Medicine > All about peg L-Aspara (Peg L-Asparaginase) injection

All about peg L-Aspara (Peg L-Asparaginase) injection

Name of Medicine:- L-Aspara

Active Ingredient:-  Peg L-Asparaginase

Chemical Formula:- C1377H2208N382O442S17

Description:- L-Aspara is administered as an injection. It is available in the strength of 3,750 IU per 5 mL solution.

What is L-Aspara?

L-Aspara (Peg L-Asparaginase) is an anti-cancer regimen. It is used for the treatment of a type of Blood Cancer. This medication tends to interfere with the processes responsible for the production, growth and spread of cancer cells. It works by stopping or slowing the multiplication p[rocess of the cancer cells in the human body. 

Clinical Relevance 

L-Aspara is a formulation of Peg L-Asparaginase. It is a prescription medicine used as a first-line treatment method for Acute Lymphoblastic Leukemia. This medication is also used in the treatment of Acute Lymphoblastic Leukemia with Hypersensitivity to Asparaginase. It is indicated for use in combination with other medicines. 

Clinical Pharmacology 

Pharmacodynamics 

Peg L-Asparaginase’s effect may occur by the selective killing of leukemic cells because of depleting plasma L-asparagine. Leukemic cells having a low expression of asparagine synthetase are comparatively less capable of producing L-asparagine and therefore rely more on exogenous L-asparagine for survival. When asparagine undergoes depletion, tumor cells cannot proliferate.

During remission induction, one dose of SC-PEG (2500 International Units/m2) leads to a sustained therapeutic serum asparaginase activity without excessive toxicity or marked differences in the total proportion of patients with low end-induction minimum residual disease (MRD).

Pharmacodynamic (PD) response was investigated by plasma measurement and cerebrospinal fluid (CSF) asparagine concentrations with an LC-MS/MS assay (liquid chromatography-mass spectrometry). The concentration of Asparagine in plasma was sustained below the assay limit of quantification for more than 18 days after one dose of calaspargase pegol, 2,500 IU/m2, during the induction phase of treatment. The mean cerebrospinal asparagine concentrations reduced from a pretreatment concentration of 0.8 μg/mL (N=10) to 0.2 μg/mL on Day 4 (N=37) and stayed reduced at 0.2 μg/mL (N=35) 25 days after administering one of 2,500 U/m2 in the induction phase.

Volume of distribution 

L-asparaginases have been established as essential components for the treatment of acute leukemias for more than 40 years. Their antitumor effect is a result of the depletion of asparagine which is an amino acid required for leukemic cells, and subsequent inhibition of protein synthesis resulting in considerable cytotoxicity. The efficacy and safety of this compound have been limited by a high rate of hypersensitivity reactions and the development of anti-asparaginase antibodies, which are responsible for the neutralization of their activity. PEG-asparaginase is a form of Escherichia coli L-asparaginase that is covalently associated with polyethylene glycol. It was synthesized to reduce the immunogenicity of the enzyme and prolong its half-life. In recent years, clinical trials have proven the need for intramuscular PEG-asparaginase in the frontline treatment of pediatric and adult patients. Present trials and studies are calculating the feasibility of intravenous administration of PEG-asparaginase.

Mechanism of action 

The active ingredient of this drug, L-asparaginase, is an enzyme that works to catalyze the conversion of the amino acid L-asparagine into aspartic acid and ammonia both. This process is responsible for the depletion of malignant cells of their required asparagine. The depletion of asparagine works by blocking protein synthesis and proliferation of tumor cells, specifically in the G1 phase of the cell cycle. This results in the death of the tumor cell. This compound is critical in protein synthesis in acute lymphoblastic leukemia cells which cannot produce this amino acid because of lack of the enzyme asparagine synthase.

Pegylation tends to decrease enzyme antigenicity and while increasing its half-life. Succinimidyl carbamate is used as a PEG linker in order to facilitate attachment to asparaginase and enhance the stability of the compound. SC-PEG urethane linkages formed with lysine groups are more stable hydrolytically. 

Toxicity 

Adverse effects that occur in patients receiving L-Aspara (Peg L-Asparaginase) include hepatotoxicity because it tends to increase serum transaminases (ALT, AST). it may also induce hypersensitivity reactions such as anaphylaxis, erythema, and bronchospasm.

The following have been observed with calaspargase pegol use:

  • Pancreatitis

  • Hepatotoxicity

  • Hemorrhage

  • Thrombosis 

Pancreatitis: It may occur in some patients receiving L-Aspara (Peg L-Asparaginase injection). Patients experiencing stomach pain during the course of L-Aspara should be monitored and tested for Pancreatitis.

Hepatotoxicity: Hepatic function tests should be periodically, and trough levels of this medication should be evaluated during the recovery phase of the treatment.

Thrombosis: Thrombotic effects, involving sagittal sinus thrombosis may be experienced by some patients receiving L-Aspara (Peg L-Asparaginase injection). L-Aspara injection should be discontinued if such a reaction continues for a longer period.

Clinical Trials 

The chemotherapy drug, namely L-asparaginase, has been a vital segment of acute lymphoblastic leukemia therapy for more than 30 years. The two main disadvantages of L-asparaginase are:

  • The need for frequent intramuscular injection. 

  • A very high rate of allergic reactions. 

Due to this, L-asparaginase seemed like an ideal target for pegylation, and PEG-L-asparaginase was developed in the 1970s and 1980s. This chemotherapeutic drug has undergone extensive testing and appears to retain its antileukemic effectiveness and allow less frequent administration than the native compound. While the actual cost to patients for PEG-L-asparaginase is greater than that of multiple injections of other L-asparaginases, the reduced need for physician visits and treatment of complications of therapy can create overall treatment costs considerably less than that of the conventional L-asparaginases. In the latest review, the history of therapy with L-asparaginase, the development of PEG-L-asparaginase, and clinical trials in which it has been administered have been outlined clearly.

Interactions 

When Peg Asparaginase is combined with other medications it causes various and different interactions with other medications. During the drug interaction study, when L-Aspara is inhibited with other medications, some activities are observed in the absorption of  Peg Asparaginase and the reported reactions are - 

  • Adverse risk can be increased when Peg Asparaginase is used in combination with other drugs like- Abatacept, Adalimumab, Azacitidine, etc. 

  • Metabolism can be decreased or increased depending on the ingredient of the medication. 

  • The risk of severe infections can be increased when live antigen is combined with Peg Asparaginase. 

  • The use of Peg Asparaginase may also increase the immunosuppressive activities of Cyclosporine. 

Drug-Drug interactions 

  • Adalimumab:- may increase the risk of serious bacterial infections while using in combination with Peg Asparaginase and it may interact vigorously. It can also cause some side effects like fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, and weight loss. Do not use any other tablets without consulting with your healthcare professional. 

  • Lomitapide:- This medication causes liver problems and using Lomitapide with Peg Asparaginase also increases the risk of liver impairment. Avoid the use of alcohol during treatment with this medication. Side effects like unusual bleeding or bruising, skin rash, itching, and loss of appetite may occur. Discontinuation of these medications may cause certain adverse reactions therefore do not stop using this medication as per your own will. 

  • Natalizumab:- using L-Aspara (Peg Asparaginase) and natalizumab may cause some life-threatening infections. To minimize the risk of such side effects your medical practitioner may perform some special tests and monitor them closely, if he/she finds anything unusual several dose adjustments may be required. 

Food interactions 

  • Alcohol with Peg Asparaginase can cause some severe hepatotoxic effects. Avoid chronic alcohol consumption because it can lead to hepatotoxicity. 

Drug-Disease interactions 

  • Hepatic dysfunction:- Patients during treatment with Peg Asparaginase can experience liver failure and hepatic reactions like - hepatitis and increased liver enzymes. Close monitoring of liver function is required.

  • Bleeding disorders:- Risk of severe bleeding can be increased in patients because L-Aspara (Peg Asparaginase) interferes with coagulation factors (proteins in the blood that help control bleeding), and both thrombosis and hemorrhage have been observed. Immediately report your signs and symptoms of bleeding to your healthcare provider and he/she will perform clinical monitoring. 

  • Pancreatic dysfunction:- Extreme caution is recommended in patients who have a history of pancreatitis. Peg Asparaginase injection decreases the insulin synthesis or inflammation and necrosis of cells of the pancreas. 

Drug Category 

  • Antineoplastic Agents: L-Aspara (Peg L-Asparaginase injection) belongs to a class of drugs known as Antineoplastic Agents. Such medicines are also referred to as chemotherapy, chemo, or cytotoxic drugs. These drugs are used in the treatment of cancer. Antineoplastic Agents are available in many different forms.

  • Pegylated Agents: It is a process by which polyethylene glycol (PEG) chains are conjugated to proteins (therapeutic proteins), peptides, or any molecule. Through this technique, the molecular mass of the therapeutic protein is raised. The compounds that go through this process are known as Pegylated Agents. 

  • Asparaginase: This drug is used in the treatment of acute lymphocytic leukemia (ALL). Asparaginase works to starve tumor cells of needed nutrients and thereby slows down tumor cell growth.

Dosage and Administration 

Recommended Dose

The injection is administered either intramuscularly or intravenously. It should be administered to the patients after every 14 days and not more frequently than this.  The recommended dosage strength of L-Aspara (Peg L-Asparaginase injection) is 2,500 International Units/m2. It is advised to use only one dose per vial. Discard the leftover. Also, this injection is administered by a nurse under the strict supervision of a medical practitioner. 

Overdosage 

In case of an overdose, the patient may experience adverse events like a sudden increase in liver enzymes, allergic reactions (including skin rash and itching), or other reactions. The patient should be monitored and given supportive care accordingly. 

Adverse Reactions 

L-Aspara (Peg L-Asparaginase injection) may cause certain side effects. Some people experience a mild, moderate, or severe reaction during the course of this medicine. Such reactions should be closely monitored and supportive care should be given to the patients. If side effects last longer than a usual period, L-Aspara injection should be discontinued. 

Injection site reactions may be experienced by some patients receiving L-Aspara (Peg L-Asparaginase injection) including skin rash, dry skin, swelling of hands and legs, itching, and irritability. These reactions may be accompanied by fever, cough, and other flu-like symptoms. 

Pancreatitis may occur in some patients receiving L-Aspara (Peg L-Asparaginase injection). Effects like stomach pain, nausea, vomiting, rapid pulse, and tenderness when touching the abdomen should not be ignored. 

Severe thrombosis, including sagittal sinus thrombosis, may occur in some patients receiving L-Aspara (Peg L-Asparaginase injection). Effects such as throbbing or cramping pain, swelling in one leg, swollen veins, and warm skin around the painful areas should be monitored.

L-Aspara (Peg L-Asparaginase injection) may cause Gastrointestinal Disorders including frequent dyspepsia (discomfort or pain in the upper abdomen), anal fissure, ileus, pancreatitis, dysphagia (difficulty in swallowing), gastritis, and colitis. Other common effects like malaise and temperature intolerance may occur in patients. 

Other common adverse events that may occur during the course of L-Aspara (Peg L-Asparaginase injection) are tinnitus and vertigo;  insomnia, depression, anxiety, confusional state, and affect lability; palpitations, angina pectoris, cardiomegaly, and myocardial infarction.

Warnings and Precautions 

Pancreatitis

Pancreatitis may occur in some patients receiving L-Aspara (Peg L-Asparaginase injection). Patients experiencing stomach pain during the course of L-Aspara should be monitored and tested for Pancreatitis. 

Thrombosis

Serious thrombotic effects, involving sagittal sinus thrombosis may be experienced by some patients receiving L-Aspara (Peg L-Asparaginase injection). L-Aspara injection should be discontinued if such a reaction continues for a longer period.

Coagulopathy

This is a condition in which the patient loses its blood's ability to clot. The patient receiving L-Aspara (Peg L-Asparaginase injection) should be monitored closely for such effects and reactions.

Serious Allergic Reactions

Serious allergic reactions may be experienced by some patients receiving L-Aspara (Peg L-Asparaginase injection). This condition is common in patients who are known to be hypersensitive. L-Aspara injection should be discontinued if such a reaction continues for a longer period.

Pregnant Women

L-Aspara injection can cause fetal harm when administered to a woman during pregnancy. This injection is not safe for use in patients who are pregnant or are planning to become pregnant. Women with child-bearing potential are highly advised to use proper contraception at least 28 days before starting the course of L-Aspara.

Nursing Mothers

It is not yet known if L-Aspara (Peg L-Asparaginase injection) is excreted in human milk or not. As many other drugs are excreted in breast milk, it becomes necessary to take precautionary steps in order to avoid adverse events. Therefore, breastfeeding should be discontinued while receiving treatment with L-Aspara.

Packaging and Storage

L-Aspara (Peg L-Asparaginase injection) is supplied as a sterile solution in Type I single-use vial containing 3,750 IU of L-Asparaginase per 5 mL solution. Store the vial in a refrigerator from 2°C to 8ºC. Do not shake or freeze the solution. Do not place the vial under direct light or heat. Protect the injection from moisture. Know the methods to dispose of the used and expired packs of L-Aspara injection from a pharmacist. Pregnant women should not handle L-Aspara injections without protection such as gloves.