Consumer medicine information

Oncaspar

Pegaspargase

BRAND INFORMATION

Brand name

Oncaspar Powder for Injection

Active ingredient

Pegaspargase

Schedule

SUMMARY CMI

ONCASPAR^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ONCASPAR?

ONCASPAR contains pegaspargase which is a form of an enzyme called asparaginase. Pegaspargase may sometimes be called pegylated (or "PEG") asparaginase. ONCASPAR is used to treat leukaemia. It belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

For more information, see Section 1. Why am I using ONCASPAR? in the full CMI.

2. What should I know before I use ONCASPAR?

Do not use if you have ever had an allergic reaction to ONCASPAR or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ONCASPAR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ONCASPAR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ONCASPAR?

ONCASPAR must only be given by healthcare professionals trained in administering anticancer medicines. ONCASPAR is given by injection into a muscle (intramuscular) or, if not suitable, into a vein (intravenous). Your doctor will decide upon the doses you will receive and how often. This depends on your, age, body weight and height. ONCASPAR may be given in combination with other drugs. Your doctor will decide whether premedication is necessary.

More instructions can be found in Section 4. How do I use ONCASPAR? in the full CMI.

5. What should I know while using ONCASPAR?

Things you should do	Remind any doctor, nurse, dentist or pharmacist you visit that you are using ONCASPAR. Keep all appointments with your doctor and always discuss with your doctor any problems during or after treatment with ONCASPAR.
Things you should not do	Do not start taking any other medicines, prescription or over-the-counter, without first telling your doctor.
Driving or using machines	Do not drive or use machines when using ONCASPAR because it may make you feel drowsy, tired or confused.
Looking after your medicine	It is unlikely that you will be asked to store ONCASPAR yourself. It will usually be stored in the pharmacy or on the hospital/clinic ward.

For more information, see Section 5. What should I know while using ONCASPAR? in the full CMI.

6. Are there any side effects?

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being given ONCASPAR. ONCASPAR, like all other medicines, may cause unwanted side effects. Side effects are very common with anti-cancer medicines such as ONCASPAR and they may be serious. You may need medical treatment if you get some of the side effects.

If you experience serious allergic reactions with symptoms such as rash, itching, swelling, hives, shortness of breath, fast heartbeat and drop in blood pressure, severe skin reaction called toxic epidermal necrolysis, violent shaking (seizures) and loss of consciousness, very high fever, severe stomach pain which may spread to your back, vomiting, increase in blood sugar levels, headaches, high blood pressure, visual disturbances, change in urine output, swelling of the feet and ankles, change in colour of your skin or urine or stool, fast heart rate, breathing difficulty and weakness, leg pain, chest pain or shortness of breath after taking ONCASPAR – please seek urgent medical attention.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

ONCASPAR^®

Active ingredient(s): Pegaspargase powder for solution for injection/infusion

Consumer Medicine Information (CMI)

This leaflet provides important information about using ONCASPAR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ONCASPAR.

Where to find information in this leaflet:

1. Why am I using ONCASPAR?
2. What should I know before I use ONCASPAR?
3. What if I am taking other medicines?
4. How do I use ONCASPAR?
5. What should I know while using ONCASPAR?
6. Are there any side effects?
7. Product details

1. Why am I using ONCASPAR?

ONCASPAR contains pegaspargase which is a form of an enzyme called asparaginase. This enzyme breaks down asparagine, an important building block in making proteins, without which cells cannot survive. Normal cells can make asparagine for themselves, while some cancer cells cannot. ONCASPAR lowers asparagine levels in blood cancer cells and stops the cancer growing.

Pegaspargase may sometimes be called pegylated (or "PEG") asparaginase.

ONCASPAR is used to treat leukaemia. It belongs to a group of medicines called antineoplastic or cytotoxic medicines.
You may also hear of these being called chemotherapy medicines.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use ONCASPAR?

Warnings

Do not use ONCASPAR if:

you are allergic to pegaspargase or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
have severe hepatic (liver) disease.
have ever had pancreatitis (inflammation of the pancreas).
have ever had blood clots following asparaginase therapy.
have ever had severe bleeding following asparaginase therapy.

You should tell your doctor:

if you have had serious allergic reactions to other forms of asparaginase, for example itching, flushing or swelling of the airways, because major allergic reactions to ONCASPAR can occur.
if you suffer from a bleeding disorder or have had serious blood clots.
if you get a fever. This medicine may make you more susceptible to infections.
if you have had poor liver function or are taking other medicines which may harm the liver.
if ONCASPAR is used in combination with other cancer treatments, liver damage (severe, life-threatening, and potentially fatal cases of hepatic veno-occlusive disease (VOD)) can occur.
if ONCASPAR is used in combination therapy this may result in injury to central nervous system.
if you have or have had liver, lung or heart disease.
if you suffer abdominal pain. Inflammation of the pancreas can occur with ONCASPAR that in some cases can cause death if left untreated.

This medicine can lead to fluctuations in clotting factors and may increase the risk of bleeding and/or clotting.

A side effect called osteonecrosis (bone damage) has been reported in children and adolescents receiving ONCASPAR (higher incidence seen in girls), when taken at the same time as glucocorticoids (e.g. dexamethasone). Glucocorticoids are medicines used to treat many different conditions including severe allergies, asthma, skin problems, and inflammatory diseases.

If you have not told your doctor about any of the above, tell your doctor before you are given ONCASPAR.

If you are the parent of a child being treated with ONCASPAR, tell the doctor if any of the above conditions apply to your child.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

It is important to tell your doctor if you are pregnant or intend to become pregnant, or if you are breastfeeding or intend to breastfeed.

Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

Like most cytotoxic medicines ONCASPAR is not recommended for use during pregnancy. If there is any need to consider this medicine during your pregnancy, your doctor will discuss with you the benefits and risks of using it. Men must also use effective contraception while they or their partners are being treated with ONCASPAR.

Breastfeeding

Do not breastfeed if you are taking this medicine.

The active ingredient in ONCASPAR may pass into breast milk and there is a possibility that your baby may be affected.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and ONCASPAR may interfere with each other. In particular, it is especially important to tell your doctor if you are using any of the following medicines:

immunisation with live vaccines within 3 months of completing your leukaemia treatment. This will increase the risk of severe infections.
other medicines used to treat leukaemia or cancer
medicines which reduce blood clotting such as anticoagulants (e.g. warfarin and heparin), dipyridamol, aspirin and other anti-inflammatory medicines. If used at the same time as ONCASPAR, there is a higher risk of bleeding disorders.
medicines which require cell division for their effect, for example, methotrexate (a medicine used for cancer as well as arthritis treatment) may have a decrease in its effect.
prednisone, a steroid medicine. If used at the same time as ONCASPAR, the effects on the clotting ability of your blood are increased.
Glucocorticoids when used at the same time as ONCASPAR may increase the risk of steroid-induced osteonecrosis (bone damage) in children and adolescents, with a higher incidence seen in girls. Therefore, if you experience any new bone pain (i.e. pain in hip, knee or back), inform your doctor as soon as possible.

ONCASPAR can also cause changes in liver function which can affect how other medicines work.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ONCASPAR.

4. How do I use ONCASPAR?

You should be treated with ONCASPAR by a doctor who is trained in treating patients with leukaemia. Treatment will normally take place in a hospital because of the need for hospital facilities and skilled personnel.

How much is given

ONCASPAR must only be given by healthcare professionals trained in administering anticancer medicines.
Your doctor will decide upon the doses you will receive and how often. This depends on your age, body weight and height.
ONCASPAR may be given in combination with other drugs.

How ONCASPAR is given

ONCASPAR is given by injection into a muscle (intramuscular) or, if not suitable, into a vein (intravenous). Before administration, you might receive a combination of medicines which may include paracetamol, and an antihistamine to help reduce your chances of getting allergic reactions. Your doctor will decide whether such premedication is necessary.
Ask your doctor if you want more information about the dose of ONCASPAR and the other medicines you will be receiving and how they are given while you are being treated with ONCASPAR.

If you use too much ONCASPAR

As ONCASPAR is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience severe side effects after being given this medicine, tell your doctor or nurse immediately.

You may need urgent medical attention.

5. What should I know while using ONCASPAR?

Things you should do

Keep all appointments with your doctor and always discuss with your doctor any problems during or after treatment with ONCASPAR.
Do not start taking any other medicines, prescription or over-the-counter, without first telling your doctor.

Driving or using machines

Do not drive or use machines when using this medicine because it may make you feel drowsy, tired or confused.

Looking after your medicine

It is unlikely that you will be asked to store ONCASPAR yourself. It will usually be stored in the pharmacy or on the hospital/clinic ward.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects

What to do

Gastrointestinal

Inflammation or other disorders of the pancreas (pancreatitis) causing severe stomach pain which may spread to your back
Vomiting

Kidney and liver related

Loss of kidney function (e.g. change in urine output, swelling of feet and ankles)
Problems with your liver (e.g. change in colour of your skin or urine or stool

Respiratory and heart

Chest pain or shortness of breath (which may be a symptom of blood clots in the lungs, called pulmonary embolism)
Fast heartbeat, fast heart rate, breathing difficulty, and weakness

Blood and investigations

Increase in blood sugar levels (hyperglycaemia)
Drop in blood pressure
Decreased number of white blood cells

Musculoskeletal

Bone damage (osteonecrosis)
Leg pain (which could be a symptom of thrombosis)

Nervous system

Headaches, high blood pressure and visual disturbances, which are symptoms of a condition called encephalopathy
Serious allergic reactions that may cause loss of consciousness and could be life-threatening (anaphylactic shock)
Violent shaking (seizures) and loss of consciousness

Skin

Rash, itching, swelling, hives
Severe skin reaction called toxic epidermal necrolysis

General

Very high fever

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

Less serious side effects

What to do

Gastrointestinal

Loss of appetite, feeling sick, being sick, stomach cramps, diarrhoea, general weakness or weight loss
Build-up of fluid in the stomach (ascites)
Cysts in your pancreas

Kidney and liver related

Laboratory results of elevated liver enzymes or bilirubin)
Liver failure, jaundice, blocked bile flow from the liver (cholestasis), destruction of liver cells (liver cell necrosis)

Respiratory and heart

Palpitations

Blood and investigations

Blood clots
Fever with low counts of white blood cells
Severe bleeding or bruising
Decreased number of red blood cells
Decreased number of platelets
High levels of fat and cholesterol in your blood
Low potassium in your blood
Reduced thyroid function which may cause tiredness, weight gain and feeling cold
High levels of urea in your blood
Antibodies against ONCASPAR
High levels of ammonia in your blood
Decreased blood sugar levels
Anaemia
Increased level of calcium in your blood (hypercalcemia)
Abnormally low level of sodium in your blood (hyponatremia)

Musculoskeletal

Back, joint or abdominal pain
Bone damage (osteonecrosis)
Pain or swelling at the injection site

Mouth

Mouth sores
Swollen salivary glands (parotitis)

Nervous system

Changes in EEG (a trace of the electrical activity of your brain)
Mild twitching of the fingers
Sleepiness, confusion
Damage to, or disease affecting nerves (peripheral neuropathy), which may impair sensation, movement, gland or organ function
Encephalopathy, characterised by headache, confusion, seizures and visual loss which resolves after some time
Stroke

General

Severe infection with very high fever
Fever and flu-like symptoms
Dehydration

Speak to your doctor if you have any of these less serious side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Your doctor has information on monitoring for such side effects and their treatment.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

Each vial contains 750 units pegaspargase per 1 mL (3,750 units in 5 mL)

What ONCASPAR contains

Active ingredient (main ingredient)	Pegaspargase powder for solution for injection/infusion
Other ingredients (inactive ingredients)	Sodium dihydrogen phosphate monohydrate Disodium phosphate heptahydrate Sodium chloride Sucrose Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment)

Do not take this medicine if you are allergic to any of these ingredients.

What ONCASPAR looks like

ONCASPAR is a white to off white powder. After reconstitution, the solution is clear, colourless and free from visible foreign particles.

Each pack contains 1 glass vial with 3,750 U pegaspargase.

(Aust R 303807).

Who distributes ONCASPAR

Servier Laboratories (Aust.) Pty. Ltd.
www.servier.com.au
Level 4, Building 9
588A Swan Street
Burnley, 3121, Victoria
Phone: 1800 153 590

This leaflet was prepared in May 2024.

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Oncaspar Powder for Injection

Active ingredient

Pegaspargase

Schedule

1 Name of Medicine

Pegaspargase.

2 Qualitative and Quantitative Composition

Oncaspar (pegaspargase) is a modified version of the enzyme asparaginase. Pegaspargase, the active substance, is a covalent conjugate of Escherichia coli (E. coli) derived asparaginase with monomethoxypolyethylene glycol (mPEG) using a succinimidyl-succinate linker.
L-asparaginase is a tetrameric enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 69 to 82 molecules of mPEG are linked to L-asparaginase; the molecular weight of each mPEG molecule is about 5 kDa. Oncaspar activity is expressed in units. One unit is defined as the quantity of enzyme required to liberate 1 micromol ammonia per minute at pH 7.3 and 37°C.
Each vial contains 3,750 U pegaspargase. After reconstitution, 1 mL of solution contains 750 U pegaspargase (750 U/mL). The potency of this product should not be compared to any other pegylated or non-pegylated protein of the same therapeutic class.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for solution for injection/infusion.

Appearance.

Lyophilised white to off-white powder. After reconstitution, the solution is clear, colourless and free from visible particles. 1 mL of solution contains 750 U pegaspargase.

4 Clinical Particulars

4.1 Therapeutic Indications

Oncaspar is indicated as a component of antineoplastic combination therapy in patients with acute lymphoblastic leukaemia (ALL).

4.2 Dose and Method of Administration

Treatment should be prescribed by physicians and administered by health care personnel experienced in the use of antineoplastic products. The product should only be given in a clinical setting where appropriate resuscitation equipment is available. Patients should be closely monitored and carefully observed for any adverse reactions throughout the administration period (also see Section 4.4 Special Warnings and Precautions for Use). As a routine precautionary measure patients should be monitored for one hour after administration.
Oncaspar does not contain antimicrobial preservative. It is for single use in one patient only. Discard any unused solution.

Recommended premedication.

Premedicate patients with paracetamol, an H-1 receptor blocker (e.g. diphenhydramine), and an H-2 receptor blocker (e.g. famotidine) 30-60 minutes prior to administration of Oncaspar to decrease the risk and severity of both infusion and hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use).

Dosage.

Patients ≤ 21 years of age.

The recommended dose for paediatric patients with a body surface area (BSA) < 0.6 m² and infants < 1 year of age is 82.5 U (equivalent to 0.1 mL)/kg body weight every 14 days.
The recommended dose for paediatric patients with a BSA > 0.6 m² and ≤ 21 years of age is 2,500 U (equivalent to 3.3 mL)/m² BSA every 14 days.

Patients > 21 years of age.

The recommended dose for adult patients > 21 years of age is 2,000 U (equivalent to 2.67 mL)/m² BSA every 14 days.
For patients ≥ 65 years of age, the recommended dose has not been established.
Refer to local clinical practice guidelines (e.g. EviQ) for further details regarding prevention, management (including potential dose adjustments) and monitoring of side effects in patients receiving Oncaspar as part of a multicomponent chemotherapy regimen (also see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

For intramuscular (IM) or intravenous (IV) administration only.
For smaller volumes, the preferred route of administration is IM.

Instructions for reconstitution of the vial of lyophilised powder.

1. Inject 5.2 mL water for injections into the vial using a syringe and 21 gauge needle.
2. Gently swirl the vial until the powder is reconstituted.
3. After reconstitution, the solution should be clear, colourless and free from visible foreign particles. Do not use if the reconstituted solution is cloudy or if a precipitate has formed. Do not shake.
4. The solution should be used as soon as possible following reconstitution. Reconstituted solution must be used within: 6 hours when stored at room temperature; 24 hours when stored at 2-8⁰C.

Dilution of the reconstituted Oncaspar vial prior to administration.

For intravenous infusion, dilute Oncaspar solution with 100 mL sodium chloride 9 mg/mL (0.9%) or 5% dextrose, using sterile/aseptic technique. After dilution, administer immediately into a running infusion of either sodium chloride 9 mg/mL (0.9%) or 5% dextrose, respectively. The dose is usually given over a period of 1-2 hours. Do not infuse other drugs through the same intravenous line during administration of Oncaspar. If storage is necessary, hold at 2-8°C for not more than 24 hours or 6 hours at room temperature (not to exceed 25°C).
For instructions on reconstitution of the lyophilised formulation before administration, see Instructions for use, handling and disposal.

Monitoring of asparaginase levels.

It is recommended to monitor the trough serum asparaginase activity two weeks after administration of Oncaspar. If activity falls below 0.1 U/mL, it may be necessary to switch to another asparaginase preparation (also see Section 4.4 Special Warnings and Precautions for Use, Asparaginase antibodies).

Instructions for use, handling and disposal.

Oncaspar must be handled and administered with care.
Do not administer if the product, before any manipulation:
has been frozen;
has been stored at room temperature (not to exceed 25°C) for more than 48 hours;
has been shaken or vigorously agitated;
has visible foreign matter, or discoloration;
has passed the expiry date.

4.3 Contraindications

Oncaspar is contraindicated in patients with:
history of anaphylactic or severe hypersensitivity reactions to the active substance or to any of the excipients;
history of serious thrombosis during previous asparaginase therapy;
history of pancreatitis including pancreatitis related to previous asparaginase therapy;
history of serious haemorrhagic events during previous asparaginase therapy;
history of severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

It is strongly recommended that every time Oncaspar is administered to a patient, the name and lot number of the product are recorded in order to link the patient and the lot of the product.

Anaphylaxis and serious hypersensitivity reactions.

Hypersensitivity reactions including life-threatening anaphylaxis, have been observed with Oncaspar, particularly in patients with known hypersensitivity to E. coli derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus, and rash.
Premedicate patients 30-60 minutes prior to administration of Oncaspar (see Section 4.2 Dose and Method of Administration).
Because of the risk of allergic reactions Oncaspar administration should be performed under medical observation. Monitor patients for one hour after administration of Oncaspar in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines).
Discontinue Oncaspar in patients with serious hypersensitivity reactions. Adequate medical treatment and provisions should be available for immediate use in the event of an anaphylactic reaction.

Pancreatic toxicities.

Pancreatitis.

Pancreatitis has been reported in patients receiving Oncaspar. Haemorrhagic or necrotising pancreatitis with fatal outcomes has been reported.
There is an increased risk of pancreatitis in patients > 10 years of age, with doses greater than the recommended dose, and in the presence of other components of the backbone therapy (such as anthracycline agents, cytarabine and cyclophosphamide).
If pancreatitis is suspected, Oncaspar should be discontinued; if pancreatitis is confirmed, Oncaspar should not be restarted.
Patients should be informed of the signs and symptoms of pancreatitis, which if left untreated, could be fatal. This includes persistent abdominal pain which can be severe and may radiate to the back.
Serum amylase and/or lipase measurements should be performed frequently to identify early signs of pancreatic inflammation.
If treatment is terminated due to pancreatitis, appropriate investigations (e.g. ultrasound) should be performed at least four months following termination of therapy. As the precise pathogenesis is unknown, only supportive measures can be recommended. Disturbances of exocrine pancreatic function can result in diarrhoea.

Hyperglycaemia.

As hyperglycaemia may occur with the use of Oncaspar, blood and urine glucose levels should be monitored.
As impaired glucose tolerance may occur with concomitant use of Oncaspar with prednisone, blood glucose levels should be monitored.

Coagulopathy.

Serious thrombotic events, including sagittal sinus thrombosis may occur in patients receiving Oncaspar. Oncaspar should be discontinued in patients experiencing serious thrombotic events.
In the presence of corticosteroids, osteonecrosis (avascular necrosis) is a possible complication of hypercoagulability observed in children > 10 years of age with a higher incidence seen in girls (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
Increased prothrombin time (PT), increased partial thromboplastin time (PTT), hypofibrinogenemia and antithrombin III decrease may occur in patients receiving Oncaspar. A baseline coagulation profile should be established and then periodically monitored during and after treatment; particularly when other medicinal products with coagulation inhibiting pro-coagulant/anticoagulant effects such as, methotrexate, daunorubicin, corticosteroids, acetylsalicylic acid, and non-steroidal anti-inflammatory medicinal products are used concomitantly (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When there is a marked decrease in fibrinogen or Antithrombin III (ATIII) deficiency, consider appropriate replacement therapy.

Osteonecrosis.

In the presence of glucocorticoids, osteonecrosis (avascular necrosis) is a possible complication of hypercoagulability observed in children and adolescents with a higher incidence seen in girls (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, close monitoring in children and adolescents is recommended in order to detect any clinical signs/symptoms of osteonecrosis. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment as per standard guidelines of treatment of ALL and supportive care principles.

Hepatic toxicities.

Administration of Oncaspar with hepatotoxic products can result in severe hepatic toxicity. Caution is required when Oncaspar is given in combination with hepatotoxic products. Monitor the patient for changes in liver function parameters.
There may be an increased risk of hepatotoxicity in Philadelphia chromosome positive patients for whom treatment with kinase inhibitors (e.g. imatinib) is combined with asparaginase therapy. There is also an increased risk of hepatic effects (such as increase in transaminases, bilirubin increased, hypofibrinogenemia) among patients > 18 years of age. This should be taken into account when considering the use of Oncaspar in this patient population.
Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a rare, life-threatening hepatic condition that can be associated with high-dose chemotherapy.
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of hepatic VOD, have been observed in patients treated with Oncaspar in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy (see Section 4.8 Adverse Effects (Undesirable Effects)).
Signs and symptoms of VOD include rapid weight gain, fluid retention with ascites, hepatomegaly, thrombocytopenia and rapid increase of bilirubin. The identification of risk factors like pre-existing liver disease or history of VOD is essential for its prevention. Prompt recognition and appropriate management of VOD is imperative. Patients who experience this condition should be treated according to standard medical practice.
Due to the risk of hyperbilirubinemia, it is recommended to monitor bilirubin levels at baseline and prior to each dose.

Central nervous system toxicities.

Combination therapy with Oncaspar can result in central nervous system toxicity. Cases of encephalopathy (including reversible posterior leukoencephalopathy syndrome) have been reported. If Oncaspar is used in association with neurotoxic therapies (such as vincristine and methotrexate), the patient should be closely monitored.
Oncaspar may cause central nervous system symptoms manifesting as seizures, confusion, and somnolence.

Myelosuppression.

Oncaspar causes myelosuppression, either directly or indirectly (by altering myelosuppressive effects of other agents such as methotrexate or 6-mercaptopurine). Therefore, use of Oncaspar could increase the risk of infections in patients.
The peripheral blood count and the patient's bone marrow should be monitored closely. Dose reductions of concurrently administered myelosuppressive agents may be considered.

Asparaginase antibodies.

Similar to other protein-based products, anti-drug antibodies can develop with the administration of Oncaspar (see Section 4.8 Adverse Effects (Undesirable Effects)). The appearance of anti-asparaginase antibodies may be associated with low asparaginase activity levels. As a precaution, measurement of the asparaginase activity level in serum or plasma is recommended. In cases of accelerated reduction of asparaginase activity, switching to an asparaginase preparation derived from another bacterial source may be considered.

Hyperammonaemia.

Asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid and glutamic acid, with ammonia as the shared by-product of both reactions. Intravenous administration of asparaginase may therefore cause serum levels of ammonia to rise sharply following administration.
The symptoms of hyperammonaemia are often transient in nature and can include nausea, vomiting, headache, dizziness and rash. In severe cases, encephalopathy can develop with or without hepatic impairment, especially in older adults, which can be life-threatening or fatal. If symptoms of hyperammonaemia exist (e.g. nausea, vomiting, lethargy, irritation), ammonia levels should be monitored closely.

Use in the elderly (age > 65).

There is limited data available for patients older than 65 years.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects on protein-bound drugs.

The decrease in serum proteins caused by Oncaspar can increase the toxicity of other medicinal products that are protein-bound.

Effects on use with other chemotherapeutic agents.

Immediately preceding or concomitant treatment with vincristine can increase the toxicity of Oncaspar and increases the risk of anaphylactic reactions. Therefore, vincristine should be given in a timely manner before administration of Oncaspar in order to minimise toxicity.
Oncaspar may affect the action of other chemotherapeutic agents requiring cell division for their effect (i.e. methotrexate, cytarabine). This effect can be either synergistic or antagonistic, depending on the timing of administration of the agents. Adherence to the treatment schedule is therefore recommended to minimise these potential interactions.

Effects on metabolism and clearance of other drugs.

Oncaspar has the potential to interfere with metabolism and clearance of other medicinal products, based on its effects on protein synthesis and hepatic function, as well as from its combined use with other chemotherapeutic drugs known to interact with CYP enzymes.
Asparaginase may increase the risk of glucocorticoid-induced osteonecrosis in children > 10 years of age, with a higher incidence seen in girls (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Coagulation effects.

The use of Oncaspar can lead to fluctuating levels of coagulation factors. This could increase the risk of bleeding and/or thrombosis. Caution is needed when anticoagulants such as: coumarin, heparin, dipyridamole, acetylsalicylic acid or nonsteroidal anti-inflammatory drugs are given concomitantly.
Alterations in coagulation parameters (e.g. fall in fibrinogen and ATIII deficiency) can be more pronounced when glucocorticoids, such as prednisone and Oncaspar are given concomitantly.
Pegaspargase may increase the risk of glucocorticoid-induced osteonecrosis in children and adolescents when both treatments are given simultaneously, with a higher incidence seen in girls, through a potential increase in exposure of dexamethasone (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Oral contraceptive effects.

An indirect interaction cannot be ruled out between Oncaspar and oral contraceptives; due to pegaspargase hepatotoxicity that may impair the hepatic clearance of oral contraceptives.
Therefore, the combination of Oncaspar and oral contraceptives is not recommended. A method other than oral contraception should be used in women of childbearing potential (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effects on live vaccines.

Simultaneous vaccination of live vaccines with Oncaspar may increase the risk of severe infections attributable to the patient's underlying disease and the usually combined chemotherapy. Vaccination with live vaccines should only be given after consultation with the treating oncologist. The timing of vaccination after chemotherapy may be dependent on the anti-leukaemic agents used; and might be administered at the earliest, three to six months after the termination of the entire anti-leukaemic treatment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of pegaspargase on fertility have not been established.
Men and women of childbearing potential should use effective contraception during treatment and for at least 6 months after Oncaspar discontinuation. Since an indirect interaction between components of the oral contraception and pegaspargase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical situation. A method other than oral contraceptives should be used in women of childbearing potential (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
(Category D)
There are no adequate data from the use of Oncaspar and limited data from the use of asparaginase in pregnant women.
No studies of reproductive toxicity were conducted with pegaspargase. Embryotoxicity studies with native L-asparaginase have given evidence of teratogenicity in rats treated from day 6 to 15 of gestation with a no observed effect level (NOEL) for teratogenic effects at 300 U/kg IV. In rabbits doses of 50 or 100 U/kg IV (600 or 1200 U/m²) on days 8 and 9 of gestation induced congenital malformations in viable foetuses; no NOEL has been determined. Multiple malformations and embryolethal effects were observed with doses in the therapeutic range. Investigations of the effect on fertility and peri- and postnatal development were not conducted.
Due to teratogenicity shown in animal studies with native L-asparaginase, Oncaspar should not be used during pregnancy.
It is not known whether pegaspargase is excreted into breast milk. Potential risk to newborns/infants breast feeding cannot be excluded. Therefore, as a precautionary measure, breast feeding should be discontinued during treatment with Oncaspar and not resumed until after treatment with Oncaspar has ceased.

4.7 Effects on Ability to Drive and Use Machines

The following adverse reactions have been reported in patients treated with Oncaspar along with other chemotherapeutic agents: somnolence, confusion, dizziness, syncope, seizure. Patients should not drive or operate machinery while receiving Oncaspar if they experience these or other CNS-related events (see Section 4.4 Special Warnings and Precautions for Use).

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).
The adverse reactions described in this section are gathered from a combination of adverse reactions from clinical trial data and post-marketing experience with Oncaspar in ALL patients.
The safety profile for Oncaspar is based on randomised, controlled, prospective, open label, multicenter studies using Oncaspar at a dose of 2500 U/m² administered intravenously (IV) as a first line treatment of ALL during the Induction phase (studies DFCI 001-011 and AALL07P4) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In addition, the safety profile includes data from other, Oncaspar pharmacokinetic studies using the intramuscular (IM) route of administration (studies CCG-1962 (see Section 5.1 Pharmacodynamic Properties, Clinical trials) and CCG-1991), as well as other post-marketing studies from the literature were also considered to determine the safety profile.
Study CCG-1991 was a randomised, multifactorial design study in which 2,957 subjects aged 1 to < 10 years with newly diagnosed standard risk ALL were administered Oncaspar 2,500 U/m² as a component of various multi-agent chemotherapy regimens using the IM route of administration.
The most common adverse reactions with Oncaspar (observed in at least 2 studies with a frequency of > 10%) included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, hypofibrinogenemia, activated partial thromboplastin time prolonged, hypertriglyceridemia, hyperglycaemia, febrile neutropenia.
The most severe adverse reactions with Oncaspar (Graded 3 or 4) consistently reported in all studies and observed in studies DFCI 11-001 and AALL07P4 with a frequency of > 5% included: anaphylactic reaction, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, hypoalbuminemia, febrile neutropenia, blood fibrinogen decreased, hyperglycaemia, lipase increased, pancreatitis, hypoglycaemia, embolism, activated partial thromboplastin time prolonged, hypersensitivity.
Adverse reactions that were reported in studies DFCI 11-001 and AALL07P4 are presented in Table 1.

Study CCG-1962, was a multi-centre randomised study of Oncaspar compared with native E. coli asparaginase as part of antineoplastic combination therapy in children aged 1 through 9 years with newly diagnosed untreated standard-risk acute lymphoblastic leukaemia. Detailed safety information was collected for pre-specified adverse reactions identified as asparaginase-induced adverse reactions and for Grade 3 and 4 non-haematologic adverse reactions according to the Children's Cancer Group (CCG) Toxicity and Complication Criteria. The per-patient incidence for these selected adverse reactions occurring at a severity of Grade 3 or 4 is presented in Table 2.

Table 3 describes adverse reactions reported with Oncaspar in the clinical program and during post-marketing experience. The frequency of side effects is defined by the following convention: very common (≥ 1/10), common (≥ 1/100 to ≤ 1/10), uncommon (≥ 1/1,000 to ≤ 1/100), rare (≥ 1/10,000 to ≤ 1/1,000), very rare (≤ 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions.

The following adverse reactions have been observed in association with asparaginase therapy. Although they have not been specifically associated with the use of pegaspargase, they may occur with the use of Oncaspar.

Blood and lymphatic system disorders.

Oncaspar can cause mild to moderate myelosuppression, and all three blood cell lines can be affected.
About half of all serious haemorrhages and thromboses affect cerebral vessels and can lead to stroke, seizures, headache or loss of consciousness. Oncaspar may also cause: neutrophil count decreased and platelet count decreased.

Gastrointestinal disorders.

About half of patients develop mild to moderate gastrointestinal reactions such as loss of appetite, nausea, vomiting, abdominal cramps, diarrhoea and weight loss.
Acute pancreatitis can occur commonly. There have been isolated reports of formation of pseudocysts (up to four months after the last treatment).
Haemorrhagic or necrotising pancreatitis occurs rarely. One case of pancreatitis with simultaneous acute parotitis has been described with asparaginase treatment. In single cases, haemorrhagic or necrotising pancreatitis with fatal outcome has been reported.
Serum amylase can rise during and also after the conclusion of Oncaspar therapy.
Oncaspar may also cause: dehydration, and hepatic failure.

General disorders and administration side conditions.

Pyrexia can occur after the injection, which usually subsides spontaneously. Oncaspar may also cause fatigue, and pain.

Hepatobiliary disorders.

Alteration of liver parameters is very common. A dose independent rise in serum transaminases and serum bilirubin is commonly observed.
Rapid weight gain, fluid retention with ascites, hepatomegaly, associated with rapid increase of serum bilirubin and persistent thrombocytopenia might indicate a risk of developing severe VOD, which if left untreated, can be fatal (see Section 4.4 Special Warnings and Precautions for Use).
Fatty liver can be observed very frequently. There have been rare reports of hepatic cell necrosis, cholestasis, icterus and hepatic failure with fatal outcome.
Impaired protein synthesis can lead to a decline in the serum proteins. There is a dose independent decrease in serum albumin in the majority of patients during the treatment.
The type of side effects of Oncaspar largely coincides with that of native non pegylated asparaginase (e.g. native E. coli asparaginase).

Immune system disorders.

Specific antibodies to pegaspargase have been measured. Neutralising antibodies reducing clinical efficacy were also observed. Oncaspar may also cause anaphylactic shock.
Hypersensitivity reactions to Oncaspar, including: life-threatening anaphylaxis, angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus and rash, can occur during therapy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

An alteration in serum lipid levels was observed and changes in serum lipid values, in most cases without clinical symptoms, are very common.
A rise in serum urea occurs regularly, is dose independent and nearly always a sign of pre-renal metabolic imbalance.

Nervous system disorders.

Oncaspar may cause central nervous system dysfunctions manifesting as convulsion, and less frequently confusional state and somnolence (mildly impaired consciousness).
In rare cases, a reversible posterior leukoencephalopathy syndrome (RPLS) may occur.
In very rare cases, mild tremor in the fingers has been described.

Renal and urinary disorders.

Acute renal failure may develop in rare cases during treatment with asparaginase containing regimens.

Skin and subcutaneous tissue disorders.

Allergic reactions can manifest in the skin. One case of toxic epidermal necrolysis (Lyell's syndrome) has been described in association with asparaginase.

Vascular disorders.

Oncaspar may cause haemorrhage, and superior sagittal sinus thrombosis.

Endocrine disorders.

Alterations in endocrine pancreatic function are observed commonly and are expressed mainly in the form of abnormal glucose metabolism. Both diabetic ketoacidosis and hyperosmolar hyperglycaemia have been described, which generally respond to administration of exogenous insulin.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia) or 0800 764 766 [0800 POISON] (New Zealand).
There have been a few cases of accidental overdose have been reported with Oncaspar. Following overdose, increased liver enzymes, rash and hyperbilirubinaemia have been observed. There is no specific pharmacological treatment. In case of overdose, patients must be carefully monitored for signs and symptoms of adverse reactions, and appropriately managed with symptomatic and supportive treatment.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacodynamics.

Pharmacodynamic effect of Oncaspar was evaluated in two studies, Study CCG-1962 and Study AALL07P4.
In Study CCG-1962, pharmacodynamics were assessed in 57 newly diagnosed paediatric patients with standard-risk Acute Lymphoblastic Leukaemia (ALL) who received three intramuscular (IM) doses of Oncaspar (2,500 U/m²), one each during induction and two delayed intensification treatment phases (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
A reduction in serum asparagine concentration was evident by the 4th day after the first Induction dose and reached an apparent nadir by the 10th day after the dose. Low concentrations of approximately 1 microM persisted for approximately 3 weeks. An apparent trend was observed where asparagine concentration fell to < 3 microM when asparaginase activity was > 0.1 U/mL. Cerebrospinal fluid (CSF) asparagine fell from pre-treatment concentrations of 2.3 microM to 1.1 microM on Day 7 and 0.6 microM on Day 28 of induction. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in clinical trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The pharmacodynamic effect of Oncaspar was also assessed in 47 evaluable subjects with high risk B-precursor ALL (Study AALL07P4) who received IV doses of Oncaspar 2,500 U/m² during the induction and consolidation phases (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Within 24 hours following the induction and first consolidation dose, Oncaspar depleted plasma L-asparagine concentrations to below the assay limit of quantification. Depletion was sustained for approximately two weeks. Following the induction dose, CSF asparagine concentrations were reduced by the 4th day and remained largely undetectable by Day 18 after dosing. These results demonstrate that a 2,500 U/m² dose of Oncaspar provides maintenance of L-asparagine depletion for approximately two weeks following dosing.

Mechanism of action.

Pegaspargase is a PEGylated form of the enzyme L-asparaginase which catalyses the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The PEGylation does not change the enzymatic properties of the asparaginase, but it influences the pharmacokinetics and immunogenicity of the enzyme. The mechanism of action of pegaspargase is thought to be based on selective destruction of leukaemic cells due to depletion of plasma L-asparagine.
Leukaemic cells with low expression of asparagine synthetase have a reduced ability to synthesise L-asparagine and therefore depend on an extracellular source of asparagine for protein synthesis and survival. Normal cells, however, due to their ability to synthesise L-asparagine, are less affected by the depletion of plasma L-asparagine.

Clinical trials.

The efficacy of Oncaspar was evaluated based upon three clinical studies using Oncaspar solution for injection/infusion in the first line treatment of ALL in both standard and high risk patients: Study CCG-1962, Study AALL07P4, and Study DFCI 11-001.
For the relapse/refractory haematological diseases, Oncaspar efficacy was based on pooled data from 94 ALL patients with a history of prior clinical allergic reactions to native E. coli asparaginase, from six open-label studies.
Clinical studies in first line (non-hypersensitive population) in ALL.

Study CCG-1962.

The safety and effectiveness of Oncaspar was evaluated in an open-label, multicentre, randomised, active-controlled study (Study CCG-1962). In this study, 118 paediatric patients aged 1 to 9 years with previously untreated standard-risk ALL were randomised 1:1 to Oncaspar or native E. coli asparaginase as part of combination therapy. Oncaspar was administered IM at a dose of 2,500 U/m² on Day 3 of the 4 week induction phase and on Day 3 of each of two 8-week delayed intensification phases. Native E. coli asparaginase was administered IM at a dose of 6,000 U/m² three times weekly for 9 doses during induction and for 6 doses during each delayed intensification phase.
One determination of effectiveness was based on demonstration of similar asparagine depletion (magnitude and duration) in the Oncaspar and native E. coli asparaginase treatment groups. The protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤ 1 microM. The proportion of patients with this level of depletion was similar between the two study arms during all 3 phases of treatment at the protocol-specified time points.
In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of asparaginase in the treatment phase and remained low for approximately 3 weeks for both Oncaspar and native E. coli asparaginase groups. Serum asparagine concentrations during the induction phase are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification phases are similar to the pattern of serum asparagine depletion in the induction phase.

Note.

Oncaspar (2,500 U/m² IM) was administered on Day 3 of the 4-week induction phase. Native E. coli asparaginase (6,000 U/m² IM) was administered 3 times weekly for 9 doses during induction.
CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF asparagine decreased from a mean pre-treatment concentration of 3.93 microM to 1.53 microM on Day 5 and 0.55 microM at 26 days after administration of Oncaspar. These findings were similar to those observed in the native E. coli asparaginase treatment arm.
Event-free survival (EFS) for the Oncaspar and native E. coli asparaginase arms are summarised in Table 4 Study CCG-1962 was not designed to evaluate for differences in EFS rates.

Study AALL07P4.

This was a pilot study conducted by the Children's Oncology Group (COG) in newly diagnosed patients 1 to < 31 years of age with National Cancer Institute (NCI) high risk B-precursor ALL. This was an open label, controlled, randomised study comparing an investigational pegylated asparaginase versus Oncaspar in the first line treatment of ALL.
White blood cell (WBC) criteria were: (a) Age 1.000-9.999 years: WBC ≥ 50,000/micro litre; (b) Age 10.000-30.999 years: Any WBC; (c) Prior steroid therapy: any WBC. Patients were not allowed prior cytotoxic chemotherapy with the exception of steroids and intrathecal cytarabine.
A total of 166 patients were randomised, 163 of whom were treated with the study drug; of these, 54 patients were treated with Oncaspar 2500 U/m². Oncaspar was administered IV during induction/extended induction, consolidation, delayed intensification and interim maintenance phases of an augmented Berlin-Frankfurt-Münster (aBFM) treatment regimen.
The primary objective of the study was to determine the pharmacokinetic comparability of the investigational pegylated asparaginase versus Oncaspar when given intravenously during induction and consolidation. Efficacy outcomes collected for both treatment arms included Minimal Residual Disease (MRD) at Day 29 of induction, EFS and OS rates.
In the full analysis set, the percentage of patients in the Oncaspar treatment arm with evaluable MRD negative status (< 0.1% leukaemia cells in bone marrow) at Day 29 of induction was 80% (40/50). At 4 years, the EFS and overall survival (OS) for the Oncaspar treatment arm were, 81.8% [95% CI: 62.9, 91.7] and 90.4% [95% CI: 78.5, 95.9], respectively.

Study DFCI 011-001.

Study DFCI 011-001, conducted by the Dana-Farber Cancer Institute (DFCI), is an ongoing, active-controlled, randomised, multicenter study of an intravenous investigational pegylated asparaginase versus intravenous Oncaspar, in children and adolescents aged 1 to < 22 years with newly diagnosed ALL treated with a DFCI ALL consortium therapeutic backbone.
A total of 239 patients were randomised, 237 of whom were treated with study drug (146 male/91 female); of these, 119 patients (115 with a diagnosis of ALL) were treated with Oncaspar 2,500 U/m². Treatment was administered during induction (Day 7), and then every 2 weeks for a total of 30 weeks post-induction therapy. Randomisation of patients was stratified based on risk group (standard/high/very high risk), including both B- and T-cell ALL.
The primary objective of the study was to assess the safety and feasibility of administering the investigational pegylated asparaginase compared with Oncaspar, when administered intravenously as a single dose during induction and every 3 weeks for 30 weeks post-induction therapy. Efficacy outcomes collected for both treatment arms included rates.
In the full analysis set, the percentage of patients in the Oncaspar arm with evaluable Low End-Induction MRD (< 0.001 detectable disease by PCR) at Day 32 was 87.9% (80/91). The one-year EFS was 98.0% [95% CI: 92.3, 99.5]; the one-year OS was 100 [95% CI: 100, 100] in this study.
ALL patients with hypersensitivity to native E. coli asparaginase. Six open-label studies evaluated Oncaspar in relapse/refractory haematological diseases. In these studies, a total of 94 patients with ALL and a history of prior clinical allergic reactions to native E. coli asparaginase were exposed to Oncaspar. One patient received Oncaspar doses of 250 and 500 U/m² IV. The remaining patients were treated with 2000 or 2500 U/m² administered IM or IV. Patients received Oncaspar as a single agent or in combination with multi-agent chemotherapy.
Using the highest therapeutic response from 65 patients with ALL (from 5 studies) treated with Oncaspar, complete remission was observed in 30 patients (46%), partial remission in 7 patients (11%) and haematological improvement in 1 patient (2%). In contrast, in the other study, 29 patients with ALL were treated with Oncaspar; 11 patients were evaluated for response during induction. Of these, 3 patients achieved complete remission (27%), 1 patient had partial remission (9%), 1 patient had haematologic improvement (9%) and 2 patients had therapeutic efficacy (18%). Therapeutic efficacy was defined as a clinical improvement which did not meet the criteria for other beneficial outcomes. During the maintenance phase, 19 patients were evaluated, with 17 patients achieving complete remission (89%), and 1 patient with therapeutic efficacy (5%).

5.2 Pharmacokinetic Properties

Pharmacokinetic assessments of Oncaspar were based on an enzymatic assay measuring asparaginase activity after IM (CCG-1962) and IV (AALL07P4, DFCI 11-001) administration.
In Study CCG-1962, mean asparaginase activity peaked on Day 5 after the injection and averaged 1 U/mL. The mean half-life of absorption from the injection site was 1.7 days and the elimination half-life was 5.5 days. The volume of distribution at steady-state and clearance were estimated at 1.86 L/m² and 0.169 L/m² per day, respectively.
In Study AALL07P4, PK parameters after a single 2,500 U/m² IV dose during Induction were calculated by noncompartmental PK analysis from sequential plasma asparaginase activity samples and are depicted in Table 5 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The C_max and AUC of Oncaspar trended lower in males, subjects with larger BMI, and older age subjects (> 10 years). During Induction, following a single IV dose of Oncaspar 2,500 U/m², asparaginase activity ≥ 0.1 U/mL was sustained for up to 18 days post-dose in 95.3% of subjects.
In Study DFCI 11-001, assessments of asparaginase activity were performed following a single IV dose of Oncaspar 2,500 U/m² during induction, and every two weeks during post-induction (see Section 5.1 Pharmacodynamic Properties, Clinical trials). During induction, plasma asparaginase activity ≥ 0.1 U/mL was sustained in 93.5% of subjects 18 days after administration. During the post-induction phase, a nadir (trough) asparaginase activity above 0.4 U/mL was sustained in 100% of subjects from Week 7 up until Week 25. These results indicate that, when Oncaspar 2,500 U/m² is administered as single and repeated doses every two weeks, clinically relevant asparaginase activity is sustained over the entire dosing interval (i.e. two weeks).

Pharmacokinetics in special patient groups.

The controlled studies were not designed to formally evaluate the pharmacokinetics of Oncaspar in specific populations. A population pharmacokinetic evaluation of Oncaspar based on data obtained from Studies AALLP074 (IV), DFCI 11-001 (IV), and CCG-1962 (IM) identified that clearance (linear and saturable) increased approximately proportional to BSA and volume of distribution increased slightly more proportional to BSA. No statistically significant differences in PK characteristics between male and female subjects were identified in this analysis.

Renal impairment.

The impact of renal impairment on the PK of Oncaspar has not been evaluated. As pegaspargase is a protein with a high molecular weight, it is not excreted renally and no change in the pharmacokinetics of Oncaspar in patients with renal impairment is expected.

Hepatic impairment.

Oncaspar is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).

Use in elderly.

Data are minimal for the use of Oncaspar in elderly patients.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity of pegaspargase was not adequately investigated, but pegaspargase is not expected to be genotoxic.

Carcinogenicity.

Long-term investigations of carcinogenicity in animals were not conducted with pegaspargase.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate, sodium chloride, sucrose, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment).

6.2 Incompatibilities

This medicine must not be mixed with other medicines except those mentioned, see Section 4.2 Dose and Method of Administration. For interactions, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Oncaspar must be stored under refrigerated conditions (2° to 8°C).
Do not freeze.

6.5 Nature and Contents of Container

Container type.

Oncaspar lyophilised formulation is available in 5 mL Type I glass vials with a rubber stopper (chlorobutyl) and an aluminium seal with flip-off cap.

Pack size.

1 vial.

6.6 Special Precautions for Disposal

Oncaspar is for single use only. Any unused solution or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

CAS number.

130167-69-0.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

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