is As 2 O 3 , with a molecular weight of 197.84 g/mol and the following structural formula: Arsenic trioxide is a white to off-white powder. It is practically insoluble to sparingly soluble in water. It dissolves in solutions of alkali hydroxides (NaOH 1 M). It is practically insoluble in ethanol, chloroform and ethyl ether. Arsenic trioxide injection is available in 10 mL or 6 mL, single-dose vials containing 10 mg or 12 mg of arsenic trioxide respectively. Arsenic trioxide injection 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. Arsenic trioxide injection is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 1 mg/mL in 10 mL vial and 2 mg/mL in 6 mL vial. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) for solubilization, and sodium hydroxide and hydrochloric acid for pH adjustment to pH 8. 1

10. OVERDOSAGE Manifestations Manifestations of Arsenic Trioxide Injection (arsenic trioxide) over-dosage include convulsions, muscle weakness, and confusion. Management For symptoms of Arsenic Trioxide Injection (arsenic trioxide) overdosage, immediately discontinue Arsenic Trioxide Injection and consider chelation therapy. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Arsenic trioxide injection is supplied as a sterile, clear, colorless solution in glass, single-dose vials. It is available as follows: 10 mg/10 mL (1 mg/mL) Unit of Sale Each NDC number 83090-009-01 One Single-dose vial in a carton NDC number 83090-009-05 10 mL Single-dose vial (10 mL fill) NDC number 83090-009-10 10 Single-dose vials in a carton 12 mg/6 mL (2 mg/mL) Unit of Sale Each NDC number 83090-010-01 One Single-dose vial in a carton NDC number 83090-010-05 10 mL Single-dose vial (6 mL fill) NDC number 83090-010-10 10 Single-dose vials in a carton Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Arsenic trioxide injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1