ARSENIC TRIOXIDE- arsenic trioxide_injection, solution

The mechanism of action of Arsenic Trioxide for Injection 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 arsenic trioxide injection. However, in a single arm trial of arsenic trioxide injection (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 arsenic trioxide injection infusion, and then returned towards baseline by the end of 8 weeks after arsenic trioxide injection infusion. The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As III III V V V III V V V III III III V V III V V Distribution The volume of distribution (V ss III III ss Elimination Metabolism Much of the As III V V III V V Excretion Approximately 15% of the administered arsenic trioxide injection dose is excreted in the urine as unchanged As III III V V III Specific Populations Patients with Renal Impairment The effect of renal impairment on the pharmacokinetics of As III V V V 0-infinity III 0-infinity III Systemic exposure to MMA V V V Use in Specific Populations ( 8. 6 Patients with Hepatic Impairment The effect of pharmacokinetics of As III V V V III V V V 0-24 max 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 0-24h Use in Specific Populations ( 8. 4 Drug Interaction Studies No formal assessments of pharmacokinetic drug-drug interactions between arsenic trioxide injection and other drugs have been conducted. The methyltransferases responsible for metabolizing arsenic trioxide are not members of the cytochrome P450 family of isoenzymes.

Arsenic trioxide injection is an arsenical indicated: For induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. 2 Arsenic trioxide injection is indicated for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Relapsed or refractory APL: Induction : 0. 15 mg/kg intravenously daily until bone marrow remission. Do not exceed 60 doses for total induction. 2 Consolidation: 0. 15 mg/kg intravenously daily for 25 doses over a period up to 5 weeks. 2 Relapsed or Refractory APL A treatment course including arsenic trioxide injection monotherapy for patients with relapsed or refractory APL consists of 1 induction cycle and 1 consolidation cycle [see Clinical Studies ( 14. 2 For the induction cycle, the recommended dose of arsenic trioxide injection is 0. 15 mg/kg intravenously daily until bone marrow remission or up to a maximum of 60 days. For the consolidation cycle, the recommended dose of arsenic trioxide injection is 0. 15 mg/kg intravenously daily for 25 doses over a period of up to 5 weeks. Begin consolidation 3 to 6 weeks after completion of induction therapy. During induction therapy, monitor coagulation studies, blood counts, and chemistries at least 2-3 times per week through recovery. During consolidation, monitor at least weekly. Management of some adverse reactions may require dose interruption, dose reduction, or permanent discontinuation of arsenic trioxide injection [see Warnings and Precautions ( 5 Adverse Reactions ( 6 Table 2: Dose Adjustments for Adverse Reactions Adverse Reaction(s) Dose Modification Differentiation syndrome, defined by the presence of 2 or more of the following: Temporarily withhold arsenic trioxide injection. Treat with dexamethasone 10 mg intravenously every 12 hours until the resolution of signs and symptoms for a minimum of 3 days. Resume treatment when the clinical condition improves and reduce the dose of the withheld drug(s) by 50%. Increase the dose of the withheld drug(s) to the recommended dosage after 7 days in the absence of recurrence of symptoms of differentiation syndrome. If symptoms re-appear, decrease arsenic trioxide injection to the previous dose. QTc Prolongation greater than 450 msec for men or greater than 460 msec for women: Withhold treatment with arsenic trioxide injection and any medication known to prolong the QTc interval. Replete electrolytes. After the QTc normalizes, resume treatment with arsenic trioxide injection at a 50% reduced dose (0. 075 mg/kg once daily) for 7 days. If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase the dose of arsenic trioxide injection to 0. 11 mg/kg once daily for 7 days. The dose of arsenic trioxide injection can be increased to 0. 15 mg/kg in the absence of QTc prolongation during that 14-day dose-escalation period. Hepatotoxicity, defined by 1 or more of the following: Withhold treatment with arsenic trioxide injection. Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is less than 1. 5 times the ULN and AP/AST are less than 3 times the ULN. Increase the dose of the withheld drug back to the recommended dosage after 7 days on the reduced dose in the absence of worsening of hepatotoxicity. Discontinue the withheld drug permanently if hepatotoxicity recurs. Other severe or life- threatening (grade 3-4) nonhematologic reactions Temporarily withhold arsenic trioxide injection. When the adverse reaction resolves to no more than mild (grade 1), resume arsenic trioxide injection reduced by 2 dose levels (see Table 3 below). Moderate (grade 2) nonhematologic reactions Reduce the dose of arsenic trioxide injection by 1 dose level (see Table 3 below). Leukocytosis (WBC count greater than 10 Gi/L) Administer hydroxyurea. Hydroxyurea may be discontinued when the WBC declines below 10 Gi/L. Myelosuppression, defined by 1 or more of the following: Consider reducing the dose of arsenic trioxide injection by 1 dose level (see Table 3 below). If myelosuppression lasts 50 days or occurs on 2 consecutive cycles, assess a marrow aspirate for remission status. In the case of molecular remission, resume arsenic trioxide injection at 1 dose level lower (see Table 3 below). Table 3: Dose Reduction Levels for Hematologic and Nonhematologic Toxicities Dose Level Arsenic trioxide injection mg/kg intravenously once daily Starting level 0. 075 Reconstitution Dilute arsenic trioxide injection 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, arsenic trioxide injection 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 arsenic trioxide injection 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 arsenic trioxide injection vial is single-dose and does not contain any preservatives. Unused portions of each vial should be discarded properly. Do not mix arsenic trioxide injection with other medications. Safe Handling Procedures Arsenic trioxide injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.

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 The most common adverse reactions (greater than 30%) were leukocytosis, neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, abdominal pain, hepatic toxicity, fever, rigors, fatigue, insomnia, tachycardia, QTc prolongation, edema, hyperglycemia, hypokalemia, hypomagnesemia, dyspnea, cough, rash or itching, sore throat, arthralgia, headaches, paresthesia, and dizziness. 1 To report SUSPECTED ADVERSE REACTIONS, contact STI Pharma LLC, Inc. at 1-888-301-9680 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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: Nervous system disorders: Hematologic disorders: Infections and infestations: Investigations: Musculoskeletal and connective tissue disorders: Respiratory, thoracic, and mediastinal disorders: Ear and labyrinth disorders: Neoplasms benign, malignant and unspecified: Skin and subcutaneous tissue disorders:.

Arsenic Trioxide for Injection is contraindicated in patients who are hypersensitive to arsenic. Hypersensitivity to arsenic.

Lactation: Advise women not to breastfeed. 2 Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with arsenic trioxide injection; dose reduction may be warranted. 6 Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with arsenic trioxide injection. 7 Risk Summary Based on the mechanism of action [see Clinical Pharmacology ( 12. 1 2 see Data 2 2 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. 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/m 2 2 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 arsenic trioxide injection, discontinue breastfeeding during treatment with arsenic trioxide injection and for two weeks after the final dose. Pregnancy Testing Arsenic trioxide injection can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with arsenic trioxide injection [see Use in Specific Populations ( 8. 1 Contraception Females Advise females of reproductive potential to use effective contraception during and after treatment with arsenic trioxide injection 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 arsenic trioxide injection 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, arsenic trioxide injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13. 1 The safety and efficacy of arsenic trioxide injection 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 arsenic trioxide injection 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. The safety and efficacy of arsenic trioxide injection 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 arsenic trioxide injection 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. Exposure of arsenic trioxide may be higher in patients with severe renal impairment [see Clinical Pharmacology (12. 3) The use of arsenic trioxide for injection 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 arsenic trioxide for injection in patients with hepatic impairment [see Clinical Pharmacology (12.

RECENT MAJOR CHANGES
Dosage and Administration ( 2. 1 Warnings and Precautions ( 5.
DRUG INTERACTIONS
Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and arsenic trioxide injection 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 arsenic trioxide injection. 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 arsenic trioxide injection. Drugs That Can Lead to Hepatotoxicity Concomitant use of these drugs and arsenic trioxide injection, 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 arsenic trioxide injection. Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.

OVERDOSAGE
Manifestations of Arsenic Trioxide for Injection overdosage include convulsions, muscle weakness and confusion. If symptoms of arsenic trioxide injection 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.
NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with arsenic trioxide injection 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/m basis.
CLINICAL STUDIES
Arsenic trioxide injection 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 arsenic trioxide injection 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 arsenic trioxide injection >= 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 arsenic trioxide injection, 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 injection 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.
REFERENCES
“Hazardous Drugs”, OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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ARSENIC TRIOXIDE- arsenic trioxide_injection, solution Product manual source documgent