Prescription Drug Information: Arsenic Trioxide

ARSENIC TRIOXIDE — arsenic trioxide injection, solution
Fresenius Kabi USA, LLC

1. INDICATIONS AND USAGE

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

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 2-3 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.

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. 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 condition improves and reduce the dose of Arsenic Trioxide Injection by 50%. Increase the dose of Arsenic Trioxide Injection to the recommended dosage after one week in the absence of recurrence of symptoms of differentiation syndrome. If symptoms re-appear, decrease Arsenic Trioxide Injection to the previous dose.
QTc (Framingham formula)Prolongation greater than 450 msec for men or greater than 460 msec for women[see Warnings and Precautions (5.2)]	Withhold Arsenic Trioxide Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. After the QTc normalizes and electrolyte abnormalities are corrected, resume treatment with Arsenic Trioxide Injection at a 50% reduced dose (0.075 mg/kg/day daily) for one week after resolution. If the 50% reduced dose is tolerated for one week (in the absence of QTc prolongation), increase the dose of Arsenic Trioxide Injection to 0.11 mg/kg/day daily for the next week [see Dosage and Administration (2.1)]. The dose of Arsenic Trioxide Injection can be increased to 0.15 mg/kg/day in the absence of QTc prolongation during that 14-day dose-escalation period.
Hepatotoxicity, defined by 1 or more of the following: − Total bilirubin (TB) greater than 3 times the upper limit of normal (ULN) − Aspartate aminotransferase (AST) greater than 5 times the ULN − Alkaline phosphatase (AP) greater than 5 times the ULN[see Warnings and Precautions (5.4)]	Withhold Arsenic Trioxide Injection. Resume treatment at a 50% reduced dose of the withheld drug when TB is less than 1.5 times the ULN and AP/AST are less than 3 times the ULN. Increase the dose of the withheld drug back to the recommended dosage after one week on the reduced dose in the absence of worsening of hepatotoxicity. Discontinue the withheld drug permanently if hepatotoxicity recurs.

Table 2: Dosage Modifications for Adverse Reactions of Arsenic Trioxide Injection (Cont’d.)

Other severe or life-threatening (grade 3-4) nonhematologic reactions[see Adverse Reactions (6)]	Temporarily withhold Arsenic Trioxide Injection. When the adverse reaction resolves to no more than mild (grade 1), resume Arsenic Trioxide Injection reduced by 2 dose levels (see Table 3 below).
Moderate (grade 2) nonhematologic reactions[see Adverse Reactions (6)]	Reduce the dose of Arsenic Trioxide Injection by 1 dose level (see Table 3 below).
Leukocytosis (WBC count greater than 10 Gi/L)[see Adverse Reactions (6.1)]	Administer hydroxyurea. Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L.
Myelosuppression, defined by 1 or more of the following: − absolute neutrophil count less than 1 Gi/L − platelets less than 50 Gi/L lasting more than 5 weeks[see Adverse Reactions (6)]	Consider reducing the dose of Arsenic Trioxide Injection by 1 dose level (see Table 3 below). If myelosuppression lasts ≥ 50 days or occurs on 2 consecutive cycles, assess a marrow aspirate for remission status. In the case of molecular remission, resume Arsenic Trioxide Injection at 1 dose level lower (see Table 3 below).

Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities

Dose Level	Arsenic Trioxide Injection mg/kg intravenously once daily
Starting level	0.15
-1	0.11
-2	0.10
-3	0.075

2.4 Preparation and Administration

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.

Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administer Arsenic Trioxide Injection as an intravenous infusion over 2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.

The Arsenic Trioxide Injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly. Do not mix Arsenic Trioxide Injection with other medications.

Safe Handling Procedures

Arsenic Trioxide Injection is a hazardous drug. Follow applicable special handling and disposal procedures.¹

3. DOSAGE FORMS AND STRENGTHS

Injection: 10 mg arsenic trioxide in 10 mL clear solution in a single-dose vial

4. CONTRAINDICATIONS

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

5. WARNINGS AND PRECAUTIONS

5.1 Differentiation Syndrome

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, 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)].