Trisenox

Pronunciation

Generic Name: Arsenic Trioxide
Class: Antineoplastic Agents
VA Class: AN900
CAS Number: 1327-53-3

Warning(s)

  • Experience of Supervising Clinician
  • Use under the supervision of a qualified clinician experienced in the management of acute leukemia.1

  • Acute Promyelocytic Leukemia (APL) Differentiation Syndrome
  • Risk of developing potentially fatal APL differentiation syndrome.1

  • If signs or symptoms suggestive of APL differentiation syndrome (e.g., unexplained fever, dyspnea, weight gain, abnormal chest auscultatory findings, radiographic abnormalities) occur, initiate high-dose corticosteroid therapy (e.g., dexamethasone phosphate 10 mg IV twice daily for 3 days or longer until symptoms resolve) immediately regardless of the patient's leukocyte count; discontinuance of arsenic trioxide generally is not required.1

  • ECG Abnormalities
  • Risk of potentially fatal atypical ventricular tachycardia (torsades de pointes) and complete atrioventricular block,1 4 6 8 10 particularly in patients with a history of torsades de pointes, CHF, or preexisting QT interval prolongation, and in those receiving drugs that might prolong the QT interval or produce electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia).1

  • ECG and Electrolyte Monitoring
  • Prior to initiation of therapy, perform baseline ECG and determine serum electrolyte (potassium, calcium, and magnesium) and creatinine concentrations.1 6 7

  • If baseline QTc interval >500 msec, institute appropriate corrective measures and reassess with serial ECGs prior to considering arsenic trioxide therapy.1

  • Correct preexisting electrolyte abnormalities; if possible, discontinue drugs known to prolong the QT interval.1

  • During therapy, maintain serum potassium concentrations >4 mEq/L and serum magnesium concentrations >1.8 mg/dL and monitor ECGs weekly (more frequently in clinically unstable patients).1 10

  • If QT interval >500 msec during therapy, correct any concomitant risk factors immediately and weigh the risks/benefits of continued therapy.1 11

  • If syncope and/or rapid or irregular heartbeat occurs, hospitalize patient for careful monitoring; discontinue arsenic trioxide until QTc interval decreases to <460 msec, electrolyte abnormalities are corrected, and syncope and irregular heartbeat resolve.1

Introduction

Antineoplastic agent.1

Uses for Trisenox

Refractory or Relapsed Acute Promyelocytic Leukemia

Induction of remission and consolidation of acute promyelocytic leukemia (APL) that is refractory to retinoid and anthracycline therapy or has relapsed following such therapy;1 4 16 17 used in patients whose disease is characterized by the presence of the t(15;17) translocation or promyelocytic leukemia-retinoic acid receptor (PML-RAR)-α gene expression.1 5

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Actuarial 18-month relapse-free survival rate: 56%.17

Newly Diagnosed Acute Promyelocytic Leukemia

As a component of therapy for newly diagnosed APL in combination with other agents and consolidation chemotherapy.17 20 25

Combination therapy with arsenic trioxide and tretinoin has been used as an alternative to chemotherapy for induction and postremission therapy in newly diagnosed APL; may consider use of these regimens in select patients who cannot tolerate standard anthracycline-containing chemotherapy (e.g., geriatric patients with poor performance or patients with cardiac dysfunction).27 28 29

Trisenox Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.1

Administration

Administer by IV infusion.1

IV Administration

For solution compatibility information, see Compatibility under Stability.

IV solutions of the drug contain no preservatives; discard any unused portion of single-use ampul.1

Do not mix with other drugs.1

Dilution

Immediately after withdrawing the appropriate dose of the drug from the ampul, dilute with 100–250 mL of 5% dextrose injection or 0.9% sodium chloride injection.1

Rate of Administration

Administer by IV infusion over 1–2 hours; if acute vasomotor reactions occur, longer infusion periods (e.g., up to 4 hours) may be used.1

Dosage

Pediatric Patients

Acute Promyelocytic Leukemia
Induction Therapy
IV

In children ≥5 years of age, 0.15 mg/kg daily.1 Continue until bone marrow remission occurs or for a maximum of 60 doses.1

Consolidation Therapy
IV

In children ≥5 years of age, 0.15 mg/kg daily for 25 doses, administered over a period of up to 5 weeks.1 Initiate 3–6 weeks after completion of induction therapy.1

Adults

Acute Promyelocytic Leukemia
Induction Therapy
IV

0.15 mg/kg daily.1 Continue until bone marrow remission occurs or for a maximum of 60 doses.1

Consolidation Therapy
IV

0.15 mg/kg daily for 25 doses, administered over a period of up to 5 weeks.1 Initiate 3–6 weeks after completion of induction therapy.1

Cautions for Trisenox

Contraindications

  • Known hypersensitivity to arsenic trioxide or any ingredient in the formulation.1

Warnings/Precautions

Warnings

For warnings regarding experience of supervising clinician, APL differentiation syndrome, ECG abnormalities, and ECG and electrolyte monitoring, see Boxed Warning.

Hyperleukocytosis

Possible hyperleukocytosis (leukocyte count ≥10,000/mm3).1 11

Carcinogenicity

Carcinogenicity studies not performed using IV arsenic trioxide; however, arsenic trioxide is a human carcinogen.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

General Precautions

Adequate Patient Monitoring

Perform hematologic and coagulation tests and determine serum electrolyte concentrations at least twice weekly during induction therapy (more frequently in clinically unstable patients) and at least weekly during consolidation therapy.1

Monitor ECG weekly (more frequently in clinically unstable patients) during induction and consolidation therapy.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Arsenic is distributed into milk in humans;1 discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <5 years of age.1

Used in 7 children 5–16 years of age with APL in one study and in 13 children and young adults 4–21 years of age with refractory or relapsed APL in another study; 5 and 11 achieved complete responses, respectively.1 11 26

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Potential for prolonged elimination.1 Use with caution in patients with renal failure.1

Common Adverse Effects

Leukocytosis, GI effects (nausea, vomiting, diarrhea, abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, dizziness.1

Interactions for Trisenox

Extensively metabolized in the liver.1 Methyltransferases involved in metabolism of arsenic trioxide are not CYP isoenzymes.1

Has no inhibitory effects on metabolism of substrates of major CYP isoenzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11).1

No formal drug interaction studies to date.1

Drugs that Prolong the QT Interval

Potential pharmacologic interaction (additive effects on prolongation of the QT interval).14 15

Drugs that May be Associated with Electrolyte Abnormalities

Potential pharmacologic interaction (additive effects on prolongation of the QT interval).1

Specific Drugs

Drug

Interaction

Comments

Amphotericin B

Additive effects on prolongation of QT interval1

Use with caution1

Antiarrhythmics producing QT-interval prolongation

Additive effects on prolongation of QT interval1

Use with caution1

Diuretics (potassium-wasting)

Additive effects on prolongation of QT interval1

Use with caution1

Pimozide

Additive effects on prolongation of QT interval14 15

Concomitant use not recommended14 15

Thioridazine

Additive effects on prolongation of QT interval1

Use with caution1

Ziprasidone

Additive effects on prolongation of QT interval14 15

Concomitant use not recommended14 15

Trisenox Pharmacokinetics

Pharmacokinetics of trivalent arsenic have not been characterized.1

Distribution

Extent

Arsenic is stored mainly in liver, kidney, heart, lung, hair, and nails.1

Inorganic arsenical preparations cross the placenta in animals.1

Elimination

Metabolism

Arsenic trioxide is extensively metabolized via reduction by arsenate reductase and methylation (mainly in the liver) by methyltransferases.1

Elimination Route

Trivalent arsenic is excreted in urine.1

Stability

Storage

Parenteral

Solution

25°C (may be exposed to 15–30°C).1 Do not freeze.1

Chemically and physically stable after dilution for 24 hours at room temperature and 48 hours when refrigerated.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible1

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • Mechanism of action not fully elucidated.1 5

  • Believed to induce apoptosis (programmed cell death) of promyelocytic leukemia cells.1 5

Advice to Patients

  • Importance of informing clinicians if unexplained fever, dyspnea, or weight gain occurs.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Boxed Warning and see Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Arsenic Trioxide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

1 mg/mL (10 mg)

Trisenox

Cephalon

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

1. Cephalon. Trisenox (arsenic trioxide) injection prescribing information. Frazer, PA; 2006 Jul.

2. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

3. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 ed.). 1987:18-24.

4. Anon. FDA approves arsenic trioxide for leukemia treatment in record time for a cancer drug development program. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2000 Sep 26.

5. Soignet SL, Maslak P, Wang ZG et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998; 339:1341-8. [IDIS 430941] [PubMed 9801394]

6. Food and Drug Administration. Torsades de pointes arrhythmia and sudden death associated with the use of arsenic trioxide. Medwatch safety information summaries 2001. Rockville, MD; March 2001. From FDA website.

7. Food and Drug Administration: Healthcare providers reminded to closely monitor patients on arsenic trioxide. Medwatch safety information summaries 2001. Rockville, MD; March 2001. From FDA website. Correction.

8. Dear health care provider letter regarding the importance of close monitoring of patients on arsenic trioxide. Seattle, WA: Cell Therapeutics; 2001 March.

9. Unnikrishnan D, Dutcher JP, Varshneya N et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood. 2001; 97:1514-6. [IDIS 459938] [PubMed 11222403]

10. Ohnishi K, Yoshida H, Shigeno K et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med. 2000; 133:881-5. [IDIS 456624] [PubMed 11103058]

11. Cell Therapeutics, Seattle, WA: Personal communication.

12. Westervelt P, Brown RA, Adkins DR et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood. 2001; 98:266-71. [IDIS 466692] [PubMed 11435292]

13. Dear doctor letter commenting on the report of sudden death in 3 patients receiving arsenic trioxide. Seattle, WA: Cell Therapeutics; 2001 Jul 24.

14. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Geodon (ziprasidone) capsules [February 15, 2002]. From FDA web site.

15. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Orap (pimozide) [November 14, 2002]. From FDA web site.

16. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]

17. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Aug 8.

18. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97[[030]]414). Rockville, MD; [May 5, 2003]. From FDA web site.

19. Soignet SL, Frankel SR, Douer D et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001; 19:3852-60. [IDIS 469715] [PubMed 11559723]

20. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Aug 18.

21. Shen ZX, Shi ZZ, Fang J et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004; 101:5328-35. [PubMed 15044693]

22. Hussein MA, Saleh M, Ravandi F et al. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2004; 125:470-6. [PubMed 15142117]

23. Munshi NC, Tricot G, Desikan R et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia. 2002; 16:1835-7. [PubMed 12200700]

24. Sekeres MA. Arsenic trioxide as a treatment for myelodysplastic syndrome. Curr Hematol Rep. 2005; 4:59-63. [PubMed 15610661]

25. Powell BL, Moser B, Stock W et al. Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. Proc ASCO. 2007; Abstract No. 2..

26. Fox E, Razzouk BI, Widemann BC et al. Phase I trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood. 2008; 111:566-73. [PubMed 17959855]

27. Estey E, Garcia-Manero G, Ferrajoli A et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006; 107:3469-73. [PubMed 16373661]

28. Mathews V, George B, Lakshmi KM et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006; 107:2627-32. [PubMed 16352810]

29. Douer D. ATO: the forefront of APL treatment? Blood. 2006; 107:2588-2589.

HID. Trissel LA. Handbook on injectable drugs. 14th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2007:171.

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