Moxetumomab Pasudotox-Tdfk: Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview:

Moxetumomab pasudotox-tdfk is a medication that garnered US FDA (United States Food and Drug Administration) approval on September 13, 2018. It is indicated for the treatment of adults diagnosed with relapsed or refractory hairy cell leukemia (HCL), a subtype of HCL (a rare blood cancer impacting lymphocytes, a type of white blood cell) that does not respond to standard treatments and who have undergone at least two previous systemic therapies, which must include treatment using a purine nucleoside analog. This groundbreaking treatment provides fresh optimism for patients facing challenges with this rare and often difficult-to-treat form of leukemia (blood cancer).

Drug Group:

Moxetumomab pasudotox-tdfk belongs to the drug group of immunotoxins. Immunotherapy is a type of targeted cancer therapy that combines an antibody with a toxin to kill cancer cells.

Indications:

Moxetumomab pasudotox-tdfk is indicated for treating adult patients with relapsed or refractory hairy cell leukemia, refers to HCL that has returned after treatment or relapsed or has not responded to standard treatments (refractory) and has undergone at least two previous systemic therapies, including a purine nucleoside analog (PNA).

Limitations of Use:

Moxetumomab pasudotox-tdfk is not recommended for patients with severe renal impairment (CrCl or creatinine clearance less than or equal to 29 mL/min or milliliters per minute).

Dosage Forms and Available Strengths:

For Injection: Available as one mg (milligrams). It is presented as a lyophilized cake or powder ranging from white to off-white in a single-dose vial for reconstitution and subsequent dilution.

For Patients:

What Is Hairy Cell Leukemia?

Hairy cell leukemia (HCL) is an uncommon (rare) form of blood cancer affecting WBCs or white blood cells, specifically B cells. It gets its name from the hair-like projections seen on the surface of the malignant cells under a microscope. HCL progresses slowly and is characterized by low blood counts, an enlarged spleen, and frequent infections.

How Does the Moxetumomab Pasudotox Tdfk Work?

Moxetumomab pasudotox-tdfk is a targeted therapy for hairy cell leukemia (HCL). It operates by leveraging a monoclonal antibody that specifically binds to the CD22 antigen, prominently expressed on the surface of HCL cells. Once bound, the drug-antigen complex is internalized into the leukemia cell. The attached bacterial toxin, Pseudomonas exotoxin A, is released within the cell. This toxin inhibits protein synthesis by interfering with elongation factor 2 (EF-2), a critical component of the cell's protein production machinery. The inhibition of protein synthesis ultimately leads to the malignant cell's apoptosis (programmed cell death). Moxetumomab pasudotox-tdfk is administered to patients with relapsed or refractory HCL who have undergone at least two prior systemic therapies. By combining targeted antibody therapy with a potent toxin, this drug offers a precise and effective treatment option for individuals with this specific type of leukemia.

What Are the Clinical Uses of the Moxetumomab Pasudotox-Tdfk?

Moxetumomab pasudotox-tdfk is used to treat adults with hairy cell leukemia that has come back or did not respond to previous treatments. It is given to patients who have already tried at least two other therapies. The drug is given as an intravenous (through the vein) infusion, providing a new option for those with relapsed or treatment-resistant HCL.

What Is the Dosage of the Moxetumomab Pasudotox Tdfk?

The dosage of Moxetumomab pasudotox-tdfk for treating hairy cell leukemia is as follows:

• Dosage: 0.04 mg/kg or milligrams per kilogram.

• Administration: Given as an intravenous (IV) or into-the-vein infusion.

• Schedule: Administered on days one, three, and five of each 28-day cycle.

• Duration: Treatment continues for up to six cycles, depending on the patient's response and tolerance to the therapy.

How Is Moxetumomab Pasudotox Tdfk Administered?

• Moxetumomab pasudotox-tdfk is provided as a powder to be reconstituted with a liquid and administered intravenously by a doctor in a medical setting, such as an office or hospital. Typically, it is infused slowly over 30 minutes on days one, three, and five of a 28-day treatment cycle, with the possibility of repeating this cycle up to six times. The duration of treatment is contingent upon individual responses to the medication and any side effects encountered.

• Throughout the treatment regimen, patients are advised to consume up to twelve eight-ounce glasses of fluids, such as water, milk, or juice, every 24 hours from days one to eight of each 28-day cycle.

• Moxetumomab may elicit severe reactions during or post-infusion. To mitigate these risks, patients are administered medications 30 to 90 minutes before and after the infusion. Treatment may be halted if specific side effects arise. Patients are encouraged to promptly notify the doctor if they experience symptoms like dizziness, fainting, wheezing (a high-pitched whistling sound), difficulty breathing, rapid heartbeat, muscle pain, nausea, vomiting, headache, fever, chills, cough, fainting, hot flashes, or flushing. Regular communication with the healthcare provider regarding treatment progress and associated symptoms is crucial.

• Depending on individual response and side effects, the doctor may implement dosage adjustments, treatment delays, cessation, or additional medications. Patients are urged to openly discuss their treatment experience and concerns with their healthcare provider.

What Are the Side Effects of Moxetumomab Pasudotox Tdfk?

Moxetumomab pasudotox-tdfk injection can cause side effects:

• Constipation.

• Pale skin.

• Tiredness.

• Dry eyes or eye pain.

• Eye swelling or infection.

• Vision changes.

Some of the side effects can be severe.

• Muscle cramps.

• Numbness or tingling.

• Irregular or fast heartbeat.

• Nausea.

• Seizures (sudden and uncontrolled brain disturbances affecting behavior).

Moxetumomab pasudotox-tdfk injection may also cause other side effects. Call the doctor if the patient encounters unusual problems while receiving this medication.

What Are the Things to Inform the Doctor Before Taking Moxetumomab Pasudotox Tdfk?

Before receiving Moxetumomab pasudotox-tdfk injection:

• Inform the doctor and pharmacist about any allergies to Moxetumomab, other medications, or ingredients in the injection. Check the medication guide for the ingredient list.

• Provide details about all other medications, vitamins, supplements, and herbal products being taken. The doctor may need to adjust doses or monitor for side effects.

• Mention any medical problems, past or present.

• If pregnant or planning to become pregnant, inform the doctor. It is necessary to get a pregnancy test done before starting treatment and void pregnancy during treatment and for 30 days after the final dose. Discuss birth control options with the doctor. If pregnancy occurs during treatment, contact the healthcare provider immediately, as the medication can harm the fetus.

• Inform the doctor if breastfeeding or planning to breastfeed.

Dietary Considerations:

Unless instructed otherwise by the doctor, maintain a regular diet.

Missed Dose:

If an infusion appointment is missed, contact the doctor promptly to reschedule.

Handling:

• Moxetumomab pasudotox-tdfk for injection is a sterile, preservative-free, 1 mg (milligrams) single-dose vial.

• IV Solution Stabilizer: Sterile, preservative-free, one mL (milliliter) single-dose vial, separate from Moxetumomab pasudotox-tdfk. Only one vial per drug administration.

Storage:

Refrigerate Moxetumomab pasudotox-tdfk and IV Solution Stabilizer in the original carton at two to eight degrees Celsius or °C (36 to 46 degrees Fahrenheit or °F). Avoid freezing and shaking.

Disposal:

Dispose of unneeded or expired medication safely to prevent accidental ingestion by children or pets. Contact local authorities or pharmacists for proper disposal options, including take-back programs. If unavailable, follow FDA guidelines for safe drug disposal, but avoid flushing medication down toilets.

For Doctors:

Chemical Taxonomy

• Moxetumomab Pasudotox-Tdfk Description: Moxetumomab pasudotox-tdfk is a CD22-directed cytotoxin. It comprises a recombinant murine immunoglobulin variable domain combined with a shortened version of Pseudomonas exotoxin, PE38. The fusion disrupts protein synthesis. Moxetumomab pasudotox-tdfk weighs around 63 kDa (kilodalton). It is manufactured in escherichia coli cells using recombinant DNA or deoxyribonucleic acid technology. During manufacturing, fermentation occurs in a nutrient medium containing the antibiotic Kanamycin. However, Kanamycin is eliminated during manufacturing and is undetectable in the final product.

• Moxetumomab Pasudotox-Tdfk Composition: Moxetumomab pasudotox-tdfk for injection is provided as a sterile, preservative-free lyophilized cake or powder in single-dose vials. Each vial contains 1 mg of Moxetumomab pasudotox-tdfk. Moreover, it contains glycine (80 mg), polysorbate 80 (0.2 mg), sodium phosphate monobasic monohydrate (3.4 mg), sucrose (40 mg), and sodium hydroxide for pH (potential of hydrogen) adjustment to 7.4.

• Reconstitution and Dilution Process: After reconstitution with 1.1 mL of sterile water for injection, USP, the resulting solution has a concentration of 1 mg/mL, allowing for a withdrawal volume of 1 mL. Before intravenous infusion, the reconstituted solution is mixed into an infusion bag comprising 50 mL of 0.9 percent sodium chloride injection, USP, and 1 mL of IV solution stabilizer.

• IV Solution Stabilizer Composition: The IV solution stabilizer is a sterile, preservative-free solution supplied in single-dose vials. Each vial contains 1 mL of solution, comprising citric acid monohydrate (0.7 mg), polysorbate 80 (6.5 mg), sodium citrate dihydrate (6.4 mg), water for injection, and USP. The solution's pH is 6.0.

• Latex-Free Components: Both Moxetumomab pasudotox-tdfk and IV solution stabilizer vial stoppers are constructed without natural rubber latex.

Dosage Considerations:

Recommended Dosage

• Give Moxetumomab pasudotox-tdfk at a dosage of 0.04 mg/kg through a 30-minute intravenous infusion on days one, three, and five of every 28-day cycle. Continue for up to six cycles, disease progression, or unacceptable toxicity.

Recommended Concomitant Treatment

• Hydration: Intravenously administer 34 ounces of isotonic solution before and after each Moxetumomab pasudotox-tdfk infusion. Adjust to 17 ounces for patients under 110 pounds. Encourage oral fluid intake up to 101 ounces per day.

• Thromboprophylaxis: Contemplate low-dose Aspirin from days one to eight of each cycle.

• Premedication: Administer antihistamine, Acetaminophen, and histamine-2 receptor antagonist before infusion. Use oral or intravenous corticosteroids for severe reactions.

• Post-infusion Medication: Consider antihistamines, antipyretics, and oral corticosteroids for nausea and vomiting. Encourage oral fluid intake.

Monitoring for Safety

• Check weight, blood pressure, and other parameters before each infusion. Based on clinical presentation, monitor for capillary leak syndrome (abnormal fluid and protein leakage from small blood vessels) and hemolytic uremic syndrome (red blood cell destruction).

Instructions for Reconstitution, Dilution, and Administration

• Reconstitute Moxetumomab pasudotox-tdfk with sterile water for Injection, USP. Dilute with 0.9 percent sodium chloride injection, USP, and IV solution stabilizer. Administer intravenously over 30 minutes. Use immediately and protect from light.

Warnings and Precautions

• Capillary Leak Syndrome (CLS): CLS, characterized by hypoalbuminemia (low blood albumin levels), hypotension (low blood pressure), fluid overload symptoms, and hemoconcentration, can occur with Moxetumomab pasudotox-tdfk treatment, especially within the first eight days of a cycle. Monitor weight, blood pressure, and signs of CLS, including weight gain, hypotension, and edema (swelling). Promptly address CLS with supportive measures and consider withholding or discontinuing Moxetumomab pasudotox-tdfk based on severity.

• Hemolytic Uremic Syndrome (HUS): HUS, characterized by microangiopathic hemolytic anemia (damaged red blood cells in small vessels), thrombocytopenia (low platelet count), and renal (kidney) failure, can occur with Moxetumomab pasudotox-tdfk treatment, often within the first nine days of a cycle. Monitor blood chemistry and consider HUS in hemolytic anemia, thrombocytopenia, and renal dysfunction patients. Administer prophylactic fluids and promptly address HUS with supportive measures.

• Renal Toxicity: Renal toxicity, including acute kidney injury and renal failure, may occur with Moxetumomab pasudotox-tdfk treatment. Monitor renal function before each infusion, especially in high-risk patients, and consider dose delays or modifications based on renal function changes.

• Infusion-Related Reactions: Infusion-related reactions, including chills, nausea, and headache, can occur with Moxetumomab pasudotox-tdfk treatment. Premedicate with antihistamines and antipyretics before each dose and manage severe reactions with corticosteroids.

• Electrolyte Abnormalities: Electrolyte abnormalities, particularly hypocalcemia (low calcium levels), may occur during Moxetumomab pasudotox-tdfk treatment. Monitor serum electrolytes regularly and manage abnormalities accordingly.

What Are the Pharmacological Actions of Moxetumomab Pasudotox Tdfk?

Pharmacodynamics: Moxetumomab pasudotox-tdfk may affect CD22 detection, so CD19+ B cells were measured instead. This drug treatment in HCL patients reduced circulating CD19+ B cells by 89 percent after three infusions. Reduction in other immune cells was observed on day eight but returned to baseline by day 29. Immunoglobulin levels remained stable throughout treatment.

Mechanism of Action: Moxetumomab pasudotox-tdfk targets CD22, a protein found on B-cell surfaces, leading to internalization. Once inside the cell, it ADP-ribosylates elongation factor 2, hindering protein synthesis and prompting cell death through apoptosis.

Pharmacokinetics: The pharmacokinetics of Moxetumomab pasudotox-tdfk were studied in HCL patients receiving doses from 0.005 to 0.05 mg/kg administered intravenously. Concentrations increased proportionally with dose. Steady-state exposures at recommended doses were 379 ng/mL (nanogram per millilitre) (Cmax or maximum concentration) and 626 ng·hour/mL (AUC0-last). No systemic accumulation was observed. Higher PK exposures correlated with lower baseline CD19+ B cell counts. The mean volume of distribution was 6.5 L (liters). Elimination half-life was 1.4 hours. Clearance was 25 L/hour or litre per hour after the first dose and 4 L/hour after subsequent doses. The metabolic pathway remains unknown. No significant PK differences were observed based on age, sex, race, weight, or mild hepatic or renal impairment. The impact of moderate to severe hepatic or severe renal impairment on PK is unknown. Lower PK exposure was noted in patients with high ADA titers at later cycles.

Toxicity

Carcinogenicity, mutagenicity, and effects on fertility of Moxetumomab pasudotox-tdfk have not been studied. Animal tests showed heart tissue degeneration at doses over three times recommended and brain gliosis, spinal cord axonal degeneration, and tremors at doses over ten times recommended.

What Are the Contraindications of Moxetumomab Pasudotox Tdfk?

None.

What Are the Drug Interactions of Moxetumomab Pasudotox Tdfk?

The interactions of Moxetumomab pasudotox-tdfk with other drugs are not extensively documented.

Clinical Studies

Clinical trials vary widely, so comparing adverse reaction rates between drugs or clinical trials may not accurately reflect real-world rates. Safety data for Moxetumomab pasudotox-tdfk are based on a study of 80 patients with previously treated hairy cell leukemia. The most common adverse reactions (over or equal to 20 percent) included infusion-related reactions, swelling, nausea, tiredness, headaches, fever, constipation, anemia, and diarrhea.

Hypertension (high blood pressure), febrile neutropenia, and hemolytic uremic syndrome were the most common Grade three or four reactions (more than or equal to five percent). Adverse reactions led to discontinuation in 15 percent of patients, with HUS being the most common cause.

Ocular adverse events included blurred vision and dry eyes. Laboratory abnormalities (more than or equal to 20 percent) included decreased hemoglobin and neutrophil count, increased creatinine and ALT (alanine aminotransferase) levels, and hypoalbuminemia. Immunogenicity studies showed that some patients developed antibodies to Moxetumomab pasudotox-tdfk, potentially affecting its effectiveness.

Use in Specific Populations

• Pregnancy: Moxetumomab pasudotox-tdfk may cause harm to a developing fetus based on animal studies. There is no data on its effects on pregnant women. Advise pregnant women of potential risks.

• Lactation: No information on Moxetumomab pasudotox-tdfk's presence in breast milk or its effects on infants. Consider the benefits of breastfeeding alongside potential risks.

• Reproductive Potential: Women should employ reliable contraception while undergoing treatment with Moxetumomab pasudotox-tdfk and for 30 days after. Pregnancy status should be confirmed before starting treatment.

• Pediatric Use: The safety and effectiveness have not been confirmed in pediatric (children) patients.

• Geriatric Use: Many patients in Moxetumomab pasudotox-tdfk studies were 65 or older. Older patients may have higher rates of adverse reactions and renal toxicity, but efficacy differences between age groups are not apparent due to limited data.