Pegaspargase

Usage

Pegaspargase is prescribed for the treatment of acute lymphoblastic leukemia (ALL), a type of blood cancer affecting white blood cells. It is particularly useful in patients who have experienced hypersensitivity reactions to other L-asparaginase treatments. It’s pharmacological classification is antineoplastic (anticancer) agent specifically an enzyme. It works by breaking down asparagine, an amino acid crucial for cell survival. Since leukemic cells cannot produce their own asparagine (unlike healthy cells), this depletion leads to their death.

Alternate Names

The international nonproprietary name (INN) for pegaspargase is pegaspargase. A common brand name under which it is marketed is Oncaspar.

How It Works

Pharmacodynamics: Pegaspargase is a PEGylated form of L-asparaginase, an enzyme that hydrolyzes asparagine into aspartic acid and ammonia. This depletes asparagine levels in the blood, depriving leukemic cells (which cannot synthesize asparagine) of this essential amino acid, leading to their death. Healthy cells, capable of producing asparagine, are less affected.

Pharmacokinetics: Pegaspargase is administered intravenously (IV) or intramuscularly (IM). PEGylation extends its half-life, allowing for less frequent dosing. The drug is systemically degraded, likely by the reticuloendothelial system, with proteolytic enzymes contributing to its metabolism. It is not renally excreted due to its high molecular weight.

Mode of Action: Pegaspargase exerts its effect by enzyme activity. It catalyzes the hydrolysis of asparagine, a process crucial for leukemic cell survival. This targeted mechanism of action exploits the inability of leukemic cells to synthesize their own asparagine. There is no direct receptor binding, enzyme inhibition, or neurotransmitter modulation involved in its primary mechanism.

Elimination: Pegaspargase is primarily eliminated through systemic degradation, likely by the reticuloendothelial system, rather than renal or hepatic excretion. Its terminal half-life is approximately 5.3 days for IV administration and 5.8 days for IM injection.

Dosage

Standard Dosage

Adults (over 21 years):

• 2,000 U/m² IV or IM, every 14 days. Some protocols may utilize lower doses (e.g., 1,000-2,000 U/m²) or cap the dose at 3,750 U (1 vial) to reduce toxicity.

Children (up to and including 21 years) & Adolescents:

• BSA ≥ 0.6 m²: 2,500 U/m² IV or IM, every 14 days.
• BSA < 0.6 m²: 82.5 U/kg body weight IV or IM, every 14 days.

Special Cases:

• Elderly Patients: Limited data are available for patients over 65. No specific dosage adjustments are outlined but proceed cautiously considering potential age-related physiological changes.
• Patients with Renal Impairment: No dose adjustment is required, as pegaspargase is not renally excreted.
• Patients with Hepatic Dysfunction: No specific dose adjustment. Close monitoring is recommended due to a higher risk of hepatotoxicity.
• Patients with Comorbid Conditions: Caution is advised in patients with pre-existing conditions like diabetes, cardiovascular disease, hepatic impairment, or a history of thrombosis or pancreatitis, as pegaspargase can exacerbate these conditions.

Clinical Use Cases

Pegaspargase dosing in these settings generally follows the standard dosage recommendations according to age and BSA, as described above. However, adjustments may be necessary based on the patient’s specific situation and the chemotherapy protocol being used. Clinical cases like intubation, surgical procedures, mechanical ventilation, ICU use, and other emergency situations may require careful consideration and individualization of the pegaspargase dosage based on patient factors and concomitant medications. Serum asparaginase activity monitoring is essential to ensure therapeutic levels are reached.

Dosage Adjustments

Dose adjustments are based on adverse events. Refer to Table 1 within source material for dosage modifications relating to Infusion Reaction/Hypersensitivity Reaction and Thrombosis.

Side Effects

Common Side Effects:

• Allergic reactions (rash, itching, hives, swelling)
• Nausea, vomiting, diarrhea
• Loss of appetite
• Abdominal pain
• Fatigue
• Fever, chills
• Hyperglycemia
• Increased liver enzymes
• Elevated pancreatic enzymes

Rare but Serious Side Effects:

• Anaphylaxis
• Pancreatitis
• Thrombosis (blood clots)
• Hemorrhage (bleeding)
• Liver failure
• Seizures
• Coma

Long-Term Effects:

• Impaired glucose tolerance
• Liver dysfunction
• Pancreatic insufficiency
• Increased risk of secondary malignancies

Adverse Drug Reactions (ADR):

• Anaphylaxis
• Severe pancreatitis
• Life-threatening thromboembolic events
• Severe hemorrhage

Contraindications

• History of serious hypersensitivity to pegaspargase or E. coli-derived L-asparaginase
• Severe hepatic impairment (bilirubin > 3x ULN, transaminases > 10x ULN)
• History of serious thrombosis with prior L-asparaginase therapy
• History of pancreatitis related to prior L-asparaginase therapy
• History of serious hemorrhagic events with prior L-asparaginase therapy

Drug Interactions

Pegaspargase can interact with various medications, including:

• Methotrexate: Prior administration can increase pegaspargase’s effects synergistically; subsequent administration can antagonize its effects.
• Vincristine and Prednisone: May be used in combination with pegaspargase but careful monitoring is necessary.
• Other chemotherapy drugs: Interactions may occur due to pegaspargase’s impact on hepatic function and protein synthesis.
• Anticoagulants: Increased risk of bleeding or thrombosis when used concurrently.
• Oral contraceptives: Efficacy may be reduced; non-hormonal contraception is recommended.

See source material for a more exhaustive list of drug interactions.

Pregnancy and Breastfeeding

Pegaspargase is contraindicated during pregnancy due to potential fetal harm. Non-hormonal contraception must be used during treatment and for at least 6 months after discontinuation.

Breastfeeding is contraindicated during treatment and until after pegaspargase discontinuation, as it is unknown if the drug is excreted in breast milk.

Drug Profile Summary

• Mechanism of Action: Depletes asparagine, leading to the death of leukemic cells.
• Side Effects: Allergic reactions, hyperglycemia, pancreatitis, liver toxicity, blood clots, bleeding.
• Contraindications: Hypersensitivity, severe hepatic impairment, history of thrombosis/pancreatitis/hemorrhage with prior L-asparaginase.
• Drug Interactions: Methotrexate, vincristine, prednisone, anticoagulants, oral contraceptives.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Adults >21: 2,000 U/m² every 14 days; children ≤21: 2,500 U/m² (BSA ≥0.6 m²) or 82.5 U/kg (BSA <0.6 m²) every 14 days.
• Monitoring Parameters: Blood counts, liver function tests, coagulation parameters, blood glucose, amylase, lipase, serum asparaginase activity.

Popular Combinations

Pegaspargase is commonly used in combination chemotherapy regimens for ALL, often including vincristine, prednisone, and/or methotrexate. Specific combinations and protocols vary.

Precautions

• Pre-screening for allergies, hepatic dysfunction, pancreatitis, and bleeding disorders is essential.
• Close monitoring of liver function, blood glucose, coagulation parameters, and pancreatic enzymes is crucial.
• Patients should be premedicated with antihistamines, acetaminophen, H1 and H2 blockers to minimize hypersensitivity reactions.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Pegaspargase?

A: Adults >21 years: 2,000 U/m² IV or IM every 14 days. Children/adolescents ≤21 years: 2,500 U/m² (BSA ≥ 0.6 m²) or 82.5 U/kg (BSA < 0.6 m²) IV or IM every 14 days.

Q2: How is Pegaspargase administered?

A: Intravenous (IV) infusion over 1-2 hours or intramuscular (IM) injection. For IM injections exceeding 2 mL, use multiple injection sites.

Q3: What are the most serious side effects of Pegaspargase?

A: Anaphylaxis, severe pancreatitis, thrombosis, hemorrhage, liver failure.

Q4: What are the contraindications for Pegaspargase?

A: Hypersensitivity to pegaspargase, severe hepatic impairment, history of thrombosis/pancreatitis/hemorrhage with prior L-asparaginase therapy.

Q5: Can Pegaspargase be used during pregnancy or breastfeeding?

A: No, it is contraindicated in both pregnancy and breastfeeding.

Q6: How does Pegaspargase interact with other medications?

A: It can interact with methotrexate, vincristine, prednisone, anticoagulants, and oral contraceptives. Consult source material for further drug interactions.

Q7: How should hypersensitivity reactions to Pegaspargase be managed?

A: Mild reactions may require slowing the infusion rate or antihistamines. Severe reactions necessitate immediate discontinuation of pegaspargase and administration of epinephrine, steroids, and other supportive care.

Q8: What monitoring parameters are important during Pegaspargase treatment?

A: Liver function tests, blood glucose, coagulation parameters, pancreatic enzymes (amylase and lipase), blood counts, serum asparaginase activity.

Q9: What premedications are recommended before Pegaspargase administration?

A: Acetaminophen, an H1 receptor blocker (e.g., diphenhydramine), and an H2 receptor blocker (e.g., famotidine) 30-60 minutes prior to administration.

Q10: What is the role of serum asparaginase activity monitoring?

A: Helps ensure therapeutic drug levels are achieved and can identify silent inactivation due to antibody formation. Target levels are typically ≥ 0.1 IU/mL.