Prescription Drug Information: Arsenic Trioxide (Page 2 of 4)

5.2 Cardiac Conduction Abnormalities

Patients treated with Arsenic Trioxide Injection can develop QTc prolongation, torsade de pointes, and complete atrioventricular block. In the clinical trial of patients with relapsed or refractory APL treated with Arsenic Trioxide Injection 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 Arsenic Trioxide Injection infusion, and it usually resolved by 8 weeks after Arsenic Trioxide Injection infusion. There are no data on the effect of Arsenic Trioxide Injection 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 Arsenic Trioxide Injection 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 Arsenic Trioxide Injection, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer Arsenic Trioxide Injection to patients with a 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 Arsenic Trioxide Injection 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 Framingham greater than 450 msec for men or greater than 460 msec for women, withhold Arsenic Trioxide Injection and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes and electrolyte abnormalities are corrected, resume Arsenic Trioxide Injection at a reduced dose [see Dosage and Administration (2.3)].

5.3 Encephalopathy

Serious encephalopathies were reported in patients receiving Arsenic Trioxide Injection. Monitor patients for neurological symptoms, such as confusion, decreased level of consciousness, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction. Advise patients and caregivers of the need for close observation.

Wernicke’s Encephalopathy

Wernicke’s encephalopathy occurred in patients receiving Arsenic Trioxide Injection. Wernicke’s encephalopathy is a neurologic emergency that can be prevented and treated with thiamine. Consider testing thiamine levels in patients at risk for thiamine deficiency (e.g., chronic alcohol use, malabsorption, nutritional deficiency, concomitant use of furosemide).

Administer parenteral thiamine in patients with or at risk for thiamine deficiency. Monitor patients for neurological symptoms and nutritional status while receiving Arsenic Trioxide Injection. If Wernicke’s encephalopathy is suspected, immediately interrupt Arsenic Trioxide Injection and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

5.4 Hepatotoxicity

Long-term liver abnormalities can occur in patients with APL treated with Arsenic Trioxide Injection.

During treatment with Arsenic Trioxide Injection, monitor hepatic function tests at least twice weekly during induction and at least once weekly during consolidation. Withhold Arsenic Trioxide Injection if elevations in AST or alkaline phosphatase occur to greater than 5 times the upper limit of normal and/or elevation in serum total bilirubin occurs to greater than 3 times the upper limit of normal and resume at reduced dose upon resolution [see Dosage and Administration (2.3)].

5.5 Carcinogenesis

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

5.6 Embryo-Fetal Toxicity

Arsenic Trioxide Injection 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 of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Arsenic Trioxide Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6. ADVERSE REACTIONS

The following clinically significant 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)]
  • Encephalopathy [see Warnings and Precautions (5.3)]
  • Hepatotoxicity [see Warnings and Precautions (5.4)]
  • Carcinogenesis [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory APL

Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of Arsenic Trioxide Injection. Forty patients in the Study PLRXAS01 received the recommended dose of 0.15 mg/kg, of whom 28 completed both induction and consolidation cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose.

Serious adverse reactions observed in the 40 patients with refractory or relapsed APL enrolled in Study PLRXAS01 included differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2).

The most common adverse reactions (> 30%) were nausea, cough, fatigue, pyrexia, headache, abdominal pain, vomiting, tachycardia, diarrhea, dyspnea, hypokalemia, leukocytosis, hyperglycemia, hypomagnesemia, insomnia, dermatitis, edema, QTc prolongation, rigors, sore throat, arthralgia, paresthesia, and pruritus.

Table 5 describes the adverse reactions in patients aged 5 to 73 years with APL who received Arsenic Trioxide Injection at the recommended dose. Similar adverse reactions profiles were seen in the other patient populations who received Arsenic Trioxide Injection.

Table 5: Adverse Reactions (≥ 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide Injection in Study PLRXAS01
Body System Adverse reaction Any GradeAdverse Reactions Grade ≥3Adverse Reactions
n % n %
Gastrointestinal disorders
Nausea 30 75
Abdominal pain (lower & upper) 23 58 4 10
Vomiting 23 58
Diarrhea 21 53
Sore throat 14 35
Constipation 11 28 1 3
Anorexia 9 23
Appetite decreased 6 15
Loose stools 4 10
Dyspepsia 4 10
Oral blistering 3 8
Fecal incontinence 3 8
Gastrointestinal hemorrhage 3 8
Dry mouth 3 8
Abdominal tenderness 3 8
Diarrhea hemorrhagic 3 8
Abdominal distension 3 8
Respiratory
Cough 26 65
Dyspnea 21 53 4 10
Epistaxis 10 25
Hypoxia 9 23 4 10
Pleural effusion 8 20 1 3
Post nasal drip 5 13
Wheezing 5 13
Decreased breath sounds 4 10
Crepitations 4 10
Rales 4 10
Hemoptysis 3 8
Tachypnea 3 8
Rhonchi 3 8
General disorders and administration site conditions
Fatigue 25 63 2 5
Pyrexia (fever) 25 63 2 5
Edema — non-specific 16 40
Rigors 15 38
Chest pain 10 25 2 5
Injection site pain 8 20
Pain — non-specific 6 15 1 3
Injection site erythema 5 13
Weight gain 5 13
Injection site edema 4 10
Weakness 4 10 2 5
Hemorrhage 3 8
Weight loss 3 8
Drug hypersensitivity 2 5 1 3
Nervous system disorders
Headache 24 60 1 3
Insomnia 17 43 1 3
Paresthesia 13 33 2 5
Dizziness (excluding vertigo) 9 23
Tremor 5 13
Convulsion 3 8 2 5
Somnolence 3 8
Coma 2 5 2 5
Cardiac disorders
Tachycardia 22 55
ECG QT corrected interval prolonged > 500 msec 16 40
Palpitations 4 10
ECG abnormal other than QT interval prolongation 3 8
Metabolism and nutrition disorders
Hypokalemia 20 50 5 13
Hypomagnesemia 18 45 5 13
Hyperglycemia 18 45 5 13
ALT increased 8 20 2 5
Hyperkalemia 7 18 2 5
AST increased 5 13 1 3
Hypocalcemia 4 10
Hypoglycemia 3 8
Acidosis 2 5
Table 5: Adverse Reactions (≥ 5%) in Patients with Relapsed or Refractory APL Who Received Arsenic Trioxide Injection in Study PLRXAS01 (cont’d.)
Body System Adverse reaction Any GradeAdverse Reactions Grade ≥3Adverse Reactions
n % n %
Hematologic disorders
Leukocytosis 20 50 1 3
Anemia 8 20 2 5
Thrombocytopenia 7 18 5 13
Febrile neutropenia 5 13 3 8
Neutropenia 4 10 4 10
Disseminated intravascular coagulation 3 8 3 8
Lymphadenopathy 3 8
Skin and subcutaneous tissue disorders
Dermatitis 17 43
Pruritus 13 33 1 3
Ecchymosis 8 20
Dry skin 6 15
Erythema — non-specific 5 13
Increased sweating 5 13
Facial edema 3 8
Night sweats 3 8
Petechiae 3 8
Hyperpigmentation 3 8
Non-specific skin lesions 3 8
Urticaria 3 8
Local exfoliation 2 5
Eyelid edema 2 5
Musculoskeletal, connective tissue, and bone disorders
Arthralgia 13 33 3 8
Myalgia 10 25 2 5
Bone pain 9 23 4 10
Back pain 7 18 1 3
Neck pain 5 13
Pain in limb 5 13 2 5
Psychiatric disorders
Anxiety 12 30
Depression 8 20
Agitation 2 5
Confusion 2 5
Vascular disorders
Hypotension 10 25 2 5
Flushing 4 10
Hypertension 4 10
Pallor 4 10
Infections and infestations
Sinusitis 8 20
Herpes simplex 5 13
Upper respiratory tract infection 5 13 1 3
Bacterial infection — non-specific 3 8 1 3
Herpes zoster 3 8
Nasopharyngitis 2 5
Oral candidiasis 2 5
Sepsis 2 5 2 5
Reproductive system disorders
Vaginal hemorrhage 5 13
Intermenstrual bleeding 3 8
Ocular disorders
Eye irritation 4 10
Blurred vision 4 10
Dry eye 3 8
Painful red eye 2 5
Renal and urinary disorders
Renal failure 3 8 1 3
Renal impairment 3 8
Oliguria 2 5
Incontinence 2 5
Ear disorders
Earache 3 8
Tinnitus 2 5

Other Clinically Relevant Adverse Reactions

Leukocytosis

Arsenic Trioxide Injection can induce proliferation of leukemic promyelocytes resulting in a rapid increased in white blood cell count. Leukocytosis greater than 10 Gi/L developed during induction therapy in 50% of patients receiving Arsenic Trioxide Injection monotherapy for relapsed/refractory APL. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts.

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