Trisenox Drug Information

Newly-Diagnosed Low-Risk APL TRISENOX is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Relapsed or Refractory APL TRISENOX 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.

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. For the induction cycle, the recommended dosage of TRISENOX 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 TRISENOX 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.

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 TRISENOX when used alone or in combination with tretinoin.

Table 2: Dosage Modifications for Adverse Reactions of TRISENOX 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 Temporarily withhold TRISENOX. QTc (Framingham formula) Prolongation greater than 450 msec for men or greater than 460 msec for women Withhold TRISENOX and any medication known to prolong the QTc interval. Correct electrolyte abnormalities.

If the 50% reduced dose is tolerated for one week (in the absence of QTc prolongation), increase the dose of TRISENOX to 0.11 mg/kg/day daily for the next week. 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 TRISENOX and/or tretinoin. Other severe or life-threatening (grade 3-4) nonhematologic reactions Temporarily withhold TRISENOX and tretinoin.

Moderate (grade 2) nonhematologic reactions Reduce the dose of TRISENOX and/or tretinoin by 1 dose level (see Table 3 below). Leukocytosis (WBC count greater than 10 Gi/L) Administer hydroxyurea. Do not save any unused portions for later administration.

After dilution, store TRISENOX 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 TRISENOX 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 TRISENOX vial is single-dose and does not contain any preservatives.

Discard unused portions of each vial properly. Do not mix TRISENOX with other medications. Safe Handling Procedures TRISENOX is a hazardous drug.

Follow applicable special handling and disposal procedures. 1

Clinical Trials Experience

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. Newly-Diagnosed Low-Risk APL The safety of Trisenox in combination with tretinoin was evaluated in Study APL0406, a randomized trial comparing Trisenox plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL. In the Trisenox/tretinoin group, 98% of patients completed induction therapy and 89% completed at least three consolidation cycles.

In the chemotherapy/tretinoin group, 96% completed induction therapy and 87% patients completed all three courses of consolidation therapy. Serious adverse reactions were reported in 25% of patients on the Trisenox/tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in ≥ 2% of patients who received Trisenox/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections.

Trisenox/tretinoin was discontinued due to toxicity in 1 patient during induction and in 4 patients during the first three consolidation courses, whereas chemotherapy/tretinoin was discontinued due to toxicity in 4 patients during induction and in 6 patients during consolidation. Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4. Table 4: Select Adverse Reactions of Trisenox in Combination with Tretinoin in Patients with Newly-Diagnosed APL in Study APL0 *Mostly cases of reversible peripheral neuropathy Relapsed or Refractory APL Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Trisenox.

Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2).

The most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus. Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received Trisenox at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received Trisenox.

Table 5: Adverse Reactions (≥ 5%) in Patients with Relapsed or Refractory APL Who Received Trisenox in Study PLRXAS01 Trisenox can induce proliferation of leukemic promyelocytes resulting in a rapid increase in white blood cell count. Leukocytosis greater than 10 Gi/L developed during induction therapy in 43% patients receiving Trisenox/tretinoin for newly-diagnosed low-risk APL and in 50% of patients receiving Trisenox monotherapy for relapsed/refractory APL. In the relapsed/refractory setting, a relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Trisenox. 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

Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and TRISENOX may increase the risk of serious QT/QTc interval prolongation. Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while the patient is using TRISENOX. Monitor ECGs more frequently in patients when it is not feasible to avoid concomitant use.

Drugs That Can Lead to Electrolyte Abnormalities Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Avoid concomitant use of drugs that can lead to electrolyte abnormalities. Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and TRISENOX.

Drugs That Can Lead to Hepatotoxicity Concomitant use of these drugs and TRISENOX, particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity. Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using TRISENOX.

TRISENOX is contraindicated in patients with hypersensitivity to arsenic. Hypersensitivity to arsenic.

Manifestations Manifestations of TRISENOX (arsenic trioxide) overdosage include convulsions, muscle weakness, and confusion. Management For symptoms of TRISENOX (arsenic trioxide) overdosage, immediately discontinue TRISENOX and consider chelation therapy. A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided.

Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.