Zefylti

Package leaflet: Information for the user

Zefylti 30 MU/0.5 mL solution for injection or infusion in pre-filled syringe, 48 MU/0.5 mL solution for injection or infusion in pre-filled syringe

Filgrastim
This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you may experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

1. What Zefylti is and what it is used for
2. What you need to know before using Zefylti
3. How to use Zefylti
4. Possible side effects
5. How to store Zefylti
6. Contents of the pack and other information

1. What Zefylti is and what it is used for

Zefylti is a white blood cell growth factor (granulocyte colony-stimulating factor) and belongs to a group of medicines called cytokines. Growth factors are proteins naturally produced in the body, but they can also be produced using biotechnology for use as medicines. Zefylti stimulates the bone marrow to produce a greater number of white blood cells.

A decrease in the number of white blood cells (neutropenia) can occur for various reasons, reducing the body's ability to defend itself against infections. Zefylti stimulates the bone marrow to rapidly produce new white blood cells.

Zefylti may be used:

• to increase the number of white blood cells after chemotherapy treatment, thereby helping to prevent infections;
• to increase the number of white blood cells after a bone marrow transplant, thereby helping to prevent infections;
• prior to high-dose chemotherapy to induce the bone marrow to produce more stem cells, which can be collected and reinfused after treatment. These cells may be collected from you or from a donor. The stem cells will then return to the bone marrow and produce blood cells;
• to increase the number of white blood cells if you have severe chronic neutropenia, thereby helping to prevent infections;
• in patients with advanced-stage HIV infection, to help reduce the risk of infections.

2. What you need to know before using Zefylti

Do not use Zefylti

• if you are allergic to filgrastim or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Zefylti.
Tell your doctor before starting treatment if you have:

• sickle cell anaemia, as Zefylti may trigger sickle cell crises.
• osteoporosis (bone disease)

Contact your doctor immediately during treatment with Zefylti if:

• you experience sudden signs of allergy, such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing, as these may be signs of a severe allergic reaction (hypersensitivity).
• you develop swelling of the face or ankles, blood in your urine or brown-coloured urine, or notice that you are urinating less than usual (glomerulonephritis).
• you feel pain in the upper left part of your abdomen (abdominal pain), pain under the left side of your rib cage, or pain at the tip of your left shoulder (these may be symptoms of an enlarged spleen (splenomegaly) or possible spleen rupture).
• you notice unusual bleeding or bruising (these may be symptoms of a reduced number of blood platelets (thrombocytopenia), leading to decreased blood clotting ability).

Inflammation of the aorta (the large blood vessel carrying blood from the heart to the body) has been
reported rarely in cancer patients and in healthy donors. Symptoms may include
fever, abdominal pain, malaise, back pain, and increased markers of inflammation.
Inform your doctor if you experience any of these symptoms.
Loss of response to filgrastim
If you experience a decreased response or failure to maintain response to
treatment with filgrastim, your doctor will investigate possible causes, including whether you have developed
antibodies that neutralize the activity of filgrastim.
Your doctor may decide to monitor you closely; see section 4 of the package leaflet.
If you are a patient with severe chronic neutropenia, you may be at risk of developing a blood cancer (leukaemia, myelodysplastic syndrome (MDS)). You should discuss with your doctor the risks of developing blood cancers and which tests should be performed. If you have or are at risk of developing blood cancers, you must not use Zefylti unless prescribed by your doctor.
If you are a stem cell donor, you must be between 16 and 60 years of age.
Pay special attention to other medicines that stimulate white blood cells
Zefylti belongs to a group of medicines that stimulate the production of white blood cells.
Healthcare professionals must always record the exact medicine being used.
Other medicines and Zefylti
Tell your doctor or pharmacist if you are using, have recently used, or might use any other
medicine.
Pregnancy and breastfeeding
Zefylti has not been studied in pregnant or breastfeeding women.
Zefylti is not recommended during pregnancy.
It is important that you inform your doctor if:

• you are pregnant or breastfeeding,
• you suspect you may be pregnant, or
• you are planning to become pregnant.

If you become pregnant while being treated with Zefylti, inform your doctor. Unless otherwise
instructed by your doctor, you must stop breastfeeding while using Zefylti.
Driving and using machines
Zefylti may have a slight effect on the ability to drive and use machines. This medicine
may cause dizziness. It is recommended that you wait and observe how you feel after using this
medicine before driving or operating machinery.
Zefylti contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per pre-filled syringe, i.e. it is
essentially “sodium-free”.
Zefylti contains polysorbate 80 (E433)
This medicine contains 0.02 mg of polysorbate 80 in each pre-filled syringe. Polysorbates
may cause allergic reactions. Inform your doctor if you have known allergies.
Zefylti contains sorbitol (E420)
This medicine contains 50 mg of sorbitol (E420) per mL.
Sorbitol (E420) is a source of fructose. If your doctor has diagnosed you (or your child)
with hereditary fructose intolerance (HFI), a rare genetic disorder,
you (or your child) must not take this medicine. Patients with hereditary fructose intolerance cannot properly metabolize fructose, and its accumulation may lead to serious side effects.
Before taking this medicine, inform your doctor if you (or your child) have hereditary fructose intolerance or if your child can no longer tolerate sweetened foods or drinks because they feel unwell, vomit, or experience unpleasant reactions such as bloating, stomach cramps, or diarrhoea after consuming sweet foods or drinks.

3. How to use Zefylti

Use this medicine exactly as directed by your doctor. If you have any doubts, consult your
doctor or pharmacist.
How is Zefylti administered and how much should I take?
Zefylti is generally administered as a daily injection into the tissue just beneath the skin (known as a subcutaneous injection). It may also be given as a daily slow-release injection into the vein (known as an intravenous infusion). The usual dose varies depending on the disease and body weight. Your doctor will tell you how much Zefylti you should take.
Patients receiving bone marrow transplantation after chemotherapy:
You will normally receive your first dose of Zefylti at least 24 hours after chemotherapy and at least 24 hours after receiving the bone marrow transplant.
You or the people caring for you may be taught how to administer the subcutaneous injections so that treatment can continue at home. However, you must not attempt to inject yourself unless you have first received proper instructions from a healthcare professional.
How long should I take Zefylti?
You will need to take Zefylti until the number of white blood cells has returned to normal. Blood tests will be performed regularly to monitor the number of white blood cells in your blood. Your doctor will tell you how long you should continue taking Zefylti.
Use in children
Zefylti is used to treat children undergoing chemotherapy or suffering from a severe reduction in the number of white blood cells in the blood (neutropenia). The dosage in children undergoing chemotherapy is the same as that used in adults.
If you use more Zefylti than you should
Do not increase the dose prescribed by your doctor. If you think you have injected more than you should have, contact your doctor as soon as possible.
If you forget to use Zefylti
If you have missed an injection, or if the amount injected was too small, contact your doctor as soon as possible. Do not take a double dose to make up for the missed dose.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Tell your doctor immediately during treatment:

• if you experience an allergic reaction including weakness, low blood pressure, breathing difficulties, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face, lips, mouth, tongue or throat (angioedema), and shortness of breath (dyspnoea).
• if you develop cough, fever and difficulty breathing (dyspnoea), as these may be symptoms of acute respiratory distress syndrome (ARDS).
• if kidney damage (glomerulonephritis) occurs. Kidney damage has been observed in patients receiving filgrastim. Contact your doctor immediately if you experience swelling of the face or ankles, blood in the urine, brown-coloured urine, or if you notice a decrease in the frequency of urination compared to usual.
• if you experience any of the following side effects, or a combination of them: swelling or puffiness, which may be associated with less frequent urination, difficulty breathing, abdominal swelling and a feeling of fullness, and a general feeling of fatigue. These symptoms usually develop rapidly. They could be symptoms of a condition called "capillary leak syndrome", which causes fluid and proteins to leak from small blood vessels into body tissues and requires urgent medical treatment.
• if you experience a combination of the following symptoms: fever or chills, intense feeling of cold, rapid heart rate, confusion or disorientation, shortness of breath, severe pain or discomfort, or cold, clammy skin. These may be symptoms of a condition called "sepsis" (also known as "blood poisoning"), a serious infection with a systemic inflammatory response that can be potentially fatal and requires urgent medical treatment.
• if you experience pain in the upper left part of the abdomen (abdominal pain), pain under the left side of the rib cage, or shoulder tip pain, as this may indicate a problem with the spleen (enlargement of the spleen (splenomegaly) or rupture of the spleen);
• if you are being treated for severe chronic neutropenia and have blood in your urine (haematuria). Your doctor may regularly check your urine if this side effect occurs or if protein is found in your urine (proteinuria).

A common side effect associated with the use of filgrastim is muscle or bone pain (musculoskeletal pain), which can be relieved by taking common painkillers (analgesics). In patients undergoing stem cell or bone marrow transplantation, graft-versus-host disease (GvHD) may occur: this is a reaction of donor cells against the transplant recipient; signs and symptoms include skin rash on the palms of the hands or soles of the feet, and ulcers or sores in the mouth, intestine, liver, skin, eyes, lungs, vagina and joints.
In healthy stem cell donors, an increase in white blood cells (leucocytosis) and a decrease in platelet count may be observed. This reduces the blood's ability to clot (thrombocytopenia). These events will be monitored by your doctor.

Very common side effects (may affect more than 1 in 10 people):

• Decrease in platelets, reducing blood's ability to clot (thrombocytopenia)
• Low red blood cell count (anaemia)
• Headache
• Diarrhoea
• Vomiting
• Nausea
• Unusual hair loss or thinning (alopecia)
• Tiredness (fatigue)
• Pain and swelling of the lining of the digestive tract, from mouth to anus (mucositis)
• Fever (pyrexia)

Common side effects (may affect up to 1 in 10 people):

• Inflammation of the lungs (bronchitis)
• Inflammation of the upper respiratory tract
• Urinary tract infection
• Reduced appetite
• Difficulty sleeping (insomnia)
• Dizziness
• Reduced sensation, particularly of the skin (hypoesthesia)
• Tingling or numbness of hands or feet (paraesthesia)
• Low blood pressure (hypotension)
• High blood pressure (hypertension)
• Cough, Coughing up blood (haemoptysis)
• Pain in mouth and throat (oropharyngeal pain)
• Nosebleeds (epistaxis)
• Constipation
• Oral pain
• Enlargement of the liver (hepatomegaly)
• Rash
• Redness of the skin (erythema)
• Muscle spasm
• Pain during urination (dysuria)
• Chest pain
• Pain
• Generalised weakness (asthenia)
• General feeling of being unwell (malaise)
• Swelling of hands and feet (peripheral oedema)
• Increase in certain enzymes in the blood
• Changes in blood chemistry values
• Transfusion reaction

Uncommon side effects (may affect up to 1 in 100 people):

• Increase in white blood cells (leucocytosis)
• Allergic reaction (hypersensitivity)
• Rejection of transplanted bone marrow (graft-versus-host disease)
• High levels of uric acid in the blood, which may cause gout (hyperuricaemia) (increased blood uric acid)
• Liver damage caused by blockage of small veins in the liver (veno-occlusive disease)
• Lungs not functioning properly, causing shortness of breath (respiratory failure)
• Swelling and/or fluid in the lungs (pulmonary oedema)
• Inflammation of the lungs (interstitial lung disease)
• Abnormalities on chest X-ray (pulmonary infiltration)
• Bleeding from the lungs (pulmonary haemorrhage)
• Inability to absorb oxygen in the lungs (hypoxia)
• Irregular skin rash (maculopapular rash)
• Condition that reduces bone density, making bones weaker, more fragile and prone to fractures (osteoporosis)
• Reaction at injection site

Rare side effects (may affect up to 1 in 1,000 people):

• Severe bone, chest, intestinal or joint pain (sickle cell anaemia with crisis)
• Sudden, life-threatening allergic reaction (anaphylactic reaction)
• Joint pain and swelling similar to gout (pseudogout)
• A change in the body's fluid regulation that may cause swelling (fluid volume alteration)
• Inflammation of skin blood vessels (cutaneous vasculitis)
• Purple, raised and painful lesions on limbs, and sometimes on face and neck, associated with fever (Sweet's syndrome)
• Worsening of rheumatoid arthritis
• Unusual changes in urine tests
• Reduced bone density
• Inflammation of the aorta (the large blood vessel carrying blood from the heart to the rest of the body), see section 2

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zefylti

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and on the prefilled syringe after Exp. The expiry date refers to the last day of that month.
Store and transport in a refrigerator (2°C – 8°C). Do not freeze. Keep the prefilled syringe in the outer packaging to protect it from light.
Within its shelf life and for outpatient use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for a single period of up to 72 hours. After this period, the product must not be returned to the refrigerator and must be disposed of.
Do not use this medicine if the liquid appears cloudy or contains visible particles.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package Contents and Other Information

What Zefylti contains

• Zefylti 30 MU/0.5 mL solution for injection or infusion: each pre-filled syringe contains 30 million units (MU), 300 mcg of filgrastim in 0.5 mL (equivalent to 0.6 mg/mL).
• Zefylti 48 MU/0.5 mL solution for injection or infusion: each pre-filled syringe contains 48 million units (MU), 480 mcg of filgrastim in 0.5 mL (equivalent to 0.96 mg/mL).
• The other components are sodium acetate, sorbitol (E420), polysorbate 80 (E433), nitrogen gas, and water for injections. See section 2 “Zefylti contains sorbitol (E420), polysorbate 80 (E433) and sodium”.

Description of the appearance of Zefylti and contents of the pack
Zefylti is a clear, colourless or slightly yellowish solution for injection or infusion in a pre-filled glass syringe with an injection needle (stainless steel), with and without needle safety guard.
Zefylti is available in packs containing 1 and 5 pre-filled syringes (with and without needle safety guard). Not all pack sizes may be marketed.

Marketing Authorisation Holder
CuraTeQ Biologics s.r.o
Trtinova 260/1, Cakovice,
19600 Prague
Czech Republic

Manufacturer
APL Swift Services Malta Ltd.
HF26, Hal Far Industrial Estate,
Qasam Industrijali Hal Far,
Birzebbugia, BBG 3000
Malta

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

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Instructions for administering the injection

This section contains information on how to administer a Zefylti injection. It is important that you do not attempt to self-inject unless you have received specific instructions from your doctor or nurse. Zefylti is equipped with a needle safety guard; your doctor or nurse will show you how to use it.
If you have any doubts about how to administer the injection or would like further information, please consult your doctor or pharmacist.

1. Wash your hands.
2. Remove the syringe from its packaging and take off the protective cap from the injection needle. The syringes are marked with graduation rings to allow partial use if necessary. Each graduation ring corresponds to a volume of 0.025 mL. If partial use of a syringe is required, remove the excess solution before injection.
3. Check the expiry date on the label of the pre-filled syringe (EXP). Do not use the medicine after the last day of the month stated.
4. Check the appearance of Zefylti. It should be a clear, colourless liquid. Do not use it if it shows changes in colour, cloudiness, or contains particles.
5. Clean the skin at the injection site with an alcohol swab.
6. Form a skin fold by pinching the skin between your thumb and index finger.
7. Insert the needle into the skin fold with a quick, firm motion.

8. While holding the skin fold, push the plunger slowly and evenly until the full dose has been administered and the plunger cannot be pushed any further. Do not release pressure on the plunger.
9. After injecting the liquid, remove the syringe from the skin while maintaining pressure on the plunger, then release the skin.
10. Release the plunger. The needle safety guard will automatically move forward rapidly to cover the needle.
11. Dispose of any unused medicine and waste materials derived from this medicine. Use each syringe only once.

The following information is intended for healthcare professionals only:

The solution should be inspected visually before use. Only clear solutions free from particles should be used.
Before use, inspect the syringe and use only if it is intact and shows no cracks or signs of breakage, if the needle shield is intact and properly attached, and if the needle is not exposed or bent.
Accidental exposure to freezing temperatures does not adversely affect the stability of Zefylti.
Zefylti syringes are for single use only.

Dilution prior to administration (optional)
If necessary, Zefylti may be diluted in 50 mg/mL (5%) glucose solution. Zefylti must not be diluted with sodium chloride solutions.
Dilution to a final concentration < 0.2 MU/mL (2 mcg/mL) is not recommended under any circumstances.
For patients treated with filgrastim diluted to concentrations < 1.5 MU/mL (15 mcg/mL), human serum albumin (HSA) should be added to achieve a final concentration of 2 mg/mL.
Example: In a final volume of 20 mL, total doses of filgrastim below 30 MU (300 mcg) must be administered with the addition of 0.2 mL of human serum albumin solution 200 mg/mL (20%) compliant with the European Pharmacopoeia.
When diluted in 50 mg/mL (5%) glucose solution, filgrastim is compatible with glass and polypropylene.

After dilution: The chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours at a temperature of 2 °C – 8 °C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 °C – 8 °C, unless dilution has been carried out under controlled and validated aseptic conditions.

Use of the pre-filled syringe with passive needle safety guard UltraSafe (UltraSafe Needle Guard)
The pre-filled syringe is equipped with an UltraSafe needle guard to protect against needlestick injuries. When handling the pre-filled syringe, keep hands behind the needle.

1. Perform the injection using the technique described above.
2. Push the plunger while keeping fingers on the flange until the entire dose has been administered. The passive needle guard will NOT activate unless the FULL dose has been administered.

3. Remove the syringe from the skin, then release the plunger and allow the needle to retract upward until the entire needle is protected and locked in place.

Disposal
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.