Rasburicase - An Overview

Overview:

Rasburicase is an intravenous medication given to clear the increased uric acid levels in the blood. Rasburicase is a recombinant version of the urate oxidase enzyme, which metabolizes the uric acid to an inactive molecule that can be rapidly excreted. This drug is produced from Saccharomyces cerevisiae, a genetically modified strain, and the complementary DNA (deoxyribonucleic acid) coding for this drug was cloned from the Aspergillus flavus, a fungal strain. Rasburicase is available as a lyophilized powder, which is administered through intravenous infusion.

Rasburicase is included in the World Health Organization's list of essential medicines. The United States Food and Drug Administration approved using Rasburicase to prevent and manage tumor lysis syndrome in patients receiving chemotherapy for cancers like lymphomas and leukemias.

How Does Rasburicase Work?

Uric acid is a component of urine, and it is produced from the metabolic breakdown of the purine nucleotides. Rasburicase is a recombinant version of the urate oxidase enzyme. The urate oxidase enzyme converts uric acid into allantoin. Allantoin is an inactive molecule that is poorly toxic and can be easily excreted even during renal impairment. Hydrogen peroxide, an oxidant product, is released at the end of this reaction. The antioxidant system in the body neutralizes it and produces water and oxygen as by-products. Patients with G-6-PD (glucose-6-phosphate dehydrogenase) deficiency lack the antioxidant system to neutralize the hydrogen peroxide, and it results in toxic reactions. Hence, Rasburicase should not be used in G-6-PD deficiency.

Uses:

• Used for treating high levels of uric acid in the blood in conditions like hyperuricemia in gout, rhabdomyolysis with renal failure, and other rheumatological conditions. Hyperuricemia is the main condition that requires the use of Rasburicase.

• Rasburicase is used in the treatment of tumor lysis syndrome. It is used for patients receiving chemotherapy for cancers like leukemia and lymphoma because patients receiving chemotherapy for such cancers are expected to result in tumor lysis syndrome and elevation of plasma uric acid subsequently. Hence, Rasburicase is given to managing the uric acid levels in these patients.

Dosage:

Rasburicase is available as a lyophilized powder for intravenous administration. It is supplied in 3 mL and 10 mL glass vials which contain Rasburicase at 1.5 mg/mL concentration after reconstitution.

Usual Dose for Hyperuricemia Secondary to Chemotherapy:

The adult and pediatric dosages for hyperuricemia are 0.15 or 0.2 mg/kg body weight as a 30-minute intravenous infusion once a day for five days.

• Use of Rasburicase beyond five days and more than one course of therapy is not recommended. It is approved only for a single course of treatment.

• The duration of treatment depends on the level of uric acid in the plasma.

What Are the Warnings and Precautions of Rasburicase?

1) Hemolysis: Rasburicase causes severe hemolytic reactions that are associated with G-6-PD deficiency within two to four days of initiation of therapy. It should not be used in patients with G-6-PD deficiency.

2) Methemoglobinemia: Rasburicase increases the risk of methemoglobinemia and results in hypoxemia. It is unknown whether methemoglobinemia and hemolytic anemia are due to the deficiency of methemoglobin reductase enzyme or other antioxidant enzymes.

3) Hypersensitivity Reactions: Hypersensitivity reactions may occur at any time during the course of the treatment.

4) Pregnancy: Rasburicase should not be used in pregnant women as it harms the unborn baby. Effective birth control methods should be followed to prevent pregnancy before starting this treatment.

5) Breastfeeding: Breastfeeding is not recommended during the course of this treatment, and breastfeeding should not be done for at least two weeks after the last dose.

For Patients:

What Is Hyperuricemia?

Hyperuricemia is a condition in which the uric acid levels in the blood are elevated. The normal value for uric acid is 6.8 mg/dL. It is considered hyperuricemia if the value is above 7 mg/dL. It can be due to increased production of uric acid, decreased excretion, or a combination of both. Hyperuricemia results in gout and nephrolithiasis. Hyperuricemia serves as a potent indicator for diseases like diabetes mellitus, cardiovascular diseases, metabolic syndrome, and chronic renal disease.

What Are the Causes of Hyperuricemia?

Hyperuricemia due to increased production of uric acid includes the following causes:

• High purine diet.

• Errors of purine metabolism like hypoxanthine phosphoribosyltransferase deficiency or phosphoribosylpyrophosphate synthetase overactivity.

• Cell breakdown diseases like lymphoproliferative diseases (uncontrolled production of lymphocytes), myeloproliferative diseases (a cancerous condition in which the cells in the bone marrow undergo changes), hemolysis (breakdown of red blood cells), polycythemia vera (excess red blood cells), rhabdomyolysis (breakdown of muscle tissue), tumor lysis, psoriasis, and Paget's disease (bone remodeling disorder). Exercise also causes hyperuricemia due to cell breakdown or turnover.

Hyperuricemia due to decreased uric acid excretion includes the following causes:

• Acute or chronic kidney diseases, hypovolemia, lactic acidosis, ketoacidosis, medications or toxins, hyperparathyroidism, hypothyroidism, sarcoidosis, Bartter's syndrome, and Down's syndrome.

What Happens in Hyperuricemia?

Hyperuricemia results in gout and nephrolithiasis. Gout is a condition in which uric acid deposition occurs in the blood and tissues. It causes symptoms like pain, red hot, and swollen joints especially affecting the greater toe. Uric acid is filtered and excreted by the renal system. Conditions like acidic urine, hyperuricosuria (excess urinary uric acid excretion), and dehydration influence stone formation in hyperuricemia. It causes flank pain, hematuria, colicky pain, nausea, and vomiting.

Learn More About Rasburicase

Facts to Know Before Starting Rasburicase:

When and Why Switch to Rasburicase?

Hyperuricemia is a condition that allows excessive accumulation of uric acid in the blood. Various medications are used in the treatment of hyperuricemia. Rasburicase is not the first-line drug for managing hyperuricemia. According to the guidelines, Xanthine oxidase inhibitors remain the first line of treatment for managing hyperuricemia. Rasburicase is used because it is more effective than oral Allopurinol in reducing plasma uric acid concentrations. Rasburicase is also used in patients who developed urticaria (allergic skin rashes) or angioedema (allergic swelling) due to treatment with Allopurinol.

How Effective Is Rasburicase?

Rasburicase offers beneficial effects in hyperuricemia by reducing the uric acid concentrations in the blood. It causes a decrease in uric acid levels within four hours of administration of Rasburicase. After the administration, the average uric acid concentration was maintained at or near 0.5 mg/dL throughout the treatment.

Things to Inform the Doctor Before Rasburicase Is Prescribed

1. The presence of allergic reactions should be informed to the doctor.

2. Rasburicase should not be used in G6PD deficiency (a condition in which red blood cells break down), and the presence of such deficiency should be informed.

3. Rasburicase is contraindicated in pregnancy. The patient should inform about pregnancy and pregnancy planning.

4. Breastfeeding should not be done while taking Rasburicase, and they should inform the doctor.

5. If any other medications were taken previously for hyperuricemia, they should be informed.

6. If the patient is taking medications for any other conditions, the doctor should be informed about it.

Starting Rasburicase:

How to Take a Rasburicase?

Rasburicase is not available for oral use. It is an injectable drug that is administered as an intravenous infusion by the health care provider. It is given slowly, and the drip takes at least 30 minutes to complete. It is given once a day for up to five days. During the course of the treatment, the plasma uric acid concentrations are monitored, and the duration of the treatment is decided accordingly.

Do's and Don'ts While Taking Rasburicase:

1. It is important to follow the instructions of the doctor during the course of the treatment.

2. The appointments for Rasburicase injections should not be missed.

3. It is essential to inform the doctor if symptoms like hives, rash, wheezing, difficulty breathing, pain, tightness in the chest, and swelling of the face, lips, tongue, or throat develop.

4. The doctor's advice about restrictions on food, beverages, or activity should be followed.

Advice for Caregivers:

The caregivers should inform the doctor if the patient develops symptoms like pale or yellow colored skin, dark urine; dry mouth, altered taste sensation, white patches in or around the mouth, difficulty swallowing, bad breath; fever, rapid heart rate, rapid and shallow breathing, fainting; and bluish discoloration of skin or lips, weakness, headache, and difficulty breathing.

Things to Do After Taking Rasburicase:

It is important to inform the doctor if any noticeable symptoms are present after taking Rasburicase. Any signs of allergic reactions like hives, rashes, difficulty breathing, or swelling of the face, lips, tongue, or throat should be informed to the doctor. If symptoms like anxiety, abdominal pain, fever, or headache are present, the doctor should be informed.

Diet Modifications:

The doctor may advise reducing the intake of purines in the diet. Unless specified by the doctor, a regular and balanced diet can be followed.

Look Out for the Side Effects:

If side effects are present, it is essential to adjust the treatment accordingly. The patients should familiarize themselves with the common and rare side effects of Rasburicase so that it is easier to recognize the symptoms. Rasburicase may cause some other side effects that are not listed here.

The common side effects include

• Nausea, vomiting, and abdominal pain.

• Diarrhea and constipation.

• Headache.

• Anxiety.

• Throat pain.

• Fever.

• Swelling in the hands or feet.

• Cracked lips.

• Difficulty swallowing.

• Sores, ulcers, or white spots in or around the mouth.

Less common side effects include

• Bleeding gums.

• Changes in skin color.

• Changes in vision.

• Confusions.

• Convulsion.

• Chest pain or tightness.

• Depression.

• Dizziness.

• Dry mouth.

• Muscle twitching.

• Shortness of breath.

• Wheezing.

• Coughing up blood.

Staying on Rasburicase:

Tips to Stay on Track:

The improvement in the symptoms of hyperuricemia after taking Rasburicase can be experienced during the course of the treatment. The time required for the improvement of symptoms varies by person. If any side effects occur after taking Rasburicase, it is essential to seek medical help. Skipping appointments should not be done without the doctor's advice. It should be confirmed with the physician on missing an appointment for an injection.

Things to remember,

1) It is important to stick to the dosage schedule because missing an appointment will affect the treatment outcome.

2) It is essential to follow up regularly with the doctor and inform them about improvement in symptoms.

For Doctors:

Indications:

Rasburicase is prescribed for managing high plasma uric acid concentrations in conditions like hyperuricemia in gout and for preventing and managing hyperuricemia in patients receiving chemotherapy for leukemia and lymphoma.

Mechanism of Action:

Rasburicase, a recombinant urate oxidase enzyme, converts the existing uric acid to allantoin. Allantoin is an inactive molecule that is poorly toxic, more soluble, and can be easily excreted even during renal impairment. Hydrogen peroxide, an oxidant product, is released at the end of this reaction. The antioxidant system in the body neutralizes it and produces water and oxygen as by-products.

Pharmacodynamics:

The plasma uric acid levels decreased within four hours of administration of Rasburicase. After administration of 0.15 or 0.20 mg/kg of Rasburicase daily for five days, the plasma uric acid levels were below 7.5 mg/dL for at least seven days in 98 percent of adult patients and 90 percent of pediatric patients, according to clinical studies. There is no evidence of the dose-responsive effect of uric acid control for doses 0.15 and 0.20 mg/kg of Rasburicase. In clinical studies, Rasburicase had no effect on the activity of cytochrome P-450 enzymes. Therefore, P-450-mediated drug-to-drug interactions are not seen in patients taking Rasburicase.

Absorption:

The maximum plasma concentration increased with a dose range from 0.15 to 0.20 mg/kg. The target plasma uric acid concentrations, fewer than 6.5 mg/dL in children below 13 years of age and plasma concentrations of fewer than 7.5 mg/dL in patients above 13 years of age, were achieved within 48 hours of Rasburicase administration.

Distribution:

The mean volume of distribution of Rasburicase ranged between 110 to 127 mL/kg in pediatric patients and 75.8 to 138 mL/kg in adult patients. Minimal accumulation of this drug was observed between one and five days of treatment. It is not known if Rasburicase is distributed in breast milk.

Metabolism:

Rasburicase is a recombinant enzyme that is metabolized by serum and tissue proteases to amino acids. It does not have direct hepatotoxic potential. The liver test abnormalities in patients under Rasburicase were due to other features.

Elimination:

The elimination half-life is about 16 and 21 hours for 0.15 mg/kg and 0.20 mg/kg doses of Rasburicase. The overall elimination half-life is about 18 hours for Rasburicase.

What Are the Ingredients of Rasburicase?

Rasburicase is the active ingredient. Other ingredients in this drug are mannitol, alanine, disodium phosphate dodecahydrate, disodium phosphate dihydrate, phosphate dihydrate, and sodium dihydrogen.

Warnings and Precautions:

1) Hemolysis: Rasburicase causes severe grade 3 or grade 4 hemolytic reactions that are associated with G-6-PD deficiency within two to four days of initiation of therapy. It should not be used in patients with G-6-PD deficiency. The drug should be immediately discontinued if hemolysis occurs.

2) Methemoglobinemia: Rasburicase increases the risk of methemoglobinemia and results in hypoxemia. It is unknown whether methemoglobinemia and hemolytic anemia are due to the deficiency of methemoglobin reductase enzyme or other antioxidant enzymes. The drug should be immediately discontinued, and supportive therapy such as transfusion and methylene blue should be administered.

3) Hypersensitivity Reactions: Hypersensitivity reactions like hives, rashes, and swelling of the face, lips, or throat may occur at any time during the course of the treatment.

4) Pregnancy: Rasburicase should not be used in pregnant women as it harms the unborn baby. Effective birth control methods should be followed to prevent pregnancy before starting this treatment.

5) Breastfeeding: Breastfeeding is not recommended during the course of this treatment, and breastfeeding should not be done for at least two weeks after the last dose.

6) Hydration: Adequate hydration should be maintained in patients at risk for tumor lysis syndrome while managing the plasma uric acid concentrations.

Indications and Uses:

Rasburicase is used for treating high levels of uric acid in the blood in conditions like hyperuricemia in gout, rhabdomyolysis with renal failure, and other rheumatological conditions. Rasburicase is also indicated in the treatment of tumor lysis syndrome. It is used for patients receiving chemotherapy for cancers like leukemia and lymphoma because patients receiving chemotherapy for such cancers are expected to result in tumor lysis syndrome and elevation of plasma uric acid subsequently. Hence, Rasburicase is given to manage the uric acid levels in these patients.

Dosage Strength and Forms:

Rasburicase is available as a lyophilized powder for intravenous administration. It is supplied in 3 mL and 10 mL glass vials which contain Rasburicase at 1.5 mg/mL concentration after reconstitution.

Dosage and Administration:

The adult and pediatric doses for infants and children of age one month to 17 years is 0.15 or 0.20 mg/kg body weight as a 30-minute intravenous infusion once a day for five days. The safety and efficacy for the use of Rasburicase beyond five days and more than one course of therapy have not been established. It is approved only for a single course of treatment. The duration of treatment depends on the level of uric acid in the plasma.

Considerations for Administration:

• Rasburicase should not be administered as a rapid IV (intravenous) injection and should be administered over 30 minutes of infusion.

• The filters should not be used during administration.

• It should be administered in a separate line from that used for other concomitant drugs.

• The number of vials required for proper dosage should be determined based on the patient's body weight prior to the administration. The vial containing 1.5 mg of lyophilized powder should be reconstituted with 1 mL of diluent, which is sterile water for injection, and poloxamer 188 to achieve a solution containing 1.5 mg of Rasburicase per mL.

Contraindication:

Rasburicase should not be prescribed for patients with known hypersensitivity to Rasburicase or its inactive ingredients. It should be permanently discontinued if hypersensitivity reactions occur.

Results from Clinical Trials:

• Rasburicase was administered to 265 pediatric patients with acute leukemia or non-Hodgkin's lymphoma in three studies. 0.15 or 0.20 mg/kg Rasburicase was administered as a 30-minute infusion once a day for five days. It was administered prior to antitumor therapy. The analyses from three studies were pooled together. It showed that the plasma uric acid concentration, which was more than 8 mg/dL before treatment, showed a decrease in four hours in 92 percent of the patients.

• Rasburicase was administered to 342 adult patients with leukemia, lymphoma, or another hematologic malignancy in five studies. . 0.15 or 0.20 mg/kg Rasburicase was administered as a 30-minute infusion once a day for five days across the five studies. The patients showed a decrease in plasma uric acid concentrations, and some patients did not show any response to control uric acid.

Drug Interactions:

Interactions With Other Drugs:

Rasburicase does not induce or inhibit cytochrome isoenzymes, including 1A, 2A, 2B, 2C, 2E, or 3A in vivo. The known drugs that interact with Rasburicase are Aripiprazole, papain, charcoal, Doxorubicin, Oxymetazoline nasal, antihemophilic factor, Darbepoetin alfa, Azithromycin, Sulfamethoxazole/Trimethoprim, Meperidine, Fluorouracil topical, Heparin, Levocarnitine, Phenazopyridine, vitamin A topical, bioflavonoids, Sotalol, Cyanocobalamin, cholecalciferol, and Ondansetron.

Other Specifications:

Rasburicase in G-6-PD Deficiency:

Rasburicase should not be used in G-6-PD deficient individuals, as it causes severe hemolytic reactions.

Rasburicase During Pregnancy:

Rasburicase causes harmful effects on the unborn baby and should not be used in pregnant women. Effective birth control methods should be followed to prevent pregnancy before starting this drug.

Rasburicase During Lactation:

The distribution of Rasburicase in breast milk is not known. Breastfeeding is not advised during the course of the treatment and for at least two weeks after the treatment.

Pediatric Use:

The safety of Roflumilast use in pediatric patients has not been demonstrated. COPD does not occur in children, and Roflumilast use is not recommended.

Geriatric Use:

The safety and efficacy of Rasburicase in patients above 65 years of age are not well-established.

Hepatic Impairment:

Rasburicase is metabolized by peptide hydrolysis and does not cause any hepatic impairment. Hence, dosage adjustments in patients with hepatic impairment are not required.

Renal impairment:

Rasburicase has no impact on the kidneys, and dosage for patients with renal impairment is not required.