Arsenic Trioxide – Uses, Dosage, Side Effects, Interactions

Use in Cancer

Arsenic trioxide is approved to be used with tretinoin to treat:

• Acute promyelocytic leukemia (APL) in patients whose cancer has a certain type of chromosome mutation that affects the PML gene and RARA gene. It is used:
  • In adults with newly diagnosed APL that is low risk.
  • In patients whose cancer has not gotten better or has relapsed after retinoid and anthracycline chemotherapy.

Arsenic trioxide is also being studied in the treatment of other types of cancer.

Contraindications

The following conditions are contraindicated? with this drug. Check with your physician if you have any of the following:

• deficiency in thiamine or vitamin B1
• low amount of magnesium in the blood
• high levels of potassium in the blood
• low amount of potassium in the blood
• complete heart block
• torsades de pointes, a type of abnormal heart rhythm
• prolonged QT interval on EKG
• chronic heart failure?
• abnormal EKG with QT changes from birth
• pregnancy
• a patient who is producing milk and breastfeeding
• differentiation syndrome? in acute promyelocytic leukemia
• chronic kidney disease? stage 4 (severe?)
• chronic kidney? disease stage 5 (failure)
• kidney disease with likely reduction in kidney function
• Child-Pugh class C liver impairment

Dosage?

Strengths: 2 mg/mL; 1 mg/mL

Acute Promyelocytic Leukemia

• INDUCTION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day until bone marrow remission or up to a maximum of 60 days
  CONSOLIDATION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day for 25 doses over a period of up to 5 weeks; begin consolidation 3 to 6 weeks after completion of induction therapy

Acute Promyelocytic Leukemia

4 YEARS AND OLDER:

• INDUCTION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day until bone marrow remission or up to a maximum of 60 days
  CONSOLIDATION CYCLE: 0.15 mg/kg IV over 1 to 2 hours once a day for 25 doses over a period of up to 5 weeks; begin consolidation 3 to 6 weeks after completion of induction therapy
• CrCl less than 30 mL/min: Dose adjustment(s) may be required; however, no specific guidelines have been suggested. Caution recommended.

Dose Adjustments

RECOMMENDED DOSE REDUCTION SCHEDULE:

• Starting dose: 0.15 mg/kg IV once daily
• First dose reduction: 0.11 mg/kg IV once daily
• Second dose reduction: 0.1 mg/kg IV once daily
• Third dose reduction: 0.075 mg/kg IV once daily

DOSE ADJUSTMENTS FOR ADVERSE REACTIONS:
DIFFERENTIATION SYNDROME (defined by the presence of 2 or more of the following: unexplained fever?, dyspnea?, pleural and/or pericardial effusion, pulmonary infiltrates, renal failure?, hypotension?, weight gain greater than 5 kg):

• Temporarily withhold this drug; treat with dexamethasone 10 mg IV every 12 hours until resolution for a minimum of 3 days.
• Resume this drug when the 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 reappear, decrease the dose of this drug to the previous dose.

QTC PROLONGATION GREATER THAN 450 MSEC FOR MEN OR GREATER THAN 460 MSEC FOR WOMEN:

• Withhold this drug and any medication known to prolong the QTc interval.
• Replete electrolytes.
• After the QTc normalizes, resume this drug 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.
• Increase the dose of this drug to 0.15 mg/kg in the absence of QTc prolongation during the 14-day dose-escalation period.

HEPATOTOXICITY, DEFINED BY 1 OR MORE OF THE FOLLOWING (total bilirubin? [TB?] greater than 3 times the upper limit of normal [ULN]; aspartate aminotransferase [AST] greater than 5 x ULN; alkaline phosphatase [AP] greater than 5 x ULN):

• Withhold therapy.
• Resume therapy at a 50% reduced dose of the withheld drug(s) when TB is less than 1.5 x ULN and AP/AST are less than 3 x ULN.
• Increase the dose of the withheld drug(s) back to the recommended dose after 7 days on the reduced dose in the absence of worsening hepatotoxicity.
• Discontinue the withheld drug(s) permanently if hepatotoxicity recurs.

MODERATE (GRADE 2) NONHEMATOLOGIC REACTIONS:

• Temporarily withhold this drug.
• When the adverse reaction resolves to no more than mild? (Grade 1), resume this drug reduced by 2 dose levels.

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 (absolute neutrophil count less than 1 Gi/L; platelets less than 50 Gi/L lasting more than 5 weeks):
Consider reducing the dose of arsenic trioxide injection by 1 dose level (see Table 3 below).

• If myelosuppression lasts 50 days or longer OR occurs on 2 consecutive cycles, assess a marrow aspirate for remission status.
• In the case of molecular remission, resume this drug at 1 dose level lower.

Side Effects

The Most Common

• extreme thirst
• frequent urination
• extreme hunger
• weakness
• blurred vision
• dry mouth
• nausea and vomiting
• shortness of breath
• breath that smells fruity
• decreased consciousness
• excessive tiredness
• dizziness
• headache
• diarrhea
• swelling of the arms, hands, feet, ankles, or lower legs
• rash
• itching
• unusual bruising or bleeding
• vomit that is bloody or that looks like coffee grounds
• stool that is black and tarry or contains bright red blood
• decreased urination
• hives

More Common

• abdominal pain
• constipation
• decreased appetite
• diarrhea
• headache
• heartburn
• low heart rate
• nausea
• rash
• symptoms of neuropathy (e.g., numbness, prickling or tingling, burning, freezing, throbbing and/or shooting pain in the hands and or feet)
• tiredness
• trouble swallowing
• vomiting
• weight loss

Rare

• chest pain
• heart rhythm abnormality (e.g., dizziness, fainting, or chest discomfort)
• low blood pressure
• pain in the back, arms, legs, hands, or feet
• pounding heartbeat
• severe nausea, vomiting, diarrhea, or dehydration
• signs of anemia (low red blood cells; e.g., dizziness,  pale skin, unusual tiredness or weakness, shortness of breath)
• signs of dehydration (e.g., decreased urine, dry skin, dry and sticky mouth, sleepiness, dizziness, headache, thirst, confusion)
• slow heart rate
• symptoms of high blood sugar (e.g., frequent urination, hunger, thirst)
• symptoms of kidney problems (e.g., pain in the back or side, blood in the urine, nausea, vomiting, fatigue)
• symptoms of liver problems (e.g., feeling more tired than usual, decreased appetite, yellowing of the skin or whites of the eyes, stomach pain, dark urine, nausea, vomiting, itching, or bleeding or bruising more easily than normal)
• symptoms of low levels of phosphate in the blood (e.g., muscle pain and weakness, change in mental state)
• symptoms of lung infection or inflammation (e.g., difficulty breathing, cough, or fever)
• vision changes (e.g., blurred vision, flashes of light, double vision)

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

ATO is teratogenic, genotoxic, and carcinogenic and passes through the placenta. Fetal exposure seems to be associated with bad pregnancy outcomes (preterm delivery, decreased birth weight, and fetal loss) and with lung diseases in young adults. No clinical trial is obviously possible, and the only data available are environmental exposure or animal studies.

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence; the manufacturer recommends an abstinence period of 1 week after the last dose. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk

References