ARSENIC TRIOXIDE

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 [see Dosage and Administration (2)]. ●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

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