Trisenox Injection, Solution
FDA Label NDC 63459-601

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.

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.

Newly-Diagnosed Low-Risk Acute Promyelocytic Leukemia (APL)

A treatment course for patients with newly-diagnosed low-risk APL consists of 1 induction cycle and 4 consolidation cycles.

• For the induction cycle, the recommended dose of TRISENOX is 0.15 mg/kg intravenously daily in combination with tretinoin until bone marrow remission and not to exceed 60 days (see Table 1).
• For the consolidation cycles, the recommended dose of TRISENOX is 0.15 mg/kg intravenously daily 5 days per week during weeks 1-4 of an 8-week cycle for a total of 4 cycles in combination with tretinoin (see Table 1). Omit tretinoin during weeks 5-6 of the fourth cycle of consolidation.

Table 1: Recommended Dose of TRISENOX in Combination with Tretinoin

Induction (1 cycle)
TRISENOX 0.15 mg/kg once daily intravenously	until marrow remission but not to exceed 60 days
Tretinoina 22.5 mg/m2 twice daily orally	until marrow remission but not to exceed 60 days
Consolidation (4 cycles)
	Week 1	Week 2	Week 3	Week 4	Week 5	Week 6	Week 7	Week 8
TRISENOX 0.15 mg/kg once daily intravenously	Days 1-5	Days 1-5	Days 1-5	Days 1-5	--	--	--	--
Tretinoina 22.5 mg/m2 twice daily orally	Days 1-7	Days 1-7	--	--	Daysb 1-7	Daysb 1-7	--	--
aRounded to the nearest 10 mg increment bOmitted during the 4th cycle of consolidation

• Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day 1 until the end of induction therapy with TRISENOX and tretinoin is recommended.

Relapsed or Refractory APL

A treatment course including TRISENOX 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 TRISENOX 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 TRISENOX 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.

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 TRISENOX [see Warnings and Precautions (5) and Adverse Reactions (6)]. Table 2 shows the dose modifications for toxicity due to TRISENOX when used alone or in combination with tretinoin. 

Table 2:  Dose Adjustments for Adverse Reactions

Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities

*Rounded to the nearest 10 mg increment

Reconstitution

Dilute TRISENOX 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, TRISENOX is chemically and physically stable when stored for 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 intravenously 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. Unused portions of each vial should be discarded properly. Do not mix TRISENOX with other medications.

Safe Handling Procedures

TRISENOX is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Injection: 12 mg arsenic trioxide in 6 mL clear solution in a single-dose vial

TRISENOX is contraindicated in patients who are hypersensitive to arsenic.

Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with TRISENOX.  In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome.  Symptoms include unexplained fever, dyspnea, hypoxia, 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 hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When TRISENOX is used in combination with tretinoin, prednisone prophylaxis is advised [see Dosage and Administration (2.1)].

At the first signs of differentiation syndrome, interrupt treatment with TRISENOX and administer dexamethasone 10 mg intravenously twice daily.  Continue high-dose steroids until signs and symptoms have abated for at least 3 days [see Dosage and Administration (2.2)]. 

Patients treated with TRISENOX can develop QTc prolongation, torsade de pointes, and complete heart block.  In the clinical trials of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin, 11% experienced QTc prolongation > 450 msec for men and > 460 msec for women throughout the treatment cycles. In the clinical trial of patients with relapsed or refractory APL treated with TRISENOX 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 TRISENOX infusion, and it usually resolved by 8 weeks after TRISENOX infusion. There are no data on the effect of TRISENOX 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 TRISENOX 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 TRISENOX, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval.  Do not administer TRISENOX to patients with 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 TRISENOX 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 greater than 500 msec, immediately withhold treatment with TRISENOX and any medication known to prolong the QTc interval.  Correct electrolyte abnormalities. When the QTc normalizes, resume TRISENOX at a reduced dose [see Dosage and Administration (2.2)]. 

In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin.  These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin.  During treatment with TRISENOX, monitor liver chemistries at least 2-3 times per week through recovery from toxicities.  Withhold treatment with TRISENOX and/or tretinoin if elevations in AST), alkaline phosphatase, and/or serum bilirubin occur to greater than 5 times the upper limit of normal [see Dosage and Administration (2.2)].

Long-term liver abnormalities can occur in APL patients treated with TRISENOX in combination with tretinoin.  In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0-14 years) after treatment with arsenic trioxide in combination with tretinoin.

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

TRISENOX 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 and males of reproductive potential to use effective contraception during and after treatment with TRISENOX [see Use in Specific Populations (8.1, 8.3)].

The following serious adverse reactions are described elsewhere in the labeling.

• Differentiation Syndrome [see Warnings and Precautions (5.1)]
• Cardiac Conduction Abnormalities [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Carcinogenesis [see Warnings and Precautions (5.4)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.5)]

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 evaluation of TRISENOX in combination with tretinoin is based on results from a randomized trial comparing TRISENOX plus tretinoin (n=129) versus chemotherapy plus tretinoin (n=137) in patients with newly-diagnosed APL (Study APL0406) [see Clinical Studies (14.1)].  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.

Fatal adverse reactions were reported in 1 (1%) patient on the TRISENOX/tretinoin arm and 8 (6%) patients on the chemotherapy/tretinoin arm.  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.  Serious adverse reactions reported in 25% on the TRISENOX/ tretinoin arm and 24% on the chemotherapy/tretinoin arm. The serious adverse reactions reported in ≥ 2% of patients receiving TRISENOX/tretinoin were abnormal liver tests, differentiation syndrome, dyspnea, pneumonia, and other infections.

Selected hematologic and nonhematologic toxicities that occurred during induction or consolidation are presented in Table 4 for the 129 patients treated with TRISENOX plus tretinoin and the 137 patients treated with chemotherapy plus tretinoin.

Table 4:          Selected Adverse Reactions of Trisenox in Combination with Tretinoin in Patients with Newly-Diagnosed APL

*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 Phase 2 study received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

SAEs, Grade ≥3 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to TRISENOX in the Phase 2 study of 40 patients with refractory or relapsed APL included APL 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).

Table 5 describes the adverse reactions that were observed in ≥ 5% patients, between the ages of 5-73 years, treated for APL with TRISENOX at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received TRISENOX.

Table 5:          Adverse Reactions (Any Grade) Occurring in ≥ 5% of Patients Treated with TRISENOX Monotherapy for Relapsed or Refractory APL

Leukocytosis: TRISENOX in combination with tretinoin 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. Hyperleukocytosis due to TRISENOX may warrant treatment with hydroxyurea [see Dosage and Administration (2.2)]. 

The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

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

Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion

Hematologic disorders: Pancytopenia, bone marrow necrosis

Infections and infestations: Herpes zoster

Investigations: Gamma-glutamyltransferase increased

Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis

Respiratory, thoracic, and mediastinal disorders: Differentiation syndrome, like retinoic acid syndrome, has been reported with the use of TRISENOX for the treatment of malignancies other than APL [see Boxed Warning].

Ear and labyrinth disorders: Deafness

Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma

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 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 administration 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. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use. 

Risk Summary

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, TRISENOX 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 (see Data). 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. There are no studies with the use of TRISENOX in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

One patient was reported to deliver a live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. A second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have a normal pregnancy outcome. A third patient was a pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had a normal pregnancy outcome after treatment and monitoring. A fourth patient who became pregnant while receiving arsenic trioxide had a miscarriage. 

Animal Data

Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of arsenic trioxide on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m² basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite (approximately 5 times the projected human dose on a mg/m² basis), on gestation days 6, 7, 8, or 9. Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m² basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.

Risk Summary

Arsenic trioxide is excreted in human milk. There is no information on the effects of arsenic trioxide on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child from TRISENOX, discontinue breastfeeding during treatment with TRISENOX and for two weeks after the final dose.

Pregnancy Testing

TRISENOX can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with TRISENOX [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during and after treatment with TRISENOX and for six months after the final dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during and after treatment with TRISENOX and for three months after the final dose.

Infertility

Males

Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, TRISENOX may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and efficacy of TRISENOX in combination with tretinoin in pediatric patients has not been established.

The safety and efficacy of TRISENOX as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with TRISENOX at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years. No differences in efficacy and safety were observed by age. 

Use of TRISENOX in combination with tretinoin in newly-diagnosed adult patients with low-risk APL is supported by a randomized, controlled trial that included 16 patients between the ages of 60 and 70 years. No differences in efficacy and safety were observed by age. A literature review included an additional 77 patients treated with arsenic trioxide in combination with tretinoin as part of induction and consolidation therapy for low and high risk APL, with ages ranging from 60 to 84 years. These studies showed lower survival rates in older patients. Monitor elderly patients frequently during treatment with TRISENOX.  

The safety and efficacy of TRISENOX as a single agent in older patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Six patients age 65 and above (age range: 65 to 73 years) were treated with TRISENOX at the recommended dose. A literature review included an additional 4 patients treated with arsenic trioxide for relapsed or refractory APL with ages ranging from 69 to 72 years. No differences in efficacy and safety were observed by age. 

Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted.

The use of TRISENOX in patients on dialysis has not been studied.

Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.

Manifestations of TRISENOX (arsenic trioxide) overdosage include convulsions, muscle weakness, and confusion. 

If symptoms of TRISENOX (arsenic trioxide) overdosage develop, the injection should be immediately discontinued and chelation therapy should be considered.

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.

TRISENOX is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is As₂O₃, with a molecular weight of 197.8 and has the following structural formula:

TRISENOX is available in 10 mL, single-dose vials containing 12 mg of arsenic trioxide. TRISENOX is formulated as a sterile, nonpyrogenic, clear solution of arsenic trioxide in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. TRISENOX is preservative-free. Arsenic trioxide, the active ingredient, is present at a concentration of 2 mg/mL. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) and hydrochloric acid, which is used to adjust the pH to 7.5 - 8.5.

The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha.

Cardiac Electrophysiology

A dedicated QTc study was not performed with TRISENOX. However, in a single-arm trial of TRISENOX (0.15 mg/kg daily), 16 of 40 patients (40%) had a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion.

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As^III). As^III is the pharmacologically active species of arsenic trioxide. Monomethylarsonic acid (MMA^V), and dimethylarsinic acid (DMA^V) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (As^V) a product of As^III oxidation. The pharmacokinetics of arsenical species ([As^III], [As^V], [MMA^V], [DMA^V]) were determined in 6 APL patients following once-daily doses of 0.15 mg/kg for 5 days per week. Over the total single-dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (As^III), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of As^III declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to As^III (mean AUC_0-24) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMA^V and DMA^V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but, due to their longer half-life, accumulate more upon multiple dosing than does As^III. The mean estimated terminal elimination half-lives of the metabolites MMA^V and DMA^V are 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single-dose administration. As^V is present in plasma only at relatively low levels.

Distribution

The volume of distribution (V_ss) for As^III is large (mean 562 L, N=10) indicating that As^III is widely distributed throughout body tissues. V_ss is also dependent on body weight and increases as body weight increases.

Elimination

Metabolism

Much of the As^III is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V) by methyltransferases primarily in the liver. The metabolism of arsenic trioxide also involves oxidation of As^III to As^V, which may occur in numerous tissues via enzymatic or nonenzymatic processes. As^V is present in plasma only at relatively low levels following administration of arsenic trioxide.

Excretion

Approximately 15% of the administered TRISENOX dose is excreted in the urine as unchanged As^III. The methylated metabolites of As^III (MMA^V, DMA^V) are primarily excreted in the urine. The total clearance of As^III is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg.

Specific Populations

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of As^III, As^V, and the pentavalent metabolites MMA^V and DMA^V was evaluated in 20 patients with advanced malignancies. Patients were classified as having normal renal function (creatinine clearance [CrCl] > 80 mL/min, n=6), mild renal impairment (CrCl 50-80 mL/min, n=5), moderate renal impairment (CrCl 30-49 mL/min, n=6), or severe renal impairment (CrCl < 30 mL/min, n=3). Following twice-weekly administration of 0.15 mg/kg over a 2-hour infusion, the mean AUC_0-∞ for As^III was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC_0-∞ for As^III was approximately 48% higher than that in the normal group.

Systemic exposure to MMA^V and DMA^V tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. As^V plasma levels were generally below the limit of assay quantitation in patients with impaired renal function [see Use in Specific Populations (8.6)]. The use of arsenic trioxide in patients on dialysis has not been studied.

Patients with Hepatic Impairment

The effect of pharmacokinetics of As^III, As^V, and the pentavalent metabolites MMA^V and DMA^V was evaluated following administration of 0.25-0.50 mg/kg of arsenic trioxide in patients with hepatocellular carcinoma. Patients were classified as having normal hepatic function (n=4), mild hepatic impairment (Child-Pugh class A, n=12), moderate hepatic impairment (Child-Pugh class B, n=3), or severe hepatic impairment (Child-Pugh class C, n=1). No clear trend toward an increase in systemic exposure to As^III, As^V, MMA^V or DMA^V was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC in the mild and moderate hepatic impairment groups. However, the one patient with severe hepatic impairment had mean dose-normalized AUC_0‑24 and C_max values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMA^V and DMA^V in this severely hepatically impaired patient were 2.2-fold and 4.7-fold higher, respectively, than those in the patients with normal hepatic function [see Use in Specific Populations (8.7)].

Pediatric Patients

Following IV administration of 0.15 mg/kg/day of arsenic trioxide in 10 APL patients (median age = 13.5 years, range 4-20 years), the daily exposure to As^III (mean AUC_0-24h) was 317 ng·hr/mL on Day 1 of Cycle 1 [see Use in Specific Populations (8.4)].

Drug Interaction Studies

No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes. In vitro incubation of arsenic trioxide with human liver microsomes showed no inhibitory activity on substrates of the major cytochrome P450 (CYP) enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11. The pharmacokinetics of drugs that are substrates for these CYP enzymes are not expected to be affected by concomitant treatment with arsenic trioxide. 

Carcinogenicity studies have not been conducted with TRISENOX by intravenous administration [see Warnings and Precautions (5.4)].

Arsenic trioxide and trivalent arsenite salts have not been demonstrated to be mutagenic to bacteria, yeast, or mammalian cells. Arsenite salts are clastogenic in vitro (human fibroblast, human lymphocytes, Chinese hamster ovary cells, Chinese hamster V79 lung cells). Trivalent arsenic was genotoxic in the chromosome aberrations assay and micronucleus bone marrow assay in mice.

The effect of arsenic on fertility has not been adequately studied in humans. Decreased testicular weight and impaired spermatogenesis have been reported in animal studies. Male Wistar rat pups were administered 1.5 mg/kg sodium arsenite solution via the intraperitoneal route from postnatal days 1 to 14 and testes were collected for evaluation on postnatal days 15, 21, and 50. Results of this study revealed an altered morphology of the seminiferous tubules along with degeneration of spermatogenic cells, increased number of sperm with abnormal morphology, and decreased sperm counts. In beagle dogs administered intravenous arsenic trioxide for 90 days, reduced inner cell layers within seminiferous tubules and significantly decreased numbers of spermatocytes, spermatozoa, and sperm cells were observed at doses of 1 mg/kg/day and higher.  The 1 mg/kg/day dose is approximately 3 times the recommended human daily dose on a mg/m² basis.

TRISENOX in combination with tretinoin was investigated in Study APL0406 (NCT00482833), a multicenter, randomized, open-label trial in patients with newly-diagnosed low-risk APL (white blood cell count at diagnosis ≤10 Gi/L). The patients were randomized 1:1 to receive TRISENOX/tretinoin for induction and consolidation or chemotherapy/tretinoin for induction, consolidation, and maintenance.

Patients in the TRISENOX/tretinoin group received induction treatment with TRISENOX 0.15 mg/kg intravenously once daily in combination with tretinoin 22.5 mg/m² (rounded to the nearest 10 mg increment) orally twice daily until hematologic complete remission (CR) or for a maximum of 60 days. Patients in this group who achieved a CR during induction received four 8-week cycles of consolidation treatment with TRISENOX 0.15 mg/kg intravenously once daily for 5 days every week during weeks 1-4 of the 8-week cycle, in combination with tretinoin 22.5 mg/m² (rounded to the nearest 10 mg increment) orally twice daily during weeks 1-2 and 5-6 of the 8-week cycle.  Tretinoin was omitted during weeks 5-6 of the last cycle.

Patients in the chemotherapy/tretinoin group received idarubicin 12 mg/m² intravenously once daily on days 2, 4, 6, and 8 in combination with tretinoin 22.5 mg/m² (rounded to the nearest 10 mg increment) orally twice daily, starting on day 1, until hematologic CR or for a maximum of 60 days. Patients in this group who achieved a CR during induction received consolidation and maintenance treatment with tretinoin in combination with chemotherapy.

The trial enrolled 162 patients with a morphologic diagnosis of APL. The median age of patients was 45 years in the TRISENOX/tretinoin arm and 47 years in the chemotherapy/tretinoin arm, and 52% and 46% were male in the TRISENOX/tretinoin and chemotherapy/tretinoin arms, respectively. Baseline characteristics were balanced between treatment arms, including median WBC count, platelet count, PML-RARA isoform, and FLT3-ITD status.

Efficacy was based on event-free survival (EFS) rate at 2 years. EFS was defined as the time from randomization to the occurrence of treatment failure, defined as no achievement of CR or CRi after induction therapy, no achievement of molecular remission after 3 consolidation courses, molecular relapse, hematologic relapse, or death. The primary analysis of EFS was based on the difference between the two treatment arms in patients achieving EFS at 2 years. With a median follow-up of 34.4 months, the 2 year EFS rate of the modified ITT (mITT) population (patients who received at least one dose of the assigned treatment) was 94% in the TRISENOX/tretinoin arm (n=77) versus 82% in the chemotherapy/tretinoin arm (n=79), a treatment difference of 11% (95% CI: 1, 22; p-value 0.048). Overall survival (OS) for the mITT population was 99% (95% CI: 93, 100) in the TRISENOX/tretinoin arm versus 91% (95% CI: 86, 97) in the chemotherapy/tretinoin arm.  The difference in 2-year OS rate between the arms was 8% (95% CI: 0, 16).

Figure 1:                     Event-Free Survival for Newly-Diagnosed APL

The number of patients in the plot is based on the mITT population. 

TRISENOX has been investigated in Study PLRXAS01, an open-label, single-arm trial in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen. Patients received TRISENOX 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or up to a maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with a confirmatory bone marrow ≥ 30 days later) rate in this population of previously treated patients was 28 of 40 (70%). Among the 22 patients who had relapsed less than one year after treatment with tretinoin, there were 18 complete responders (82%). Of the 18 patients receiving TRISENOX ≥ one year from tretinoin treatment, there were 10 complete responders (55%). The median time to bone marrow remission was 44 days and to onset of CR was 53 days. Three of 5 children, 5 years or older, achieved CR. No children less than 5 years old were treated.

Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with TRISENOX, at the same dose, for 25 additional days over a period up to 5 weeks. In follow-up treatment, 18 patients received further TRISENOX as a maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with a median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with a median follow-up time of 483 days (range 280 to 755).

Cytogenetic conversion to no detection of the APL chromosome rearrangement was observed in 24 of 28 (86%) patients who met the response criteria defined above, in 5 of 5 (100%) patients who met some, but not all, of the response criteria, and 3 of 7 (43%) of patients who did not respond. RT-PCR conversions to no detection of the APL gene rearrangement were demonstrated in 22 of 28 (79%) of patients who met the response criteria, in 3 of 5 (60%) of patients who met some, but not all, of the response criteria, and in 2 of 7 (29%) of patients who did not respond.

Responses were seen across all age groups tested, ranging from 6 to 72 years. The ability to achieve a CR was similar for both genders. There were insufficient patients of Black, Hispanic, or Asian derivation to estimate relative response rates in these groups, but responses were seen in members of each group. 

• “Hazardous Drugs”, OSHA. [Accessed on February 12, 2015 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

TRISENOX (arsenic trioxide) injection is supplied as a sterile, clear, colorless solution in 10 mL glass, single-dose vials.

NDC 63459-601-06 12 mg/6 mL (2 mg/mL) vial in packages of ten vials.

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) (See USP Controlled Room Temperature). Do not freeze.

TRISENOX is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

• Differentiation Syndrome
  
  Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, dizziness/lightheadedness, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high-dose corticosteroids. Advise patients to immediately report any of these symptoms.
• ECG Abnormalities – QT Prolongation
  
  Advise patients that TRISENOX may cause ECG abnormalities, including QT prolongation. QT prolongation is an increase in the time it takes the heart to relax between beats. If extreme, this prolongation has the potential to cause fainting, irregular heartbeat, or more serious side effects. Advise patients to immediately report any of these symptoms. Advise patients to provide a complete list of current medications as caution should be taken when TRISENOX is coadministered with other medications that can cause QT prolongation or lead to electrolyte abnormalities.
• Other Side Effects
  
  Advise patients of the expected adverse reactions of TRISENOX. Most patients in clinical trials experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse reactions have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy. Advise patients to call their physician at the onset of any treatment-related adverse reactions.
• Embryo-Fetal Toxicity
  
  Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions 5.5 and Use in Specific Populations 8.1)].
  
  Advise females and males of reproductive potential to use effective contraception during treatment with TRISENOX. Advise females to use effective contraception for six months and males to use effective contraception for three months after completing treatment with TRISENOX [see Use in Specific Populations (8.3)].
• Potential Effect on Male Fertility
  

Advise male patients of the potential risk to future fertility following treatment with TRISENOX, as decreased testicular weight and impaired spermatogenesis have been reported in animal studies.

• Lactation
  
  Advise females to discontinue breastfeeding during treatment with TRISENOX and for two weeks after treatment with TRISENOX [see Use in Specific Populations (8.2)].

Rx only


Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

TRISENOX® is a registered trademark of Cephalon, Inc. or its affiliates.

US Patent Nos. 6,723,351; 6,855,339; 6,861,076; 6,884,439; 6,982,096; 8,273,379.

©2000-2018 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd., or its affiliates.

All rights reserved.

TRI-011

NDC 63459-601-06

10 x 6 mL

Single-Dose Vials

Rx only

Trisenox®

(arsenic trioxide)

injection

NEW CONCENTRATION

12 mg/6 mL (2 mg/mL)

Single-Dose Vial – Discard Unused Portion

For Intravenous Use Only