TRISENOX† is a sterile injectable solution of arsenic trioxide. The molecular formula of the drug substance in the solid state is As ₂ O ₃ , with a molecular weight of 197.8 g.

TRISENOX† is available in 10 mL, single-use ampules containing 10 mg of arsenic trioxide. TRISENOX† is formulated as a sterile, nonpyrogenic, clear solution of arsenic trixoide 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 1.0 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 7.0-9.0.

TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (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.

The response rate of other acute myelogenous leukemia subtypes to TRISENOX has not been examined.

TRISENOX should be diluted 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 ampule. The TRISENOX ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not save any unused portions for later administration. Do not mix TRISENOX with other medications.

TRISENOX should be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.

Stability

After dilution, TRISENOX is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.

Dosing Regimen

TRISENOX is recommended to be given according to the following schedule:

Induction Treatment Schedule: TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Total induction dose should not exceed 60 doses.

Consolidation Treatment Schedule: Consolidation treatment should begin 3 to 6 weeks after completion of induction therapy. TRISENOX should be administered intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks.

Handling And Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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

NDC 63459-600-10 10 mg/10 mL (1 mg/mL) ampule in packages of ten ampules.

Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). Do not freeze.

Do not use beyond expiration date printed on the label.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication NIH 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.

2. Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592.

3. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.

5. Jones RB, et al. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA J Clin. 1983;33:258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990;47:1033-1049.

7. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm. 1996;53:1669-1685.

Manufactured for: Cephalon, Inc. Frazer, PA 19355. Revised July 2006. FDA Rev date: 1/7/2003

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 which 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.

Serious adverse events (SAEs), grade 3 or 4 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).

The following table describes the adverse events that were observed in patients treated for APL with TRISENOX at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received TRISENOX.

Adverse Events (any grade) Occurring in ≥ 5% of 40 Patients with APL who Received TRISENOX (arsenic trioxide) injection at a dose of 0.15 mg/kg/day

No formal assessments of pharmacokinetic drug-drug interactions between TRISENOX and other agents have been conducted. Caution is advised when TRISENOX is coadministered with other medications that can prolong the QT interval (e.g. certain antiarrhythmics or thioridazine) or lead to electrolyte abnormalities (such as diuretics or amphotericin B).

(see BOXED WARNING)

TRISENOX (arsenic trioxide) should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia.

APL Differentiation Syndrome (see BOXED WARNING): Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome (see BOXED WARNING and ADVERSE REACTIONS).

Hyperleukocytosis: Treatment with TRISENOX has been associated with the development of hyperleukocytosis ( ≥ 10 x 10³/µL) in 20 of 40 patients. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts. Hyperleukocytosis was not treated with additional chemotherapy. WBC counts during consolidation were not as high as during induction treatment.

QT Prolongation (see BOXED WARNING): QT/QTc prolongation should be expected during treatment with arsenic trioxide and torsade de pointes as well as complete heart block has been reported. Over 460 ECG tracings from 40 patients with refractory or relapsed APL treated with TRISENOX were evaluated for QTc prolongation. Sixteen of 40 patients (40%) had at least one ECG tracing with 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. In these ECG evaluations, women did not experience more pronounced QT prolongation than men, and there was no correlation with age.

Complete AV block: Complete AV block has been reported with arsenic trioxide in the published literature including a case of a patient with APL.

Carcinogenesis: Carcinogenicity studies have not been conducted with TRISENOX by intravenous administration. The active ingredient of TRISENOX, arsenic trioxide is a human carcinogen.

Pregnancy: TRISENOX may cause fetal harm when administered to a pregnant woman. Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arseni-cals cross the placental barrier when given orally or by injection. The reproductive toxicity of arsenic trioxide has been studied in a limited manner. 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.

There are no studies in pregnant women using TRISENOX. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Women of childbearing potential should be advised to avoid becoming pregnant.

Laboratory Tests: The patient's be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase. ECGs should be obtained weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for information on carcinogenesis. 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 produced an increase in the incidence of chromosome aberrations and micronuclei in bone marrow cells of mice. The effect of arsenic on fertility has not been adequately studied.

Pregnancy: Pregnancy Category D. See WARNINGS section.

Nursing Mothers: Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: There are limited clinical data on the pediatric use of TRISENOX. Of 5 patients below the age of 18 years (age range: 5 to 16 years) treated with TRISENOX, at the recommended dose of 0.15 mg/kg/day, 3 achieved a complete response.

Safety and effectiveness in pediatric patients below the age of 5 years have not been studied.

Patients with Renal or Hepatic Impairment: Safety and effectiveness of TRISENOX in patients with renal and hepatic impairment have not been studied. Particular caution is needed in patients with renal failure receiving TRISENOX, as renal excretion is the main route of elimination of arsenic.

If symptoms suggestive of serious acute arsenic toxicity (e.g., convulsions, muscle weakness and confusion) appear, TRISENOX (arsenic trioxide) 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 contraindicated in patients who are hypersensitive to arsenic.

Mechanism of Action

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 PML/RAR-alpha.

Pharmacokinetics

The pharmacokinetics of trivalent arsenic, the active species of TRISENOX, have not been characterized.

Metabolism

The metabolism of arsenic trioxide involves reduction of pentavalent arsenic to trivalent arsenic by arsenate reductase and methylation of trivalent arsenic to monomethylarsonic acid and monomethylarsonic acid to dimethylarsinic acid by methyltransferases. The main site of methylation reactions appears to be the liver. Arsenic is stored mainly in liver, kidney, heart, lung, hair and nails.

In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11.

Excretion

Disposition of arsenic following intravenous administration has not been studied. Trivalent arsenic is mostly methylated in humans and excreted in urine.

Special Populations

The effects of renal or hepatic impairment or gender, age and race on the pharmacokinet-ics of TRISENOX have not been studied (see PRECAUTIONS).

Drug Interactions

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 (see PRECAUTIONS).

Clinical Studies

TRISENOX has been investigated in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen, in an open-label, single-arm, non-comparative study. Patients received 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 ATRA, there were 18 complete responders (82%). Of the 18 patients receiving TRISENOX ≥ one year from ATRA 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 arsenic trioxide 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. Reverse Transcriptase - Polymerase Chain Reaction 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.

Another single center study in 12 patients with relapsed or refractory APL, where patients received TRISENOX (arsenic trioxide) injection doses generally similar to the recommended dose, had similar results with 9 of 12 (75%) patients attaining a CR.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ARSENIC TRIOXIDE - INJECTION

(AR-sen-ik try-OX-ide)

COMMON BRAND NAME(S): Trisenox

WARNING: Arsenic trioxide is a strong medication that can cause serious, rarely fatal side effects. To decrease your risk, your doctor will monitor you closely during treatment.

Infrequently, this medication may cause a serious condition called APL differentiation syndrome. Tell your doctor immediately if the following effects occur: unusual/unexplained fever, shortness of breath/difficulty breathing, and/or weight gain. Your doctor may direct you to weigh yourself regularly and report any sudden weight gain. Your doctor may also perform certain exams or tests (e.g., lung exam, X-rays) to determine if this syndrome has developed.

Infrequently, this medication can also cause serious (rarely fatal) heart problems (e.g., AV block, torsades de pointes-type arrhythmias). Tell your doctor if you have any medical history of heart problems (e.g., fast/irregular heartbeat, heart failure), kidney problems, low levels of minerals in your blood (e.g., calcium, potassium, magnesium). Also tell your doctor if you take any medications that increase your risk for these heart problems or low levels of minerals (see also Drug Interactions section). To decrease your risk, your doctor may order a heart rhythm test (EKG) or blood tests before and during treatment.

Seek immediate medical attention if you develop severe dizziness, fainting, or fast/irregular heartbeat.

USES: Arsenic trioxide is used to treat a type of leukemia (acute promyelocytic leukemia-APL) when other types of treatment (e.g., chemotherapy) have not worked well or no longer work.

HOW TO USE: Learn all preparation, mixing, and usage instructions in the product package. If any of the information is unclear, consult your doctor or pharmacist. Before using, check this medication visually for particles. If particles are present, do not use the liquid. Do not mix arsenic trioxide with other medications.

This medication is given by injection into a vein by a health care professional over 1 to 2 hours, usually once daily or as directed by your doctor. The injection may be injected more slowly (e.g., over 4 hours) if you have a reaction to the medication such as dizziness, flushing, or fast heartbeat.

The dosage and length of treatment is based on your weight, medical condition, and response to treatment. Your doctor will order tests (e.g., EKG, blood minerals) to find the right dose for you. Your next dose may need to be rescheduled if your heartbeat or blood tests are abnormal.

Learn how to handle, use, and discard chemotherapy and medical supplies safely. Consult your pharmacist.

SIDE EFFECTS: See also Warning section.

Pain/redness/swelling at the injection site, nausea, vomiting, diarrhea, stomach/abdominal pain, tiredness, cough, headache, or dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Both leukemia and this medication can lower the body's ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as unexplained fever, chills, or persistent sore throat.

Tell your doctor immediately if any of these unlikely but serious side effects occur: easy bleeding/bruising, nosebleed, increased thirst, change in the amount of urine, blurred vision, bone/joint pain, decreased appetite, unusual weight loss, muscle pain/stiffness/spasm, numbness/tingling, swollen hands/legs/feet.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, severe dizziness/fainting, fast/irregular heartbeat, coughing up blood, mental/mood changes (e.g., confusion), muscle weakness, seizures, bloody/black/tarry stool, vomit that looks like coffee grounds.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice any other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to arsenic; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain heart problem (QT prolongation in the EKG).

Before using this medication, tell your doctor or pharmacist your medical history, especially: other heart problems (e.g., slow/fast/irregular heartbeat, heart failure), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death), kidney disease, low blood minerals (e.g., low potassium or low magnesium levels), diabetes.

This drug may make you dizzy. Use caution while driving, using machinery, or doing any other activity that requires alertness. Limit alcoholic beverages.

Wash your hands well to prevent the spread of infections. Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This drug should not be used during pregnancy. It may harm the unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. Talk with your doctor about effective forms of birth control.

This medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: drugs that may affect the heart rhythm (e.g., amiodarone, procainamide, quinidine, sotalol).

Other drugs besides arsenic and those listed above that may affect the heart rhythm (QT prolongation in the EKG) include dofetilide, pimozide, droperidol, ziprasidone, and erythromycin, among others. Before using arsenic, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: aspirin and other NSAIDs (e.g., ibuprofen), drugs that lower blood minerals (e.g., amphotericin B, water pills/"diuretics" such as furosemide, hydrochlorothiazide), drugs that may harm the immune system (e.g., chemotherapy, corticosteroids such as prednisone).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as ibuprofen, naproxen, or aspirin) that may increase your risk of bleeding. Low-dose aspirin should be continued if prescribed by your doctor for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day). Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: seizures, muscle weakness, confusion.

NOTES: Laboratory and/or medical tests (e.g., electrolytes, complete blood count, EKG) should be performed while you are using the medication to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. Keep all medical/lab appointments. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not freeze.

After mixing, this product may be stored at room temperature for up to 24 hours or refrigerated between 36-46 degrees F (2-8 degrees C) for up to 48 hours. Safely discard any unused liquid after those times.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.