Trisenox (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Corden Pharma Latina S.p.A. (Italy)

Secondary Packaging

ALMAC PHARMA SERVICES, Limited (United Kingdom)

ATC Code

L01XX27 (Arsenic trioxide)

Active Substance

Arsenic trioxide (USAN)

Dosage Form

Trisenox

Concentrate for solution for infusion 1 mg/1 ml: amp. 10 ml 10 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a colorless, transparent solution.

Excipients: sodium hydroxide – 1.2 mg, 1M sodium hydroxide solution or 1M hydrochloric acid solution – to pH 8.0, water for injections – up to 1 ml.

10 ml – glass ampoules (5) – cardboard inserts (2) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Antineoplastic agent. In vitro experiments, Arsenic trioxide causes morphological changes and apoptosis, characterized by DNA fragmentation in human promyelocytic leukemia cells of the NB4 line.

Furthermore, Arsenic trioxide leads to damage or degradation of the promyelocytic leukemia/retinoic acid receptor-alpha (PML/RAR-alpha) chimeric protein. Arsenic trioxide is effective for inducing and consolidating remission in patients with acute promyelocytic leukemia (APL).

When used in patients with resistance to retinoids and chemotherapeutic drugs, high rates of complete remission (visual absence of leukemic cells in the bone marrow and restoration of platelet and leukocyte counts in peripheral blood), conversion to a normal genotype (absence of t(15;17) translocation), and a negative test result for the PML/RAR-alpha chimeric protein are observed.

Pharmacokinetics

Upon direct addition of inorganic lyophilized arsenic trioxide to a liquid medium, it hydrolyzes to form arsenious acid (As³⁺). As³⁺ is the pharmacologically active component of arsenic trioxide.

As³⁺ has a large volume of distribution (V_d greater than 400 L), indicating significant distribution of this element in tissues with minimal binding to plasma proteins. Furthermore, the V_d value depends on body weight, increasing with increasing body weight. In general, arsenic primarily accumulates in the liver, kidneys, and heart, and to a lesser extent in the lungs, hair, and nails.

The metabolism of arsenic trioxide occurs predominantly in the liver and involves the oxidation of As³⁺, the active derivative of arsenic trioxide, to arsenic acid (As⁵⁺), as well as oxidative methylation involving methyltransferase to monomethylarsonic acid (MMA⁵⁺) and dimethylarsinic acid (DMA⁵⁺).

The concentration of the pentavalent metabolites MMA⁵⁺ and DMA⁵⁺ in plasma increases slowly (they appear in plasma 10-24 hours after the first administration of arsenic trioxide); however, considering the longer half-life (T_1/2), upon repeated administration of the drug, their accumulation is more pronounced than that of As³⁺. The degree of accumulation of these metabolites depends on the dosing regimen. Compared to a single administration, upon repeated use of the drug, the degree of accumulation increases approximately 1.4-8 times. The concentration of As⁵⁺ in plasma is relatively low.

Approximately 15% of the administered dose is excreted in the urine as unchanged As³⁺. The methylated metabolites of As³⁺ (MMA⁵⁺ and DMA⁵⁺) are predominantly eliminated by the kidneys. The decrease in plasma concentration of As³⁺ compared to C_max occurs in two phases, with an average terminal T_1/2 of 10-14 hours. The total clearance of As³⁺ after a single administration of the drug at a dose of 7-32 mg (0.15 mg/kg) is 49 L/h, and renal clearance is 9 L/h. The average estimated terminal T_1/2 values for the metabolites of As³⁺ are 32 hours and 70 hours, respectively.

Indications

For induction and maintenance of remission in relapsed/refractory acute promyelocytic leukemia characterized by the presence of t(15;17) translocation and/or the promyelocytic leukemia/retinoic acid receptor-alpha gene after treatment with retinoids and chemotherapy.

ICD codes

Dosage Regimen

Administered intravenously as an infusion.

Before starting therapy, the patient should be hospitalized to assess the severity of disease symptoms and to ensure careful monitoring of their condition. Administration is carried out under the supervision of a physician experienced in the treatment of acute leukemias.

A single dose is 0.15 mg/kg/day. The frequency and duration of use depend on the indications, clinical situation, and the treatment regimen used.

Adverse Reactions

Infections: Common – herpes zoster; Unknown – sepsis, pneumonia.

Blood and lymphatic system disorders Common – febrile neutropenia, leukocytosis, neutropenia, pancytopenia, thrombocytopenia, anemia; Unknown – leukopenia, lymphopenia.

Metabolism and nutrition disorders Very common – hyperglycemia, hypokalemia, hyperthermia; Common – hypernatremia, ketoacidosis, hypermagnesemia, weight increased; Unknown – dehydration, fluid retention.

Psychiatric disorders Unknown – confusion.

Nervous system disorders Very common – paresthesia, dizziness, headache; Common – convulsions.

Eye disorders Common – blurred vision.

Cardiac disorders Very common – tachycardia, QT interval prolongation on ECG; Common – pericardial effusion, ventricular extrasystoles, vasculitis, decreased blood pressure; Unknown – heart failure, ventricular tachycardia.

Respiratory, thoracic and mediastinal disorders Very common – differentiation syndrome, dyspnea; Common – hypoxia, pleural effusion, pleural pain, alveolar pulmonary hemorrhage; Unknown – pneumonitis.

Gastrointestinal disorders Very common – diarrhea, vomiting, nausea, increased ALT, increased AST; Common – abdominal pain, hyperbilirubinemia.

Skin and subcutaneous tissue disorders Very common – skin itching, skin rash; Common – erythema, facial edema.

Renal and urinary disorders Common – renal failure, increased plasma creatinine concentration.

General disorders and administration site conditions Very common – pain, fatigue, edema; Common – chest pain, chills.

Contraindications

Hypersensitivity to arsenic trioxide; age under 18 years; pregnancy, breastfeeding period.

With caution

Impaired liver function; impaired renal function; in patients at risk of developing torsades de pointes ventricular tachycardia, including with the simultaneous use of drugs leading to QT interval prolongation (antiarrhythmic drugs of classes IA and III (e.g., quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g., thioridazine), antidepressants (e.g., amitriptyline), some macrolides (e.g., erythromycin), some antihistamines (e.g., terfenadine and astemizole), some antibiotics of the quinolone class (e.g., sparfloxacin), cisapride, diuretics and amphotericin B); in patients with a history of torsades de pointes ventricular tachycardia, previous therapy with QT interval prolongation; congestive heart failure; hypokalemia or hypomagnesemia.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Special Precautions

At the first symptoms suggestive of the development of APL differentiation syndrome (unexplained fever, dyspnea and/or weight gain, pathological findings on lung auscultation or radiographic examination), high-dose corticosteroid therapy (dexamethasone 10 mg IV twice daily) should be initiated immediately, regardless of the leukocyte count in peripheral blood, for at least 3 days or longer until the severity of adverse events decreases. Adding chemotherapeutic drugs to corticosteroid therapy is not recommended.

The use of arsenic trioxide can lead to QT interval prolongation and the development of complete atrioventricular block. QT interval prolongation can cause torsades de pointes ventricular tachycardia with a possible fatal outcome. Prior therapy with anthracycline antibiotics may increase the risk of QT interval prolongation.

The risk of developing torsades de pointes ventricular tachycardia depends on the degree of QT interval prolongation, concomitant use of other drugs that prolong the QT interval (such as antiarrhythmic drugs of classes 1A and III (e.g., quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g., thioridazine), antidepressants (e.g., amitriptyline), some macrolides (e.g., erythromycin), some antihistamines (e.g., terfenadine and astemizole), some antibiotics of the quinolone class (e.g., sparfloxacin) and other specific medicinal products for which an increase in the QT interval has been described (e.g., cisapride)), the presence of a history of torsades de pointes ventricular tachycardia, previous therapy with QT interval prolongation, the presence of congestive heart failure, the use of diuretics, amphotericin B, or the presence of other medical conditions leading to hypokalemia or hypomagnesemia.

Before starting therapy with this agent, a 12-lead ECG should be performed and serum electrolyte levels (potassium, calcium, and magnesium), as well as creatinine concentration, should be examined. Identified electrolyte abnormalities should be corrected, and drugs that may lead to QT interval prolongation should be discontinued if possible. In patients with risk factors for increased QTc interval or risk of developing torsades de pointes ventricular tachycardia, continuous ECG monitoring is required.

In patients with a QTc interval greater than 500 msec before deciding to start therapy with a drug containing Arsenic trioxide, measures should be taken to correct the identified abnormalities, with repeated QTc measurement in a series of several repeated ECGs. During therapy, potassium levels should be above 4 mEq/L, and magnesium levels should be above 1.8 mg/dL. If an absolute QT interval prolongation greater than 500 msec is detected in a patient, an ECG should be repeated and urgent measures should be taken to correct concomitant risk factors if present, and the possible risks and expected benefits of continuing therapy should be weighed.

If a patient develops fainting, palpitations, or arrhythmia, they should be hospitalized for continuous monitoring of heart activity and serum electrolyte levels. Administration of arsenic trioxide should be temporarily suspended until the QTc interval decreases to less than 460 msec, electrolyte levels normalize, and syncopal episodes and cardiac rhythm abnormalities regress. During induction and consolidation of remission, ECG examination should be performed twice a week, and in clinically unstable patients, even more frequently.

If signs of grade 3 toxicity are detected, administration of the drug should be suspended, the dose adjusted, or therapy discontinued earlier than the previously planned end of therapy.

During the remission induction phase, electrolyte and glucose levels, as well as blood counts, liver, kidney, and coagulation system function should be monitored at least twice a week, and in clinically unstable patients, even more frequently, while during the remission consolidation phase – at least once a week.

Effect on ability to drive vehicles and operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions due to the possibility of dizziness.

Drug Interactions

The risk of torsades de pointes ventricular tachycardia is higher in individuals receiving or having previously received medicinal products that promote the development of hypokalemia or hypomagnesemia, such as diuretics or amphotericin B. When using drugs containing Arsenic trioxide in patients receiving concomitant therapy with drugs that lead to an increase in the QT/QTc interval, such as macrolide antibiotics or the antipsychotic thioridazine, as well as medicinal products that can cause hypokalemia or hypomagnesemia, caution is recommended.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.