Prospect: information for the user

Nivestim 12MU/0.2ml injectable solution and for perfusion

Nivestim 30MU/0.5ml injectable solution and for perfusion

Nivestim 48MU/0.5ml injectable solution and for perfusion

filgrastim

Read this prospect carefully before starting to use the medicine,because it contains important information for you.

-Keep this prospect, as you may need to read it again.

-If you have any doubts, consult your doctor, nurse or pharmacist.

-This medicine has been prescribed only to you, and you should not give it to other people even if they have the same symptoms as you, as it may harm them.

-If you experience any adverse effects, consult your doctor, pharmacist or nurse, even if they are not listed in this prospect. See section 4.

1.What is Nivestim and for what it is used

2.What you need to knowbefore starting touse Nivestim

3.How to use Nivestim

4.Possible adverse effects

5.Storage of Nivestim

6.Contents of the package andadditional information

Nivestim is a white blood cell growth factor (granulocyte colony-stimulating factor) and belongs to a group of medications called cytokines. Growth factors are proteins that are produced naturally in the body, but can also be produced using genetic engineering for use as a medication. Nivestim works by causing the bone marrow to produce more white blood cells.

A reduction in the number of white blood cells (neutropenia) can be caused by various reasons and makes your body less effective at fighting off infections. Nivestim stimulates the bone marrow to produce new white blood cells quickly.

Nivestim can be used:

• to increase the number of white blood cells after chemotherapy treatment to help prevent infections;
• to increase the number of white blood cells after a bone marrow transplant to help prevent infections;
• before high-dose chemotherapy to cause the bone marrow to produce more stem cells, which can be collected and administered again to you after treatment. These cells can be collected from you or 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 suffer from severe chronic neutropenia to help prevent infections;
• to help reduce the risk of infections in patients with advanced HIV infection.

No use Nivestim

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

Warnings and Precautions

Consult your doctor, pharmacist, or nurse before starting to use Nivestim.

Inform your doctor before starting treatment if you suffer from:anemia of sickle cells, as Nivestim may cause sickle cell crises;osteoporosis (bone disease).

• Inform your doctor immediately during treatment with Nivestim if:
• you have sudden signs of allergy, such as skin rash, itching, or hives, 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 experience swelling in the face or ankles, blood in the urine, or urine that is darker than usual, or if you notice that you urinate less frequently than usual (glomerulonephritis);
• you experience pain in the upper left part of the abdomen, pain below the left chest, or in the left shoulder tip (these may be symptoms of an enlarged spleen [splenomegaly] or possible spleen rupture);
• you notice unusual bleeding or petechiae (these may be symptoms of a decrease in platelets in the blood [thrombocytopenia], with a reduced ability of the blood to clot).

• Rarely, inflammation of the aorta (the large blood vessel that carries blood from the heart to the rest of the body) has been reported in cancer patients and healthy donors. Symptoms may include fever, abdominal pain, general discomfort, back pain, and increased inflammatory markers. Inform your doctor if you experience these symptoms.

Loss of response to filgrastim

If you experience a loss of response or if you are unable to maintain a response to treatment with filgrastim, your doctor will investigate the causes, including whether you have developed antibodies that may neutralize the activity of filgrastim.

Your doctor may want to monitor you closely, see section 4 of the leaflet.

If you are a patient with chronic severe neutropenia, you may be at risk of developing blood cancer (leukemia, myelodysplastic syndrome [MDS]). Discuss the risks of developing blood cancer and the tests that should be performed with your doctor. If you develop or are likely to develop blood cancers, do not use Nivestim unless your doctor indicates.

If you are a stem cell donor, you must be between 16 and 60 years of age.

Be especially careful with other products that stimulate white blood cells

Nivestim belongs to a group of medications that stimulate the production of white blood cells. Your doctor must always register the exact product you are using.

Use of Nivestim with other medications

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

Pregnancy and breastfeeding

Nivestim has not been studied in pregnant women or breastfeeding women.

The use of Nivestim during pregnancy is not recommended.

It is essential to inform your doctor if you:

• are pregnant or breastfeeding;
• believe you may be pregnant; or
• are planning to become pregnant.

If you become pregnant during treatment with Nivestim, inform your doctor.

Unless your doctor tells you otherwise, you should stop breastfeeding if you use Nivestim.

Driving and operating machinery

The influence of Nivestim on your ability to drive and operate machinery is small. This medication may cause dizziness. It is recommended to wait and see how you feel after administering Nivestim before driving or operating machinery.

Nivestim contains sodium

This medication contains less than 1 mmol of sodium (23 mg) per dose of 0.6 mg/ml or 0.96 mg/ml; this is essentially "sodium-free".

Nivestim contains sorbitol

This medication contains 50 mg of sorbitol per ml.

Sorbitol is a source of fructose. If you (or your child) suffer from hereditary fructose intolerance (HFI), a rare genetic disease, you should not receive this medication.Patients with HFI cannot break down fructose, which may cause severe adverse effects.

Consult your doctor before receiving this medication if you (or your child) suffer from HFI or if your child cannot take sweet foods or drinks because they cause nausea, vomiting, or unpleasant effects such as bloating, stomach cramps, or diarrhea.

Follow exactly the administration instructions for this medication as indicated by your doctor. In case of doubt, consult your doctor, nurse, or pharmacist again.

How is Nivestim administered and how much should I take?

Nivestim is usually administered once a day as a subcutaneous injection into the tissue just below the skin. It can also be administered once a day as a slow intravenous infusion. The usual dose varies depending on your condition and weight.Your doctor will tell you how much Nivestim you should take.

Patients with bone marrow transplant after chemotherapy:

You will usually receive your first dose of Nivestim at least 24 hours after chemotherapy and at least 24 hours after receiving your bone marrow transplant.

You or the people who care for you may be taught how to administer subcutaneous injections so that you can continue treatment at home. However, do not attempt to do so unless your healthcare professional has properly trained you.

How long do I have to take Nivestim?

You will have to take Nivestim until your white blood cell count is normal. You will have periodic blood tests to monitor the number of white blood cells in your body. Your doctor will tell you how long you need to take Nivestim.

Use in children

Nivestim is used to treat children who are receiving chemotherapy or who have severe low white blood cell count (neutropenia). The dose in children receiving chemotherapy is the same as for adults.

If you use more Nivestim than you should

Do not increase the dose that your doctor has prescribed. If you think you have injected more than the prescribed dose, contact your doctor as soon as possible.

If you forgot to use Nivestim

If you have forgotten a dose, or if you injected less than the prescribed dose, contact your doctor as soon as possible. Do not take a double dose to make up for the missed doses.

If you have any doubts about the use of this medication, ask your doctor, nurse, or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor immediatelyduring treatment:

• if you experience an allergic reaction, including weakness, low blood pressure, difficulty breathing, swelling of the face (anaphylaxis), skin rash, skin rash with itching (urticaria), swelling of the face, lips, mouth, tongue, or throat (angioedema), and shortness of breath (dyspnea);
• if you experience cough, fever, and difficulty breathing (dyspnea), as it may be a sign of acute respiratory distress syndrome (ARDS);
• if you experience kidney damage (glomerulonephritis). Kidney damage has been observed in patients receiving filgrastim. Contact your doctor immediately if you notice swelling in the face or ankles, blood in the urine, or urine that is darker than usual, or if you notice that you urinate less frequently than usual;
• if you experience any of the following side effects or a combination of them:

• swelling, which may be related to urinating less frequently, difficulty breathing, swelling, and a feeling of fullness in the abdomen, and a general feeling of fatigue. These symptoms usually develop very quickly.

These may be symptoms of a condition called "capillary leak syndrome," whichcauses blood to escape from small blood vesselsto other parts of your bodyand requires urgent medical attention.

• if you experience a combination of the following symptoms:

• fever, chills, or feeling very cold, high heart rate, confusion or disorientation, difficulty breathing, severe or extreme discomfort, and sweaty or moist skin.

These may be symptoms of a condition called "sepsis" (also known as "blood poisoning"), a severe infection with a body-wide inflammatory response that can be potentially life-threatening and requires urgent medical attention.

• ifyou experience pain in the upper left part of the abdomen, pain in the lower left side of the chest, or pain in the shoulder tip, as it could be a problem with your spleen (splenomegaly or splenic rupture);
• if you are being treated for chronic severe neutropenia and have blood in your urine (hematuria). Your doctor will perform urine tests periodically if you experience this side effect or if you find proteins in your urine (proteinuria).

A common side effect of filgrastim use is muscle or bone pain (musculoskeletal pain), which can be prevented by taking usual pain-relieving medications (analgesics). In patients undergoing a stem cell or bone marrow transplant, graft-versus-host disease (GVHD) may occur. This is a reaction of the donor cells against the patient receiving the transplant; signs and symptoms include rashes on the palms of the hands or soles of the feet, and ulcers and sores in the mouth, intestine, liver, skin, eyes, lungs, vagina, and joints.

In healthy stem cell donors, an increase in white blood cells (leukocytosis) and a decrease in platelets may be observed. This reduces your blood's ability to clot (thrombocytopenia). These effects will be monitored by your doctor.

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

• Decreased platelets, which reduces the blood's ability to clot (thrombocytopenia)
• Low red blood cell count (anemia)
• Headache
• Diarrhea
• Vomiting
• Nausea
• Unusual hair loss (alopecia)
• Fatigue (fatigue)
• Irritation and swelling of the digestive tract lining, which runs from the mouth to the anus (mucosal inflammation)
• Fever (pyrexia)

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

• Pneumonia (bronchitis)
• Upper respiratory tract infection
• Urinary tract infection
• Decreased appetite
• Difficulty sleeping (insomnia)
• Dizziness
• Decreased sensitivity, especially in the skin (hypoesthesia)
• Tickling or numbness in the hands or feet (paresthesia)
• Low blood pressure (hypotension)
• High blood pressure (hypertension)
• Cough
• Coughing up blood (hemoptysis)
• Pain in the mouth and throat (oropharyngeal pain)
• Nosebleed (epistaxis)
• Constipation
• Oral pain
• Enlarged liver (hepatomegaly)
• Rash
• Redness of the skin (erythema)
• Muscle cramp
• Pain while urinating (dysuria)
• Painin the chest
• Pain
• Generalized weakness (asthenia)
• General feeling of discomfort (general malaise)
• Swelling in hands and feet (peripheral edema)
• Increased levels of certain enzymes in the blood
• Changes inblood biochemistry
• Reaction to transfusion

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

• Intense pain in the bones, chest, intestines, or joints (anemia of sickle cell disease with crisis)
• Immediate and potentially life-threatening allergic reactions (anaphylactic reaction)
• Swelling and pain in the joints, similar to gout (pseudogout)
• A change in how your body regulates fluid levels that may result in swelling (fluid volume alterations)
• Inflammation of the skin blood vessels (cutaneous vasculitis)
• Painful, inflamed, and dark red ulcers on the extremities and, sometimes, on the face and neck that are accompanied by fever (Sweet syndrome)
• Worsening of rheumatoid arthritis
• Unusual changes in urine
• Decreased bone density
• Inflammation of the aorta (the large blood vessel that carries blood from the heart to the rest of the body), see section 2.

Reporting of side effects

If you experience side effects, consult your doctor, pharmacist, or nurse, even if they are possible side effects that do not appear in this leaflet.You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the box and on the pre-filled syringe label after CAD. The expiration date is the last day of the month indicated.

Store and transport refrigerated (between 2°C and 8°C). Do not freeze. Store the pre-filled syringe in the outer packaging to protect it from light.

The syringe may be removed from the refrigerator and left at room temperature for a single period of up to 15 days (but at a temperature not exceeding 25°C).

Do not use this medication if you see that the syringe contents are cloudy or have particles.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This will help protect the environment.

Composition of Nivestim

• The active principle is filgrastim. Each ml contains 60 million units [MU] (600 µg) or 96 million units (960 µg) of filgrastim.

• Nivestim 12 MU/0.2 ml injectable/perfusion solution: each preloaded syringe contains 12 million units (MU), 120 µg of filgrastim in 0.2 ml (corresponding to 0.6 mg/ml)
• Nivestim 30 MU/0.5 ml injectable/perfusion solution: each preloaded syringe contains 30 million units (MU), 300 µg of filgrastim in 0.5 ml (corresponding to 0.6 mg/ml)
• Nivestim 48 MU/0.5 ml injectable/perfusion solution: each preloaded syringe contains 48 million units (MU), 480 µg of filgrastim in 0.5 ml (corresponding to 0.96 mg/ml)
• The other components are glacial acetic acid, sodium hydroxide, sorbitol E420, polisorbate 80, and water for injectable preparations.

Aspect of the product and content of the package

Nivestim is a transparent and colorless injection/perfusion solution that is supplied in a preloaded syringe with a stainless steel injection needle and a needle protection.The needle cap contains epoxiprene, a derivative of natural rubber latex that may come into contact with the needle.

Nivestim is available in packages of 1, 5, 8, or 10 preloaded syringes per package. Only some package sizes may be marketed.

Marketing Authorization Holder

Pfizer Europe MA EEIG

Boulevard de la Plaine 17

1050 Bruxelles

Belgium

Responsible for manufacturing

Hospira Zagreb d.o.o.

Prudnicka cesta 60

10291 Prigorje Brdovecko

Croatia

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Spain

Pfizer, S.L.

Phone: +34 91 490 99 00

Last review date of this leaflet:05/2023.

The detailed information about this medicine is available on the European Medicines Agency website:http://www.ema.europa.eu.

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Self-administration instructions for the patient

This section contains information on how to administer Nivestim to yourself. It is essential that you do not attempt to administer the injection without first having your doctor or nurse explain how to do it.It is also essential that you dispose of the used syringes in a sharps container. If you are unsure about self-administering the injection or have any questions, consult your doctor or nurse.

How do I administer Nivestim?

Nivestim is usually administered once a day by injection, typically in the tissue located below the skin. This is known as a subcutaneous injection.

If you learn how to administer the injection yourself, you will no longer have to wait at home for a nurse to come and administer your injection or go to the hospital or clinic every day for your injection to be administered.

You will need to administer your injection approximately at the same time every day. The most suitable places for injection are:

• The front of the thighs
• The abdomen, except for the area around the navel

It is better to change the injection site every day to avoid the risk of pain in any area.

Equipment required for administration:

The following items are required for subcutaneous injection administration:

1. A new preloaded syringe of Nivestim

2. A sharps container for disposing of used syringes safely

3. Antiseptic wipes (if recommended by your doctor or nurse)

How to administer the subcutaneous injection of Nivestim?

1. Ensure that you administer the injection approximately at the same time every day.

2. Remove the preloaded syringe from the refrigerator.

3.Remove the blister pack from the preloaded syringe. When the package contains blister packs with more than one preloaded syringe, cut the blister pack along the perforated line, return the remaining blister packs with preloaded syringes to the package, and return the package to the refrigerator.

4.Open the blister pack by removing the cap. Remove the preloaded syringe from the blister pack by holding it by the syringe body.

Verify the syringe to ensure that the safety needle guard covers the syringe body.Do notpush the safety needle guard over the needle cap before the injection. This may activate or block the safety needle guard. If the safety needle guard covers the needle, it means it has been activated.

Verify that the solution is transparent, colorless, and practically particle-free.Do notinspect the product through the plastic safety device.

Verify the expiration date on the label to ensure that the product has not expired.

Ensure that you have a sharps container nearby.

Allow the preloaded syringe to reach room temperature (approximately 25°C). This will take 15-30 minutes.

• Do notuse the Nivestim syringe if:

• The carton package is open or damaged.
• The safety needle guard is missing, has come off, or has been activated.
• Themedicine is cloudy or has changed color or the liquid has particles floating in it.
• Any part of the preloaded syringe appears cracked or broken or liquid has leaked from the syringe.
• The preloaded syringe has fallen. The preloaded syringe may be broken even if you cannot see the break.
• The needle cap is missing or not properly placed.
• The expiration date printed on the label has passed.

In all the above cases, dispose of the preloaded syringe and use a new preloaded syringe.

5.Find a comfortable place to administer the injection and verify the dose prescribed.

6.Wash your hands thoroughly with water and soap

7.Take the preloaded syringe by the safety needle guard body with the needle cap pointing upwards.

• Do notsuspend by the plunger, the plunger, or the needle cap.
• Do notpull back the plunger at any time.
• Do notremove the needle cap from the syringe until you are ready to inject your medication.

8.Remove the needle cap from the syringe by holding the syringe body and pull the needle cap away from your body carefully without rotating it.Dispose of the needle cap.Do notreplace the needle cap. Do not push the plunger, touch the needle, or shake the syringe.

9.The syringe is now ready to use.You can observe a small air bubble in the syringe. You do not need to expel the air bubble before injecting the solution. Injecting the solution with an air bubble is harmless.

10.Decide where to administer the injection- Find a place on the front of your abdomen or on the front of your thighs. Choose a different injection site each time.Do notchoose an area that is sensitive, red, damaged, or has a scar. Clean this area of the skin with an antiseptic wipe.

11.Pinch a large area of the skin, being careful not to touch the area you cleaned.

12With the other hand, hold the preloaded syringe like a pencil. Use a quick "dart" motion to insert the needle into the skin at an angle of approximately 45° as shown.

13.Pull the plunger slightly to confirm that you have not hit a blood vessel. If you see blood in the syringe, remove the needle and insert it into another place. Keeping the skin pinched, push the plunger slowly and uniformly until the syringe is empty.

14.After injecting the solution, remove the needle from the skin

15.Ensure that the syringe guard covers the needle according to the instructions for the active needle guard or the passive needle guard, as indicated below.

16.Do notattempt to replace the needle cap. Place the syringe in a sharps container.

• Maintain used syringes out of reach and sight of children
• Neverput used syringes in the household trash.

Remember

Most people can learn to administer the subcutaneous injection themselves, but if it is very difficult, do not hesitate to ask for help and advice from your doctor or nurse.

Use of the Active Needle Safety Device forNivestim 12 MU/0.2 ml injectable and for perfusion

The preloaded syringes have an Active Needle Safety Device to protect you from needlesticks. When handling a preloaded syringe, keep your hands behind the needle.

1. Administer the injection using the technique described above
2. When you have completed the injection, slide the needle into the safety device until the needle is completely covered (it will make a "click").

Use of the Passive Needle Safety Device forNivestim 30 MU/0.5 ml injectable/perfusion and Nivestim 48 MU/0.5 ml injectable/perfusion

The preloaded syringes have a Passive Needle Safety Device to protect you from needlesticks. When handling a preloaded syringe, keep your hands behind the needle.

1. Administer the injection using the technique described above

1. Push the plunger while holding the syringe with your fingers until the entire dose has been administered. The passive needle guard will not activate until the entire dose has been administered.

1. Remove the needle from your skin, the plunger will move, and allow the syringe to move upwards until the needle is safely stored and locked in place.

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This information is intended only for healthcare professionals:

Nivestim does not contain preservatives: due to the possible risk of microbiological contamination, Nivestim syringes are for single use only.

Accidental exposure to freezing temperatures for a maximum of 24 hours does not affect the stability of Nivestim. Frozen preloaded syringes can be thawed and then refrigerated for future use. If exposure has been greater than 24 hours or if the syringes have been frozen more than once, then Nivestim should not be used.

Nivestim should not be diluted with sodium chloride solution. This medicine should not be mixed with other medications that are not mentioned below. Diluted filgrastim may be adsorbed to plastic or glass materials, except if it is diluted as described below.

Nivestim can be diluted, if necessary, in a 5% glucose solution. It is not recommended to dilute to final concentrations below 0.2 MU (2 µg) per milliliter. The solution should be visually inspected before use. Only transparent solutions without particles should be used. In patients treated with filgrastim diluted to concentrations below 1.5 MU/ml (15 µg/ml), human albumin serum (HAS) should be added to a final concentration of 2 mg/ml.

Example: if the final injection volume is 20 ml and the total dose of filgrastim is less than 30 MU (300 µg), 0.2 ml of a 200 mg/ml human albumin serum solution (at 20%) should be added.

When diluted in a 5% glucose solution, Nivestim is compatible with glass and various plastics, including polyvinyl chloride, polyolefin (a copolymer of polypropylene and polyethylene), and polypropylene.

After dilution: it has been demonstrated that, during use, the diluted solution for perfusion remains physically and chemically stable for 24 hours at 2-8°C. From a microbiological point of view, the product should be used immediately. If it is not used immediately, the storage times during use and the conditions prior to it are the responsibility of the user and should not normally exceed 24 hours at 2-8°C, unless the dilution was made in validated and controlled aseptic conditions.