ARSENIC TRIOXIDE: Package Insert and Label Information

ARSENIC TRIOXIDE — arsenic trioxide injection
Ingenus Pharmaceuticals, LLC

WARNING: DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES AND ENCEPHALOPATHY INCLUDING WERNICKES

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 multi-organ 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)].

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 the withheld drug(s) by 50%. ● Increase the dose of the withheld drug(s) 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. ● 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(s) 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(s) back to the recommended dosage after one week on the reduced dose in the absence of worsening of hepatotoxicity. ● Discontinue the withheld drug(s) permanently if hepatotoxicity recurs.
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/10 mL (1 mg/mL) arsenic trioxide 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, 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)].

5.2 Cardiac Conduction Abnormalities

Patients treated with arsenic trioxide injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trials 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 pre-existing 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)].

5.3 Encephalopathy

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.

Wernicke’s Encephalopathy

Wernicke’s encephalopathy occurred in patients receiving arsenic trioxide injection. 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 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.

5.4 Hepatotoxicity

Long-term liver abnormalities can occur in patients with APL treated with arsenic trioxide.

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)].

5.5 Carcinogenesis

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

5.6 Embryo-Fetal Toxicity

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)].

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