These Highlights Do Not Include All The Information Needed To Use Arsenic Trioxide Injection Safely And Effectively. See Full Prescribing Information For Arsenic Trioxide Injection.

Reconstitution

Dilute Arsenic Trioxide Injection 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 vial. Do not save any unused portions for later administration.

After dilution, store Arsenic Trioxide Injection for no more than 24 hours at room temperature and 48 hours when refrigerated.

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F 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

Principal Display Panel - 10 mL Carton Label

NDC14789- 600-10

Rx Only

Arsenic Trioxide

Injection

10 mg/10 mL (1 mg/mL)

For Intravenous Use Only

Single Dose Vials - Discard Unused Portion

10 x 10 mLSingle Dose Vials

NEXUS

PHARMACEUTICALS

• “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Arsenic Trioxide Injection is a sterile injectable solution of arsenic trioxide. The molecular formula of arsenic trioxide in the solid state is As ₂O ₃, with a molecular weight of 197.8 and has the following structural formula:

Arsenic Trioxide Injection is available in 10 mL, single-dose vials containing 10 mg of arsenic trioxide. 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. 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.

The safety and efficacy of Arsenic Trioxide Injection as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with Arsenic Trioxide Injection at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years. No differences in efficacy and safety were observed by age.

Use of Arsenic Trioxide Injection as monotherapy in patients with relapsed or refractory APL is supported by the openlabel, single-arm trial that included 6 patients aged 65 and older (range: 65 to 73 years). A literature review included an additional 4 patients aged 69 to 72 years who were treated with arsenic trioxide for relapsed or refractory APL. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Serious encephalopathies were reported in patients receiving Arsenic Trioxide Injection. 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.

During treatment with Arsenic Trioxide Injection, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection 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)] .

The active ingredient of Arsenic Trioxide Injection, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Arsenic Trioxide Injection is contraindicated in patients with hypersensitivity to arsenic.

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)]

Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology ( 12.3)] . Monitor patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min) frequently for toxicity; a dose reduction may be warranted.

The use of Arsenic Trioxide Injection in patients on dialysis has not been studied.

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As ^III). As ^IIIis the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA ^V), and dimethylarsinic acid (DMA ^V) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As ^V) a product of As ^IIIoxidation.

The pharmacokinetics of arsenical species ([As ^III], [As ^V], [MMA ^V], [DMA ^V]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear.

Peak plasma concentrations of arsenious acid (As ^III), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of As ^IIIdeclined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As ^III(mean AUC _0-24h) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2- fold accumulation.

The primary pentavalent metabolites, MMA ^Vand DMA ^V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As ^III. The mean estimated terminal elimination half-lives of the metabolites MMA ^Vand DMA ^Vare 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single-dose administration. As ^Vis present in plasma only at relatively low levels.

Since limited data are available across all hepatic impairment groups, caution is advised in the use of Arsenic Trioxide Injection in patients with hepatic impairment [see Clinical Pharmacology ( 12.3)] . Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.

Arsenic Trioxide Injection is an arsenical 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. ( 1.2)

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.

Arsenic Trioxide Injection 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/m² 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/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² 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 Injection 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 Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1, 8.3)] .

• Hepatotoxicity: Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection 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)

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)

Injection: 10 mg/10 mL (1 mg/mL) arsenic trioxide clear solution in a single-dose vial.

Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection. In clinical trials, 16-23% of patients treated with Arsenic Trioxide Injection 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.

If differentiation syndrome is suspected, temporarily withhold Arsenic Trioxide Injection 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)] .

The following adverse reactions have been identified during postapproval use of Arsenic Trioxide Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Cardiac disorders:Ventricular extrasystoles in association with QT prolongation, ventricular tachycardia in association with QT prolongation, including torsade de pointes, atrioventricular block, and congestive heart failure

Ear and labyrinth disorders:Deafness

Hematologic disorders:Pancytopenia, bone marrow necrosis

Infections:Herpes zoster

Investigations:Gamma-glutamyltransferase increased

Musculoskeletal and connective tissue disorders:Bone pain, myalgia, rhabdomyolysis

Neoplasms benign, malignant and unspecified:Melanoma, pancreatic cancer, squamous cell carcinoma

Nervous system disorders:Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke's encephalopathy, posterior reversible encephalopathy syndrome

Skin and subcutaneous tissue disorders:Toxic epidermal necrolysis

• Lactation: Advise women not to breastfeed. ( 8.2)
• R enal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with Arsenic Trioxide Injection; 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 Injection. ( 8.7)

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.

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.

Arsenic Trioxide Injection was investigated in Study PLRXAS01, an open-label, single-arm trial in 40 patients with relapsed or refractory APL who were previously treated with an anthracycline and a retinoid regimen. Patients received Arsenic Trioxide Injection 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or for 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 tretinoin, there were 18 complete responders (82%). Of the 18 patients receiving Arsenic Trioxide Injection ≥ one year from tretinoin 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 Injection, 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 Injection 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. RT-PCR 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 sexes. There were insufficient patients of Black, Hispanic, or Asian ancestry to estimate relative response rates in these groups, but responses were seen in each group.

Patients treated with Arsenic Trioxide Injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trial of patients with relapsed or refractory APL treated with Arsenic Trioxide Injection 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 Injection infusion, and it usually resolved by 8 weeks after Arsenic Trioxide Injection infusion. There are no data on the effect of Arsenic Trioxide Injection 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 Injection 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 Injection, assess the QTc interval by electrocardiogram, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection 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 Injection 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 Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume Arsenic Trioxide Injection at a reduced dose [see Dosage and Administration ( 2.3)] .

Arsenic Trioxide Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

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.

Carcinogenicity studies have not been conducted with Arsenic Trioxide Injection by intravenous administration [see Warnings and Precautions ( 5.6)] .

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 was genotoxic in the chromosome aberrations assay and micronucleus bone marrow assay in mice.

The effect of arsenic on fertility has not been adequately studied in humans. Decreased testicular weight and impaired spermatogenesis have been reported in animal studies. Male Wistar rat pups were administered 1.5 mg/kg sodium arsenite solution via the intraperitoneal route from postnatal days 1 to 14 and testes were collected for evaluation on postnatal days 15, 21, and 50. Results of this study revealed an altered morphology of the seminiferous tubules along with degeneration of spermatogenic cells, increased number of sperm with abnormal morphology, and decreased sperm counts. In beagle dogs administered intravenous arsenic trioxide for 90 days, reduced inner cell layers within seminiferous tubules and significantly decreased numbers of spermatocytes, spermatozoa, and sperm cells were observed at doses of 1 mg/kg/day and higher. The 1 mg/kg/day dose is approximately 3 times the recommended human daily dose on a mg/m² basis.

During induction, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly. Table 2shows the dosage modifications for adverse reactions due to Arsenic Trioxide Injection when used alone.

Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection have experienced differentiation syndrome, which may be life- threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy, and multiorgan dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold Arsenic Trioxide Injection [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.1)].

Cardiac Conduction Abnormalities: Arsenic Trioxide Injection can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering Arsenic Trioxide Injection, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection to patients with a ventricular arrhythmia or prolonged QTc interval. Withhold Arsenic Trioxide Injection until resolution and resume at reduced dose for QTc prolongation [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.2)].

Encephalopathy: Serious encephalopathy, including Wernicke's, has occurred with Arsenic Trioxide Injection. Wernicke's is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving Arsenic Trioxide Injection. If Wernicke's encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Warnings and Precautions ( 5.3)].

Reconstitution

Dilute Arsenic Trioxide Injection 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 vial. Do not save any unused portions for later administration.

After dilution, store Arsenic Trioxide Injection for no more than 24 hours at room temperature and 48 hours when refrigerated.

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F 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

Principal Display Panel - 10 mL Carton Label

NDC14789- 600-10

Rx Only

Arsenic Trioxide

Injection

10 mg/10 mL (1 mg/mL)

For Intravenous Use Only

Single Dose Vials - Discard Unused Portion

10 x 10 mLSingle Dose Vials

NEXUS

PHARMACEUTICALS

• “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Arsenic Trioxide Injection is a sterile injectable solution of arsenic trioxide. The molecular formula of arsenic trioxide in the solid state is As ₂O ₃, with a molecular weight of 197.8 and has the following structural formula:

Arsenic Trioxide Injection is available in 10 mL, single-dose vials containing 10 mg of arsenic trioxide. 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. 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.

The safety and efficacy of Arsenic Trioxide Injection as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with Arsenic Trioxide Injection at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years. No differences in efficacy and safety were observed by age.

Use of Arsenic Trioxide Injection as monotherapy in patients with relapsed or refractory APL is supported by the openlabel, single-arm trial that included 6 patients aged 65 and older (range: 65 to 73 years). A literature review included an additional 4 patients aged 69 to 72 years who were treated with arsenic trioxide for relapsed or refractory APL. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Serious encephalopathies were reported in patients receiving Arsenic Trioxide Injection. 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.

During treatment with Arsenic Trioxide Injection, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection 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)] .

The active ingredient of Arsenic Trioxide Injection, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Arsenic Trioxide Injection is contraindicated in patients with hypersensitivity to arsenic.

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)]

Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology ( 12.3)] . Monitor patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min) frequently for toxicity; a dose reduction may be warranted.

The use of Arsenic Trioxide Injection in patients on dialysis has not been studied.

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As ^III). As ^IIIis the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA ^V), and dimethylarsinic acid (DMA ^V) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As ^V) a product of As ^IIIoxidation.

The pharmacokinetics of arsenical species ([As ^III], [As ^V], [MMA ^V], [DMA ^V]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear.

Peak plasma concentrations of arsenious acid (As ^III), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of As ^IIIdeclined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As ^III(mean AUC _0-24h) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2- fold accumulation.

The primary pentavalent metabolites, MMA ^Vand DMA ^V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As ^III. The mean estimated terminal elimination half-lives of the metabolites MMA ^Vand DMA ^Vare 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single-dose administration. As ^Vis present in plasma only at relatively low levels.

Since limited data are available across all hepatic impairment groups, caution is advised in the use of Arsenic Trioxide Injection in patients with hepatic impairment [see Clinical Pharmacology ( 12.3)] . Monitor patients with severe hepatic impairment (Child-Pugh Class C) frequently for toxicity.

Arsenic Trioxide Injection is an arsenical 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. ( 1.2)

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.

Arsenic Trioxide Injection 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/m² 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/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² 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 Injection 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 Injection and for 3 months after the last dose [see Use in Specific Populations ( 8.1, 8.3)] .

• Hepatotoxicity: Monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection 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)

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)

Injection: 10 mg/10 mL (1 mg/mL) arsenic trioxide clear solution in a single-dose vial.

Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection. In clinical trials, 16-23% of patients treated with Arsenic Trioxide Injection 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.

If differentiation syndrome is suspected, temporarily withhold Arsenic Trioxide Injection 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)] .

The following adverse reactions have been identified during postapproval use of Arsenic Trioxide Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Cardiac disorders:Ventricular extrasystoles in association with QT prolongation, ventricular tachycardia in association with QT prolongation, including torsade de pointes, atrioventricular block, and congestive heart failure

Ear and labyrinth disorders:Deafness

Hematologic disorders:Pancytopenia, bone marrow necrosis

Infections:Herpes zoster

Investigations:Gamma-glutamyltransferase increased

Musculoskeletal and connective tissue disorders:Bone pain, myalgia, rhabdomyolysis

Neoplasms benign, malignant and unspecified:Melanoma, pancreatic cancer, squamous cell carcinoma

Nervous system disorders:Peripheral neuropathy, paresis, seizures, confusion, encephalopathy, Wernicke's encephalopathy, posterior reversible encephalopathy syndrome

Skin and subcutaneous tissue disorders:Toxic epidermal necrolysis

• Lactation: Advise women not to breastfeed. ( 8.2)
• R enal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with Arsenic Trioxide Injection; 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 Injection. ( 8.7)

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.

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.

Arsenic Trioxide Injection was investigated in Study PLRXAS01, an open-label, single-arm trial in 40 patients with relapsed or refractory APL who were previously treated with an anthracycline and a retinoid regimen. Patients received Arsenic Trioxide Injection 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or for 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 tretinoin, there were 18 complete responders (82%). Of the 18 patients receiving Arsenic Trioxide Injection ≥ one year from tretinoin 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 Injection, 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 Injection 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. RT-PCR 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 sexes. There were insufficient patients of Black, Hispanic, or Asian ancestry to estimate relative response rates in these groups, but responses were seen in each group.

Patients treated with Arsenic Trioxide Injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trial of patients with relapsed or refractory APL treated with Arsenic Trioxide Injection 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 Injection infusion, and it usually resolved by 8 weeks after Arsenic Trioxide Injection infusion. There are no data on the effect of Arsenic Trioxide Injection 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 Injection 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 Injection, assess the QTc interval by electrocardiogram, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection 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 Injection 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 Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume Arsenic Trioxide Injection at a reduced dose [see Dosage and Administration ( 2.3)] .

Arsenic Trioxide Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

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.

Carcinogenicity studies have not been conducted with Arsenic Trioxide Injection by intravenous administration [see Warnings and Precautions ( 5.6)] .

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 was genotoxic in the chromosome aberrations assay and micronucleus bone marrow assay in mice.

The effect of arsenic on fertility has not been adequately studied in humans. Decreased testicular weight and impaired spermatogenesis have been reported in animal studies. Male Wistar rat pups were administered 1.5 mg/kg sodium arsenite solution via the intraperitoneal route from postnatal days 1 to 14 and testes were collected for evaluation on postnatal days 15, 21, and 50. Results of this study revealed an altered morphology of the seminiferous tubules along with degeneration of spermatogenic cells, increased number of sperm with abnormal morphology, and decreased sperm counts. In beagle dogs administered intravenous arsenic trioxide for 90 days, reduced inner cell layers within seminiferous tubules and significantly decreased numbers of spermatocytes, spermatozoa, and sperm cells were observed at doses of 1 mg/kg/day and higher. The 1 mg/kg/day dose is approximately 3 times the recommended human daily dose on a mg/m² basis.

During induction, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor coagulation studies, blood counts, and chemistries at least weekly. Table 2shows the dosage modifications for adverse reactions due to Arsenic Trioxide Injection when used alone.

Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with Arsenic Trioxide Injection have experienced differentiation syndrome, which may be life- threatening or fatal. Signs and symptoms may include unexplained fever, dyspnea, hypoxia, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy, and multiorgan dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroids and hemodynamic monitoring until resolution. Temporarily withhold Arsenic Trioxide Injection [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.1)].

Cardiac Conduction Abnormalities: Arsenic Trioxide Injection can cause QTc interval prolongation, complete atrioventricular block and torsade de pointes, which can be fatal. Before administering Arsenic Trioxide Injection, assess the QTc interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection to patients with a ventricular arrhythmia or prolonged QTc interval. Withhold Arsenic Trioxide Injection until resolution and resume at reduced dose for QTc prolongation [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.2)].

Encephalopathy: Serious encephalopathy, including Wernicke's, has occurred with Arsenic Trioxide Injection. Wernicke's is a neurologic emergency. Consider testing thiamine levels in patients at risk for thiamine deficiency. Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving Arsenic Trioxide Injection. If Wernicke's encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Warnings and Precautions ( 5.3)].