Arsenic Trioxide – Uses, Dosage, Side Effects, Interactions

Mechanism of Action

Inorganic arsenicals affect the bone marrow & alter the cellular composition of the blood. The vascularity of the bone marrow is inserted. Moderate doses of arsenic lower the erythrocyte count, & large doses cause morphological changes with the appearance of megalocytes & microcytes. Inorganic arsenicals also suppress the production of leukocytes.

The mechanism of action of Arsenic Trioxide 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. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis.

Indications

  • For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
  • Trisenox is indicated for induction of remission, and consolidation in adult patients with newly diagnosed low-to-intermediate risk acute promyelocytic leukemia (APL) (white blood cell count, ≤ 10 x 103/µl) in combination with all‑trans‑retinoic acid (ATRA)Relapsed/refractory acute promyelocytic leukemia (APL) (previous treatment should have included a retinoid and chemotherapy) characterized by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene. The response rate of other acute myelogenous leukemia subtypes to arsenic trioxide has not been examined.
  • Arsenic trioxide Mylan is indicated for induction of remission, and consolidation in adult patients with newly diagnosed low to intermediate-risk acute promyelocytic leukemia (APL) (white blood cell count, ≤ 10 x 103/μl) in combination with all-trans-retinoic acid (ATRA)- Relapsed/refractory acute promyelocytic leukemia (APL) (Previous treatment should have included a retinoid and chemotherapy) characterized by the presence of the t(15;17) translocation and/or the presence of promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) gene. The response rate of other acute myelogenous leukemia subtypes to arsenic trioxide has not been examined.
  • Acute Promyelocytic Leukemia (APL)
  • Refractory Acute Promyelocytic Leukemia
  • Relapsed Acute Promyelocytic Leukemia

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

What special precautions should I follow?

Before receiving an arsenic trioxide injection,

  • tell your doctor and pharmacist if you are allergic to arsenic trioxide, any other medications, or any of the ingredients in arsenic trioxide injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had liver or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan to father a child. If you are female, you will need to take a pregnancy test before starting treatment and use birth control to prevent pregnancy during your treatment and for at least 6 months after your final dose. If you are male, you and your female partner should use effective birth control while you are receiving arsenic trioxide injection and for 3 months after the final dose. If you or your partner becomes pregnant while using this medication, call your doctor. Talk to your doctor about using birth control to prevent pregnancy during your treatment with arsenic trioxide. Arsenic trioxide may harm the fetus.
  • tell your doctor if you are breastfeeding. Your doctor will probably tell you not to breastfeed during your treatment and for 2 weeks after your final dose.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of receiving arsenic trioxide.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving arsenic trioxide.

When to contact your doctor or health care provider:

Contact your healthcare provider immediately, day or night, if you should experience any of the following symptoms:

  • Fever of 100.4° F (38° C) or higher, chills (possible signs of infection)
  • Difficulty breathing or shortness of breath
  • Sudden weight gain
  • Nausea (interferes with the ability to eat and is unrelieved with prescribed medication)
  • Vomiting (vomiting more than 4-5 times in a 24-hour period)
  • Rapid heartbeat (recurrent or persistent – does not go away)
  • Diarrhea (4-6 episodes in a 24-hour period)
  • Unusual bleeding or bruising
  • Black or tarry stools, or blood in your stools
  • Extreme fatigue (unable to carry on self-care activities)

Always inform your healthcare provider if you experience any unusual symptoms.

Precautions

  • Before starting arsenic trioxide treatment, make sure you tell your doctor about any other medications you are taking (including prescriptions, over-the-counter, vitamins, herbal remedies, etc.).
  • Avoid seafood and homeopathic remedies as these may contain arsenic.
  • Do not receive any kind of immunization or vaccination without your doctor’s approval while taking arsenic trioxide.
  • Inform your healthcare professional if you are pregnant or may be pregnant prior to starting this treatment. Pregnancy category D (arsenic trioxide may be hazardous to the fetus. Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus).
  • For both men and women: Do not conceive a child (get pregnant) while taking arsenic trioxide. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.
  • Do not breastfeed while taking arsenic trioxide.
  • Decreased sensation, numbness, and tingling in fingers and toes may become progressively worse with repeated doses of arsenic trioxide. It is important to report this to your doctor.

Self-Care Tips

  • Drink at least two to three quarts of fluid every 24 hours, unless you are instructed otherwise.
  • You may be at risk of infection so try to avoid crowds or people with colds, and report fever or any other signs of infection immediately to your healthcare provider.
  • Wash your hands often.
  • Tell dentists, surgeons, and other doctors you use Arsenic Trioxide.
  • To help treat/prevent mouth sores, use a soft toothbrush, and rinse three times a day with 1/2 to 1 teaspoon of baking soda and/or 1/2 to 1 teaspoon of salt mixed with 8 ounces of water.
  • Use an electric razor and a soft toothbrush to minimize bleeding.
  • Avoid contact sports or activities that could cause injury.
  • To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals.
  • Avoid sun exposure. Wear SPF 30 (or higher) sunblock and protective clothing.
  • In general, drinking alcoholic beverages should be kept to a minimum or avoided completely. You should discuss this with your doctor.
  • Get plenty of rest.
  • Maintain good nutrition.
  • If you experience symptoms or side effects, be sure to discuss them with your healthcare team. They can prescribe medications and/or offer other suggestions that are effective in managing such problems.
  • Use birth control that you trust to avoid pregnancy while taking Arsenic Trioxide.
  • If you are male, use birth control to protect a female you are having sex with from becoming pregnant while you are using Arsenic Trioxide and for some time after stopping. Talk with your doctor about how long to use birth control after stopping Arsenic Trioxide.
  • For flu-like symptoms, keep warm with blankets and drink plenty of liquids. There are medications that can help reduce the discomfort caused by chills.
  • Acetaminophen or ibuprofen may help relieve discomfort from fever, headache, and/or generalized aches and pains. However, be sure to talk with your doctor before taking it.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Arsenic
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Arsenic-trioxide
  3. https://pubmed.ncbi.nlm.nih.gov/32231816/
  4. https://www.webmd.com/drugs/2/drug-20255/arsenic-trioxide-intravenous/details/list-contraindications
  5. https://www.drugs.com/pregnancy/arsenic-trioxide.html
  6. https://medlineplus.gov/druginfo/meds/a608017.html
  7. https://go.drugbank.com/drugs/DB01169
  8. https://www.drugs.com/mtm/arsenic-trioxide.html
  9. ChemIDplus Chemical Information Classification
  10. CompTox Chemicals Dashboard Chemical Lists
  11. ARSENIC, INORGANIC COMPOUNDS (as As)
    ARSENIC, ORGANIC COMPOUNDS
  12. Consumer Products Category Classification
  13. LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    NORMAN Suspect List Exchange Classification
  14. Arsenic and inorganic arsenic compounds
    IARC Classification
  15. PubChem
  16. NCBI

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