Arsenic Trioxide

ARSENIC TRIOXIDE- arsenic trioxide injection, solution
STI Pharma LLC

WARNING: DIFFERENTIATION SYNDROME AND CARDIAC CONDUCTION ABNORMALITIES

Differentiation Syndrome: Patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide injection have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, weight gain or peripheral edema, hypotension, and renal, hepatic, or multi-organ dysfunction, in the presence or absence of leukocytosis. If differentiation syndrome is suspected, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Temporary discontinuation of arsenic trioxide injection may be required [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1) ].

Cardiac Conduction Abnormalities: Arsenic trioxide can cause QTc interval prolongation, complete atrioventricular block, and a torsade de pointes-type ventricular arrhythmia, which can be fatal. Before initiating therapy, assess the QTc interval, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer arsenic trioxide injection to patients with ventricular arrhythmia or prolonged QTcF [see Warnings and Precautions ( 5.2) ].

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

2.1 Recommended Dosage

Relapsed or Refractory APL

A treatment course including arsenic trioxide injection monotherapy 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 dose of arsenic trioxide injection is 0.15 mg/kg intravenously daily until bone marrow remission or up to a maximum of 60 days.
  • For the consolidation cycle, the recommended dose of arsenic trioxide injection is 0.15 mg/kg intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction therapy.

2.2 Dose Modifications for Toxicities

During induction therapy, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor at least weekly. Management of some adverse reactions may require dose interruption, dose reduction, or permanent discontinuation of arsenic trioxide injection [see Warnings and Precautions ( 5) and Adverse Reactions ( 6) ]. Table 2 shows the dose modifications for toxicity due to arsenic trioxide injection when used alone.

Table 2: Dose Adjustments for Adverse Reactions
Adverse Reaction(s) Dose 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
  • Temporarily withhold arsenic trioxide injection. Treat with 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 7 days in the absence of recurrence of symptoms of differentiation syndrome.
  • If symptoms re-appear, decrease arsenic trioxide injection to the previous dose.
QTc Prolongation greater than 450 msec for men or greater than 460 msec for women:
  • Withhold treatment with arsenic trioxide injection and any medication known to prolong the QTc interval.
  • Replete electrolytes.
  • After the QTc normalizes, resume treatment with arsenic trioxide injection at a 50% reduced dose (0.075 mg/kg once daily) for 7 days.
  • If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose of arsenic trioxide injection to 0.11 mg/kg once daily for 7 days.
  • The dose of arsenic trioxide injection can be increased to 0.15 mg/kg 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
  • Withhold treatment with 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 back to the recommended dosage after 7 days on the reduced dose in the absence of worsening of hepatotoxicity.
  • Discontinue the withheld drug permanently if hepatotoxicity recurs.
Other severe or life- threatening (grade 3-4) nonhematologic reactions
  • 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
  • Reduce the dose of arsenic trioxide injection by 1 dose level (see Table 3 below).
Leukocytosis (WBC count greater than 10 Gi/L)
  • 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
  • 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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