ERWINASE 10,000 IU POWDER FOR INJECTABLE SOLUTION AND FOR PERFUSION

2. What you need to know before you take Erwinase

Do not take Erwinase:

• If you have had a severe allergic reaction (hypersensitivity) to the active substance (crisantaspase) or if you are allergic to any of the other ingredients of this medicine. You can find these substances in section 6.
• If you have severe liver failure.
• If you have had severe pancreas problems (acute pancreatitis) caused by a medicine containing L-asparaginase.
• If you have pancreatitis not related to L-asparaginase.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start taking this medicine.

• This medicine should only be used by doctors who are specialized in this type of treatment.
• Severe, potentially life-threatening allergic reactions have been reported. If you experience a reaction to the treatment, the hospital will need special medicines and equipment to treat you.
• It is possible that your body may be sensitive to the active substance after repeated treatment.
• If you experience abdominal pain, it may be a symptom of pancreatitis (inflammation of the pancreas) and you should inform your doctor immediately. Pancreatitis can be life-threatening.
• You may have too much sugar in your blood (hyperglycemia) during treatment. This can be treated with insulin.
• During treatment, your body may be less able to prevent severe bleeding. If you experience severe bleeding, treatment will be stopped. Your doctor will decide whether to restart treatment and when.
• The use of this medicine may cause or worsen reduced liver function. Your doctor will consider stopping treatment in case of a severe reaction. Treatment may be resumed under strict observation, but only when you have recovered sufficiently.
• If your doctor or nurse spills this medicine on you or on themselves, especially in the eyes, that part of the body should be washed with plenty of water for 15 minutes.
• Neurological disorders (disorders of the nervous system) with a fatal outcome have been reported. The syndrome of posterior reversible encephalopathy (characterized by headache, confusion, convulsions, and loss of vision) may require treatment with medicines to lower blood pressure and, in the case of convulsions, the use of antiepileptics.
• The destruction of cancer cells produces high levels of uric acid (a residual substance) in the blood. This can reduce kidney function.
• A weakening of the immune system has been observed during treatment with this medicine. This can make you more susceptible to infection.

Blood and urine tests

During treatment, your doctor will perform regular blood and urine tests to detect possible side effects, such as:

• Allergic reactions
• If the pancreas, kidneys, and liver are working properly.
• If you have enough blood cells.

For reasons of traceability, the healthcare professional will record the name of the product and the batch number of each dose of Erwinase you receive.

Other medicines and Erwinase

• Since Erwinase can affect liver function and the level of enzymes and proteins in the blood, it may alter the functioning of medicines that are sensitive to these.
• If Erwinase is used with other chemotherapy medicines (cancer treatment medicines), it may increase the activity or damage caused by these medicines. This applies especially to the following chemotherapy medicines: methotrexate, cytarabine, vincristine, imatinib, and prednisone (a corticosteroid).
• Sometimes, allopurinol, a medicine for gout (a painful rheumatic inflammation), may need to be administered to protect the kidneys.

Erwinase should not be mixed with other medicines before administration.

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

• If you are pregnant, you should not use this medicine unless it is absolutely necessary. Inform your doctor immediately if you are pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future.
• You should not breastfeed during treatment with this medicine.

Fertility and family planning

A negative impact on male fertility cannot be ruled out.

If appropriate, both men and women should use contraceptive methods before and during treatment with Erwinase and for some time after treatment.

Driving and using machines

When driving and using machines, you should be aware of the reduction in reaction time, nausea, and vomiting.

Erwinase contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per dose; it is essentially "sodium-free".

3. How to use Erwinase

Dosage

Your doctor will calculate your body surface area in square meters (m²) and use it to determine the dose you should receive.

Normally, your doctor will treat you with 25,000 U of Erwinase per square meter.

The amount you receive may change and will depend on the amount of asparaginase (the active substance of this medicine) in the blood, which can be checked during treatment.

Method of administration

This medicine will be administered in one of the following ways:

• Into a vein by infusion (intravenously).

• Into a muscle by injection (intramuscularly).

This medicine should be administered by your doctor or nurse by injection or infusion. Before injection or infusion, the powder is dissolved very precisely (in saline solution).

Normally, treatment is given without interruption. If treatment needs to be stopped, it may be restarted at a lower dose.

Duration of treatment

You will receive an injection three times a week for two weeks. This may change, depending on new results from clinical studies.

If you have received more Erwinase than you should

If you think you have received more Erwinase than you should, contact your doctor or another healthcare professional immediately.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medicine and the amount ingested.

If you have not received this medicine

If you think you have not received a dose, contact your doctor or another healthcare professional immediately.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The side effects listed below have been observed when this medicine was administered together with other cancer treatment.

This medicine will be administered under strict medical supervision, and your doctor may prescribe other medicines to treat these side effects. Most side effects will disappear once you stop taking this medicine.

See a doctor immediatelyif you experience any of the following side effects:

• Blue-colored lips, arms, or legs (possible symptom of hypoxia: very little oxygen in the blood), redness or inflammation of the skin, increased or decreased blood pressure, swelling of the face, lips, and/or throat, shortness of breath, increased heart rate, wheezing, difficulty swallowing, runny nose, rash, chills, flushing of the skin, difficulty breathing, vomiting, malaise (fatigue) or pale skin. Repeated treatment increases the risk of reaction. Redness, pain, swelling, bruising, or hardening at the injection site.
• Symptoms may include: coma, encephalopathy (brain disease), seeing, hearing, or feeling things that do not exist (hallucinations), muscle weakness, decreased level of consciousness, confusion, dizziness, drowsiness, fatigue, restlessness, difficulty speaking, often as a consequence of other side effects.
• This medicine may increase the risk of blood clots, which can block important blood vessels in the brain, lungs, or legs (symptoms of blood clots in the arms or legs may be accompanied by swelling). If you experience chest pain that spreads to your arms, neck, jaw, back, or stomach, feel sweaty, and are short of breath, these may be symptoms of a heart attack (myocardial infarction).
• Bleeding more frequently and having bruises, even if you have not injured yourself.
• If you have symptoms of severe pancreatitis (inflammation of the pancreas), such as severe abdominal pain with nausea and diarrhea, it is necessary to interrupt treatment and not restart it later.
• High blood sugar levels (hyperglycemia);
• Change in liver function (demonstrated by laboratory tests)

The following are other side effects that have been observed with this medicine, listed in order of frequency:

Contact your doctor immediately if you experience any of the following side effects:

Very common (affects more than 1 in 10 people)

• Generalized infection or septic shock (shock due to infection, especially potentially life-threatening shock) and other infections
• Low blood cell count (especially platelets, white blood cells, and red blood cells). Some may be due to decreased bone marrow activity.
• Increased concentration of fats, bilirubin (a residual substance produced in the blood when red blood cells stop working), and certain digestive enzymes in the blood (your doctor will monitor this)
• Weight loss
• Pain all over the body, especially muscle and joint pain
• Nausea

Common (affects less than 1 in 10 people)

• Diarrhea
• Mucositis (inflammation of the digestive tract)
• Stomach pain or discomfort
• Fever
• Fatigue
• Headache

Uncommon (affects less than 1 in 100 people)

• Complications of diabetes (high blood sugar levels)
• Increased level of ammonia in the blood
• Seizures
• Fatty liver
• Reduced kidney function

Rare (affects less than 1 in 1,000 people)

• Posterior reversible encephalopathy syndrome (a condition characterized by headache, confusion, convulsions, and loss of vision)
• Liver failure

Very rare (affects less than 1 in 10,000 people)

• A painful joint disorder known as reactive arthritis

Frequency not known (cannot be estimated from the available data)

• Loss of appetite (anorexia)
• Inflammation of the salivary glands in the back of the throat
• Decreased levels of albumin (a protein) in the blood, which can cause fluid retention.
• Blistering and peeling of the skin (toxic epidermal necrolysis)
• Muscle pain
• Kidney disorders with abnormal urine test results (high levels of protein)

Generally, side effects are reversible (they disappear once you stop taking the medicine).

Other side effects in children and young adults

Side effects affecting the liver, pancreas, and blood clotting are more frequent in adults than in children and young adults.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report them directly through the national reporting system, Spanish Medicines Monitoring System for Human Use: www.notificaRAM.es.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of this medicine

Keep this medicine out of the sight and reach of children.

The hospital will store this medicine in a refrigerator (between 2°C and 8°C) and it should not be used after the expiry date, which is stated on the packaging after "EXP". The expiry date is the last day of the month stated.

6. Container Contents and Additional Information

Composition of this Medication

• The active ingredient of this medication is crisantaspase (L-asparaginase from Erwinia chrysanthemi).
• Each vial contains 10,000 U (units) of crisantaspase.
• The other components are sodium chloride, glucose monohydrate, sodium hydroxide, and acetic acid.

Appearance of Erwinase and Container Contents

Erwinase is a white powder contained in a small glass vial.

Each container contains 5 small glass vials.

Marketing Authorization Holder

Porton Biopharma Limited

Lee View House, 13 South Terrace

Cork, T12 T0CT

Ireland

Tel: +44 1980 745 022

Email: [email protected]

Manufacturer

Almac Pharma Services Limited

Seagoe Industrial Estate

Portadown, Craigavon

BT63 5UA

United Kingdom (Northern Ireland)

This Medication has been Authorized in the EEA Member States under the Following Names:

Austria, Belgium, Finland, France, Germany, Ireland, Netherlands, Poland, Portugal: Erwinase

Date of Last Revision of this Leaflet:March 2022

Detailed information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)

SEPARATE HERE AND PROVIDE INSTRUCTIONS TO THE PATIENT

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This information is intended only for healthcare professionals:

The contents of each vial must be reconstituted with 1 ml or 2 ml of injectable saline solution (0.9%).

Slowly add the injectable saline solution (0.9%) to the inner wall of the vial, do not add it directly above or into the powder. Dissolve the contents by mixing or gently rotating, keeping the vial in a vertical position. Avoid contact between the solution and the stopper. Avoid foam formation by agitating too much or with force.

The solution should be transparent, without visible particles. If it is agitated too much and visible foam forms, fine filamentous or crystalline particles of protein aggregates may be observed. If particles or protein aggregates are visible, the reconstituted solution should be rejected.

The reconstituted injectable solution should be administered within 15 minutes of reconstitution. If it is unavoidable that more than 15 minutes elapse between reconstitution and administration, the solution should be drawn up with a sterile glass or polypropylene syringe under aseptic conditions. The syringe containing the reconstituted solution should then be stored below 25°C and used within 4 hours.

For IV infusion, it is recommended to further dilute the reconstituted Erwinase solution in 100 ml of saline solution (0.9%). To facilitate preparation, the reconstituted Erwinase solution can be directly transferred to a pre-filled bag containing 100 ml of saline solution (0.9%) for infusion.

The diluted infusion solution is recommended to be used immediately after preparation. If not used immediately, the infusion solution can be stored in a polyvinyl chloride (PVC) infusion bag. The infusion bag should be stored below 25°C and used within 4 hours.

From a microbiological point of view, the reconstituted injectable solution should be used immediately, unless the reconstitution method eliminates the risk of microbial contamination. If not used immediately, the user is responsible for the storage time and conditions.

Erwinase is a non-cytotoxic medication and does not require the special precautions necessary for the handling of these drugs. Nevertheless, when preparing or administering Erwinase, it should be taken into account that it may be sensitizing.

Inhalation of the powder or solution should be avoided. In case of contact with the skin or mucous membranes, especially the eyes, they should be rinsed with plenty of water for at least 15 minutes.

Disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

In the absence of compatibility studies, this medication should not be mixed with others. Consequently, other intravenous medications should not be infused through the same intravenous line as Erwinase.