Arsenic trioxide

Arsenic trioxide is an antineoplastic agent belonging to the pharmacological class of antimicrobials.

The FDA approves arsenic trioxide for treating refractory or relapsed acute promyelocytic leukaemia in patients with prior retinoid and anthracycline chemotherapy.

Arsenic trioxide absorbs very little systemically after being administered intravenously. The liver quickly hydrolyzes it into active arsenious acid (AsIII). The drug easily crosses the placenta and finds its way into breast milk, primarily accumulating in the liver, kidneys, heart, lungs, hair, and nails. Approximately 15% is excreted unchanged in urine.

The most common side effects of Arsenic trioxide include nausea, vomiting, low platelet count, ulcer, loss of appetite and difficulty breathing.

Arsenic trioxide is usually available as an injectable solution.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Arsenic trioxide is an antineoplastic agent belonging to the pharmacological class of antimicrobials.

The precise way arsenic trioxide works needs to be clarified. In vitro, arsenic trioxide causes NB4 human promyelocytic leukaemia cells to undergo morphological changes and DNA fragmentation, indicative of apoptosis. The fusion protein PML/RAR-alpha is likewise harmed or degraded by arsenic trioxide. Arsenic trioxide may cause cancer cells to undergo apoptosis.

Arsenic trioxide, specifically arsenious acid [AsIII], achieves peak plasma concentration at approximately 2 hours after IV administration.

After the initial administration, peak plasma concentrations of Monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) for Arsenic trioxide occur approximately 10 to 24 hours.

The area under the curve (AUC) for arsenious acid on Cycle 1, Day 1 is 194 ng·hr/mL.

The area under the curve (AUC) for arsenious acid on Cycle 1, Day 25 is 332 ng·hr/mL.

• Combined with tretinoin, arsenic trioxide is indicated for treating adults newly diagnosed with low-risk acute promyelocytic leukaemia (APL) featuring the t(15;17) translocation or PML/RAR-alpha gene expression.
• Arsenic trioxide is indicated for inducing remission and consolidation in APL patients refractory to or relapsed from retinoid and anthracycline chemotherapy, with the characteristic presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Arsenic trioxide is available in the form of an injectable solution.

Dose Adjustment in Adult Patients:

Acute promyelocytic leukaemia

Induction: 150 mcg/kg intravenously once daily for 1-2 hours (or up to 4 hours if acute vasomotor reactions happen) or until remission. Maximum: fifty doses.

Consolidation: 5 days per week at 150 mcg/kg once daily in 25 doses, with a 2-day break in between. Repeat this process for another 5 weeks. Consolidation treatment must start three to four weeks after the end of induction.

Follow the dietary guidelines while taking Arsenic trioxide; Sustain a nutritious diet and exercise regularly to ensure appropriate weight control. Avoid drinking and smoking. Add fruits and vegetables, but refrain from processed meats, fast food, fried foods, refined carbohydrates, and added sugar. Ensure that you drink enough water and eat foods high in fibre.

The dietary restriction should be individualized as per patient requirements.

• Exercise caution in hepatic or renal impairment.
• Patients receiving therapy may develop Wernicke's encephalopathy, a neurological emergency that can be treated with thiamine. In people who are at risk (e.g., chronic alcohol use, malabsorption), consider testing their thiamine levels. Give people who are deficient in thiamine or who are at risk of doing so parenterally. Maintain a watch on neurological symptoms and nutritional status. If Wernicke's encephalopathy is suspected, stop treatment right away and start parenteral thiamine.
• Arsenic trioxide is carcinogenic to humans. Observe patients in case they develop secondary primary cancers.
• Arsenic trioxide can cause fetal harm. Advise patients of the potential risk to a fetus and recommend the use of effective contraception during treatment.
• If a patient develops a QTc >500 msec, immediately withhold treatment and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. Resume therapy at a reduced dose when QTc normalizes.
• When taking arsenic trioxide therapy, monitor the results of liver function tests at least twice a week. Patients with newly diagnosed low or intermediate-risk APL treated with arsenic trioxide and tretinoin showed grade ≥3 elevations in hepatic transaminase. Hepatotoxicity may occur.

• Common Adverse Effects: QT interval prolongation, fatigue, edema, pyrexia, rigors, pain, abdominal discomfort, nausea, diarrhea, and anorexia.
• Less Common Adverse Effects: Headache, dizziness, hypotension, tachycardia, dyspnea, cough, and myalgia
• Rare Adverse Effects: Differentiation syndrome, hepatotoxicity, electrolyte abnormalities, respiratory distress syndrome, cardiac arrhythmias, renal failure, tumor lysis syndrome, hematologic changes, and hemorrhage.

The clinically relevant drug interactions of Arsenic trioxide are briefly summarized here.

Hypokalaemia or hypomagnesaemia is more likely when diuretics and amphotericin B are combined. QT prolongation risk is elevated when using Class Ia/III antiarrhythmics (such as quinidine, amiodarone, sotalol, dofetilide), antipsychotics (such as thioridazine, ziprasidone, pimozide), antidepressants (such as amitriptyline), macrolides (such as erythromycin), antihistamines (such as terfenadine, astemizole), quinolones (such as sparfloxacin), and cisapride.

The common side effects of Arsenic trioxide include

Nausea

Vomiting

Headache

Breathlessness

Increased heart rate

Decreased potassium level in blood

Paresthesia (tingling or pricking sensation)

Injection site pain

Increased liver enzymes

Increased glucose level in the blood

Fever

Diarrhea

Fatigue

Pain

Oedema (swelling due to excess fluid)

Rash or itching

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

There are insufficient published data on arsenic trioxide use during pregnancy and no studies involving pregnant women with this drug to determine whether there is a drug-associated risk of severe congenital disabilities and miscarriage.

Pregnant women may experience fetal harm from arsenic trioxide due to its mechanism of action and results from animal studies.

Rats exposed to arsenic trioxide on gestation day 9 at a dose approximately ten times the daily dose recommended for humans (mg/m2) developed teratogenicity and embryo lethality.

When given during pregnancy to mice at a dose approximately five times the projected human dose in milligrams per milliliter and to hamsters at an intravenous dose roughly equal to the projected human daily dose in milligrams per milliliter, a related trivalent arsenic called sodium arsenite caused teratogenicity.

Females and males of reproductive potential

Before starting treatment, have females who are capable of reproducing tested for pregnancy.

Encourage women who are capable of having children to use reliable contraception both during and after their treatment and for six months following the last dosage.

Arsenic trioxide may reduce male fertility in reproductively potential studies due to testicular toxicities, such as reduced testicular weight and impaired spermatogenesis.

Advise men who have female partners who are capable of having children to use reliable contraception both during their treatment and for three months following their last dosage.

• Nursing Mothers

Milk contains Arsenic excreted in it.

Due to the drug's potential for severe adverse reactions in nursing infants, a decision should be made regarding the drug's discontinuation and the nursing mother's importance.

• Pediatric Use

The safety and effectiveness of Arsenic trioxide in pediatric patients have not been established.

Dose Adjustments

Acute Promyelocytic Leukemia

Refractory or relapsing following chemotherapy with retinoid and anthracycline

Less than 4 years: Not proven to be safe or effective.

More than 4 years: Up to 60 doses of 0.15 mg/kg IV given every day until bone marrow remission

After three to six weeks, wait, and then administer 25 doses of 0.15 mg/kg IV per day (distributed over a maximum of five weeks).

Considerations for Dosing

Monitor serum electrolytes and ECG.

Dose Adjustment in Kidney Impairment Patients:

Severe: <30 mL/min of CrCl Arsenic trioxide exposure may be higher; check for toxicities and lower dosage as necessary.

Dialysis No evidence of efficacy or safety.

Dose Adjustment in Hepatic Impairment Patients:

Use caution as limited data is available for all groups of hepatic impairment.

Severe (Child-Pugh C): Watch closely for any toxicity.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Arsenic trioxide.

Signs and Symptoms

Overconsumption of Arsenic trioxide could lead to convulsions, muscle weakness and confusion.

Management

When an overdose occurs, stop the arsenic trioxide immediately and start treating the patient with supportive and symptomatic care. Based on the arsenic values found in the urine, consider chelating therapy with penicillamine at a daily dose of ≤ 1 g. If the patient is unable to take oral medication, give them dimercaprol intramuscularly at a dose of 3 mg/kg every 4 hours until the immediate life-threatening toxicity subsides, and then give them penicillamine. If coagulopathy is present, provide oral dimercaptosuccinic acid succinic acid (DCI) at a dose of 10 mg/kg or 350 mg/m2 every 8 hours for five days, then every 12 hours for two weeks. Dialysis may be necessary for severe, acute arsenic overdose.

Pharmacodynamic

Cardiac Electrophysiology

With arsenic trioxide, a specific QTc study was not conducted. But sixteen out of forty patients (or forty percent) in a single-arm trial taking arsenic trioxide (0.15 mg/kg daily) had a QTc interval longer than 500 msec. After receiving an arsenic trioxide infusion, the QTc was seen to prolong between one and five weeks, and by the end of eight weeks, it had returned to baseline.

Pharmacokinetics

• Absorption: After intravenous injection, arsenic trioxide shows negligible systemic absorption. For arsenious acid (AsIII), it takes about two hours to reach peak plasma concentration, whereas monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) takes about ten to twenty-four hours.
• Distribution: The liver, kidneys, heart, lungs, hair, and nails are where the medication primarily builds up. It quickly passes through the placenta and gets into breast milk. The distribution volume exceeds 400 litres and rises with body weight.
• Metabolism: Arsenic trioxide is quickly hydrolyzed to produce arsenious acid (AsIII), the active form. Dimethylarsinic acid (DMAV) and monomethylarsonic acid (MMAV), two less active pentavalent metabolites, are produced during oxidative methylation by methyltransferases during hepatic metabolism. Moreover, arsenic acid (AsV), a minor metabolite, is produced through oxidation.
• Excretion: Mainly excreted as urine, with 15% excreted as AsIII unchanged. AsIII has an elimination half-life of roughly 10–14 hours, MMAV of 32 hours, and DMAV of 72 hours.

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• https://www.cancer.gov/about-cancer/treatment/drugs/arsenictrioxide
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