PATIENT INFORMATION LEAFLET

Accofil 12 MU/0.2 ml (0.6 mg/ml) injectable solution and for infusion in pre-filled syringe

filgrastim

Read this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, nurse or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

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What is Accofil

Accofil contains the active ingredient filgrastim. Filgrastim is a protein produced in the bacteriaEscherichia coliusing recombinant DNA technology. It belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocytes and colony-stimulating factor [G-CSF]) produced by your own body. Filgrastim stimulates the bone marrow (the tissue where new blood cells are produced) to produce more white blood cells that help fight infections.

How is Accofil used

Your doctor has prescribed Accofil to help your body produce more white blood cells. Your doctor will tell you why you are being treated with Accofil. Accofil is useful in several different situations that are:

• Chemotherapy
• Bone marrow transplant
• Severe chronic neutropenia (low number of a type of white blood cell)
• Neutropenia (low number of a type of white blood cell) in patients with HIV infection
• Mobilization of peripheral blood stem cells (to stimulate stem cells to enter the bloodstream to be collected and used in bone marrow transplant).

No use Accofil

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

Advertencias y precauciones

Consult your doctor, pharmacist, or nurse before starting to use Accofil:

Tell your doctor if you have:

• anemia drepanocítica, Accofil may cause drepanocytic crises.
• osteoporosis (bone disease)

Inform your doctor immediately during treatment with Accofil if:

• You have pain in the upper left abdomen, pain under the left ribs, or in the left shoulder tip (these may be symptoms of spleen enlargement (splenomegaly) or possibly spleen rupture).

• Unusual bleeding or bruises that may be symptoms of a reduced number of platelets in the blood (thrombocytopenia) with reduced blood clotting ability.

• You have sudden signs of allergy such as rashes, itching, or urticaria on the skin, swelling of the face, lips, tongue, or other parts of the body, shortness of breath, wheezing (a whistling sound produced when breathing) or breathing difficulties as they may be signs of a severe allergic reaction.

• You experience swelling in the face or ankles, blood in the urine, or urine that is brown in color or note that you urinate less than usual (glomerulonephritis).

The needle cover of the pre-filled syringe contains natural rubber (a latex derivative) that may cause an allergic reaction.

In rare cases, aortic inflammation (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.

Pérdida de respuesta a filgrastim

If you experience a loss of response or failure to maintain response with filgrastim treatment, your doctor will investigate the reasons including whether you have developed antibodies that 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 have a risk of developing blood cancer (leukemia, myelodysplastic syndrome (MDS)). You should discuss the risk of developing blood cancer with your doctor and what tests should be done. If you develop or are likely to develop blood cancer, do not use Accofil unless your doctor tells you to. If you are a stem cell donor, you must be between 16 and 60 years old.

Tenga especial cuidado con otros productos que estimulan los leucocitos

Accofil is one of a group of products that stimulate white blood cell production. Your healthcare professional should always record the exact product you are using.

Otros medicamentos y Accofil

You should not receive Accofil within 24 hours before and 24 hours after receiving chemotherapy.

Please inform your doctor or pharmacist if you are taking or have recently taken other medications, including those purchased without a prescription.

Embarazo y lactancia

Accofil has not been tested in pregnant women.

It is essential to tell your doctor if:

• You are pregnant or breastfeeding;
• You think you may be pregnant; or
• You intend to become pregnant.

The passage of filgrastim into breast milk is unknown. Therefore, your doctor may decide that you should not use this medication if you are breastfeeding.

Conducción y uso de máquinas

The influence of Accofil on driving or operating machines is small. This medication may cause dizziness. It is recommended to wait and see how you feel after taking Accofil and before driving or operating machines.

Accofil contiene sorbitol y sodio

This medication contains sorbitol. Sorbitol is a source of fructose. If you (or your child) suffer from hereditary fructose intolerance (HFI), a rare genetic disorder, you should not receive this medication. HFI patients 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 dizziness, vomiting, or unpleasant effects such as swelling, stomach cramps, or diarrhea.

This medication also contains less than 23 mg of sodium (1 mmol) per dose, which is essentially "sodium-free".

Follow exactly the administration instructions of this medication as indicated by your doctor. If in doubt, consult your doctor or pharmacist again.

The amount of Accofil you need will depend on the disease for which you are taking Accofil and your body weight.

Dose

Accofil and neutropenia (low number of a type of white blood cells) associated with chemotherapy

The usual dose is 0.5 million units (5 micrograms) per kilogram of body weight per day. For example, if you weigh 60 kilograms, your daily dose will be 30 million units (300 micrograms). Treatment with Accofil usually lasts about 14 days. However, in some types of disease, a longer treatment may be necessary, lasting up to approximately one month.

Accofil and bone marrow transplant

The usual initial dose is 1 million units (10 micrograms) per kilogram of body weight per day administered by infusion. For example, if you weigh 60 kg, your daily dose will be 60 million units (600 micrograms). You will usually receive your first dose of Accofil at least 24 hours after chemotherapy and at least 24 hours after receiving your bone marrow transplant. Your doctor will then check your blood to see how the treatment is working and how long it will last.

Accofil chronic and severe neutropenia (low number of a type of white blood cells)

The usual initial dose is 0.5 million units (5 micrograms) and 1.2 million units (12 micrograms) per kilogram of body weight per day in a single dose or divided dose. Your doctor will then check your blood to see how well your Accofil treatment is working and to find the most suitable dose for you. Long-term treatment with Accofil is required for the reduction of neutropenia.

Accofil and neutropenia (low number of a type of white blood cells) in patients with HIV infection

The usual initial dose is 0.1 million units (1 microgram) and 0.4 million units (4 micrograms) per kilogram of body weight per day. Your doctor may check your blood regularly to see if the Accofil treatment is working. Once your white blood cell count has returned to normal, it may be possible to reduce the frequency of the dose to less than once a day. Long-term treatment with Accofil may be necessary to maintain a normal number of white blood cells in the blood.

Accofil and peripheral blood stem cell transplant (stem cells collected from the blood to be used in bone marrow transplant)

If you are donating stem cells for yourself, the usual dose is 0.5 million units (5 micrograms) to 1 million units (10 micrograms) per kilogram of body weight per day. Accofil treatment will last up to 2 weeks. Your doctor will check your blood to determine the best time to collect the stem cells.

If you are donating stem cells for someone else, the usual dose is 1 million units (10 micrograms) per kilogram of body weight per day. Accofil treatment will last 4 to 5 days. Your doctor will perform blood tests to determine the best time to collect the stem cells.

Administration form

This medication is administered by injection, either by intravenous infusion (IV) or by subcutaneous injection (SC) in the tissue under the skin.

If you are receiving this medication by subcutaneous injection, your doctor may suggest that you learn how to administer the injections. Your doctor or nurse will give you instructions on how to do this (see information below for instructions on injecting Accofil). Do not attempt to self-inject without these instructions. Part of the information you need is given at the end of this prospectus, but the proper treatment of your disease requires close and constant collaboration with your doctor.

Information for self-injection

This section contains information on how to administer Accofil to yourself. It is essential that you do not attempt to administer an injection without having received the necessary training from your doctor or nurse. If you are unsure of being able to inject or if you have any doubts, consult your doctor or nurse..

How do I inject Accofil??

You should administer the injection in the tissue just under the skin. This is known as subcutaneous injection. The injection should be administered daily at approximately the same time.

Equipment needed

To administer a subcutaneous injection, you will need:

• a preloaded Accofil syringe and
• alcohol-impregnated gauze.

What should I do before administering a subcutaneous injection of Accofil?

Ensure that the needle cover remains on the syringe until just before you are ready to inject.

a. Remove the preloaded Accofil syringe from the refrigerator.

b. Check the expiration date indicated on the syringe (CAD). Do not use it if the date is beyond the last day of the month shown or if it has been kept out of the refrigerator for more than 15 days or has expired in any other way.

c. Check the appearance of Accofil. It should be a clear and colorless liquid. If there are particles inside, do not use it.

d. To make the injection more comfortable, let the preloaded syringe stand at room temperature for 30 minutes or hold the preloaded syringe gently in your hands for a few minutes. Do not heat Accofil in any other way (for example, do not heat it in a microwave or in hot water)

e.Wash your hands carefully.

f. Find a comfortable and well-lit place and place everything you need within reach (the preloaded Accofil syringe and the alcohol-impregnated gauze).

How should I prepare the Accofil injection?

Before injecting Accofil, you should:

Never use a syringe that has been dropped on a hard surface.

1. Take the syringe and remove the protective needle cover gently without tilting it. Separate as indicated in Figures 1 and 2. Do not touch the needle or push the plunger.

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2

You may notice a small air bubble in the syringe. It is not necessary to eliminate the air bubble before the injection. The injection of the solution with the air bubble is harmless.

1. The syringe may contain more liquid than you need. Use the syringe scale as indicated below to adjust the correct dose of Accofil prescribed by your doctor. Expel the unnecessary liquid by pushing the plunger until the number (ml) on the syringe corresponds to the prescribed dose.
2. Check again that the Accofil dose is correct.
3. You can now use the preloaded syringe.

Where should I put the injection?

The most suitable places for the injection are:

• the upper part of the thighs, and
• the abdomen, except the area around the navel (see Figure 3).

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If someone else is administering the injection, you can also use the back of your arms (see Figure 4).

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To avoid the risk of pain at a specific point, it is best to change the injection site every day.

How do I inject??

1. Disinfect the injection site using alcohol-impregnated gauze and pinch the skin between your thumb and index finger, without squeezing (see Figure 5).

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Preloaded syringe without safety needle cover

1. Insert the needle completely into the skin as indicated by your nurse or doctor (see Figure 6).
2. Pull the plunger gently to check that you have not hit a blood vessel. If you see blood in the syringe, remove the needle and insert it in another place.
3. Hold the skin pinched, push the plunger slowly and steadily until you have administered the entire dose, until the plunger cannot move any further. Do not stop pressing the plunger!
4. Only administer the prescribed dose by your doctor.
5. After injecting the liquid, remove the needle while maintaining the pressure on the plunger, and then release the skin.
6. Place the syringe in the special container for disposal. Each syringe is for a single injection.

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Preloaded syringe with safety needle cover

1. Insert the needle completely into the skin as indicated by your nurse or doctor (see Figure 7).
2. Pull the plunger gently to check that you have not hit a blood vessel. If you see blood in the syringe, remove the needle and insert it in another place.
3. Administer only the dose prescribed by your doctor following the instructions below.
4. Hold the skin pinched, push the plunger slowly and steadily while holding the edge of your finger until you have administered the entire dose, until the plunger cannot move any further. Do not stop pressing the plunger!
5. After injecting the liquid, remove the needle while maintaining the syringe at the same angle and maintaining the pressure on the plunger, and then release the skin. The safety needle cover will automatically cover the needle and you will hear an audible "click" to confirm that the safety feature has been activated (see Figure 8). The needle safety feature will not be activated unless the entire dose has been administered.

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Remember

If you have any doubts, ask for help and advice from your doctor or nurse.

How to dispose of used syringes

• The safety needle cover prevents needlestick injuries after use, and therefore, no special precautions are required for its disposal. Dispose of the syringe as indicated by your doctor, nurse, or pharmacist.

If you use more Accofil than you should

If you use more Accofil than you should, consult your doctor or pharmacist as soon as possible.

If you forget to use Accofil

Do not administer a double dose to compensate for the missed doses. Contact your doctor to discuss when you should inject the next dose.

If you interrupt Accofil treatment

Your doctor will indicate when you should stop Accofil treatment. It is very common to have several cycles of Accofil treatment.

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

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

Inform your doctor immediately during treatment:

• If you experience an allergic reaction with weakness, low blood pressure, difficulty breathing, swelling in the face (anaphylaxis), skin rash, skin eruption (urticaria), swelling in the face, lips, mouth, tongue, or throat (angioedema), and shortness of breath (dyspnea). Hypersensitivity is common in cancer patients.

• If you experience cough, fever, and difficulty breathing (dyspnea), as this may be a sign of acute respiratory distress syndrome (ARDS). ARDS is rare in cancer patients.
• If you note pain in the upper left side of the abdomen, pain under the left thoracic cavity, or pain in the shoulder tip, as this may be related to a spleen problem (splenomegaly or splenic rupture).
• If you are being treated for chronic severe neutropenia and have blood in your urine (hematuria). Your doctor may analyze your urine periodically if you experience this side effect or if you find proteins in your urine (proteinuria).
• If you experience any of the following side effects or a combination of them: inflammation or swelling, which may be associated with reduced urination frequency, difficulty breathing, abdominal swelling, and a feeling of fullness, and a general feeling offatigue. These symptoms usually develop rapidly.

These may be symptoms of a rare condition (which can affect up to 1 in 100 people) called capillary leak syndrome, which causes blood to leak from the small blood vessels in the body and requires urgent medical attention.

• If you experience a combination of any of the following symptoms:

• fever or chills, or feeling very cold, high heart rate, confusion or disorientation, shortness of breath, much pain or discomfort, and sweaty and sticky 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 fatal and requires urgent medical attention.

If you suffer from kidney damage (glomerulonephritis). Kidney damage has been observed in patients who have received Accofil. Call your doctor immediately if you experience swelling in the face or ankles, blood in your urine, or urine that is brown in color, or if you notice that you are urinating less than usual.

A very common side effect of Accofil is muscle or bone pain (musculoskeletal pain), which can be relieved by taking conventional analgesics. In patients undergoing stem cell or bone marrow transplantation, graft-versus-host disease (GVHD) may occur: this is a reaction of the donor cells against the recipient; among the signs and symptoms are skin rash on the palms of the hands and soles of the feet and ulcers and sores in the mouth, intestine, liver, skin, or eyes, lungs, vagina, and joints. In healthy stem cell donors, a frequent observation is an increase in white blood cells (leukocytosis) and a decrease in platelets that reduces the blood's ability to clot (thrombocytopenia); your doctor will monitor these reactions.

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

• nausea
• vomiting
• hair loss (alopecia)
• fatigue (fatigue)
• inflammation or swelling of the mucous membrane lining the digestive tract from the mouth to the anus (mucosal inflammation)
• decrease in platelets, which reduces the blood's ability to clot (thrombocytopenia)
• low red blood cell count (anemia)
• fever (pyrexia)
• headache
• diarrhea

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

• inflammation of the lungs (bronchitis)

• upper respiratory tract infection
• urinary tract infection
• loss of appetite
• difficulty sleeping (insomnia)
• dizziness
• reduced sensitivity, especially in the skin (hypoesthesia)
• tingling or numbness in the hands or feet (paresthesia)
• low blood pressure (hypotension)
• high blood pressure (hypertension)
• cough
• coughing up blood (hemoptysis)
• mouth and throat pain (oropharyngeal pain)
• nasal bleeding (epistaxis)
• constipation
• oral pain
• enlarged liver (hepatomegaly)
• eruption
• skin redness (erythema)
• muscle spasms
• urination pain (dysuria)
• chest pain
• pain
• generalized weakness (asthenia)
• feeling unwell in general (general malaise)
• swelling of the hands and feet (peripheral edema)
• increase in certain blood enzymes
• changes in blood chemistry
• transfusion reaction

Rare side effects(may affect up to 1 in 100 people using Accofil):

• increase in white blood cells (leukocytosis)
• allergic reaction (hypersensitivity)
• rejection of the transplanted bone marrow (graft-versus-host disease).
• high uric acid levels in the blood that can cause gout (hyperuricemia) (increase in uric acid in the blood)
• liver damage caused by blockage of small veins within the liver (portal hypertension or hepatic veno-occlusive disease)
• the lungs do not function properly, causing shortness of breath (respiratory failure)
• swelling or fluid in the lungs (pulmonary edema)
• inflammation of the lungs (interstitial pneumonitis)
• radiographic anomaly of the lungs (pulmonary infiltration)
• bleeding in the lungs (pulmonary hemorrhage)
• poor oxygen absorption in the lungs (hypoxia)
• scaly skin rash (maculopapular rash)
• disease that causes bones to be less dense, making them weaker, more fragile, and more likely to break (osteoporosis)
• reaction at the injection site

Rare side effects (may affect up to 1 in 10,000 patients using Accofil):

• inflammation of the aorta (the large blood vessel that carries blood from the heart to the rest of the body), see section 2.
• intense pain in bones, chest, intestine, or joints (sickle cell crisis)
• sudden allergic reaction with risk of death (anaphylactic reaction)
• joint pain and swelling, similar to gout (pseudogout)
• change in how the body regulates fluid levels and can cause swelling (volume depletion)
• inflammation of the skin blood vessels (cutaneous vasculitis)
• painful lesions of a purplish color and with relief in the limbs, and sometimes in the face and neck, along with fever (Sweet syndrome)
• exacerbation of rheumatoid arthritis
• rare change in urine
• decrease in bone density

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a side effect that does not appear in this leaflet.

Reporting side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep out of sight and reach of children.

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

Store in refrigerator (between 2 °C-8 °C). Do not freeze.

The syringe can be removed from the refrigerator and left at room temperature (but not above 25ºC) for a single period of up to a maximum of 15 days and never beyond the expiration date on the label. After this period, the medication should not be refrigerated again and should be discarded.

Store the pre-filled syringe in the outer packaging to protect it from light.

Do not use Accofil if you observe turbidity or discoloration or if there are particles in it.

Do not place the cap on used needles, as you may accidentally prick yourself. Medications should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of unused medications. This will help protect the environment.

Composition of Accofil

• The active principle is filgrastim. Each pre-filled syringe contains 12 MU (1200 micrograms) of filgrastim in 0.2 ml, which corresponds to 0.6 mg/ml.
• The other components are acetic acid, sodium hydroxide, sorbitol (E420), polisorbate 80, water for injection.

Aspect of the product and content of the packaging

Accofil is a transparent and colourless solution for injection or infusion in a pre-filled syringe marked with 1/40 printed marks of 0.1 ml to 1 ml on the syringe barrel with a needle for injection. Each pre-filled syringe contains 0.2 ml of solution.

Accofil is available in packs of 1, 3, 5, 7 and 10 pre-filled syringes, with or without a safety needle guard and alcohol-impregnated gauzes.

Only some pack sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6th floor,

08039 Barcelona,

Spain

Responsible for manufacturing

Accord Healthcare Limited

Sage House, 319 Pinner Road,

North Harrow,

Middlesex HA1 4HF,

United Kingdom

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice, Poland

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

Further information on this medicinal product can be obtained by contacting the local representative of the marketing authorisation holder:

Last review date of this leaflet:

The 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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The following information is intended only for healthcare professionals:

Accofil does not contain preservatives. Due to a possible risk of microbial contamination, the pre-filled syringes of Accofil are for single use only.

Exposure to freezing temperatures up to a maximum of 48 hours does not affect the stability of Accofil. If exposure exceeds 48 hours or if it has been frozen more than once, DO NOT use Accofil.

To improve the traceability of granulocyte colony-stimulating factors, the product name (Accofil) and the batch number of the product administered must be clearly recorded in the patient's medical history.

Accofil should not be diluted with sodium chloride. This medicinal product should not be mixed with other medicinal products except for those mentioned below. The dilution of filgrastim may be adsorbed by glass and plastic materials except if it is diluted as mentioned below.

If necessary, Accofil can be diluted in 5% glucose. Dilution to a final concentration of less than 0.2 MU (2 g) per ml is not recommended at any time.

The solution must be visually inspected before use. Only solutions that are transparent and free of particles should be used.

For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 g) per ml, human serum albumin (HSA) should be added to a final concentration of 2 mg/ml. Example: in a final injection volume of 20 ml, total doses of filgrastim below 30 MU (300 µg) should be administered with the addition of 0.2 ml of human serum albumin 200 mg/ml (20%).

When diluted in 5% glucose, Accofil is compatible with glass and a variety of plastics such as PVC, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.

After dilution

Chemical and physical stability of the diluted infusion solution has been demonstrated for use within a maximum of 30 hours at 25 °C ± 2 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, the times and conditions of conservation prior to use are the responsibility of the user, and in general, should not exceed 30 hours at 25 °C ± 2 °C, unless the dilution has taken place in controlled and validated aseptic conditions.

Use of the pre-filled syringe with a safety needle guard

The safety needle guard covers the needle after injection to prevent needlestick injuries. This does not affect the normal functioning of the syringe. Press the plunger of the syringe slowly and uniformly until all the dose has been administered, until the plunger can no longer move. Keeping the pressure on the plunger, remove the syringe from the patient. The safety needle guard will cover the needle when the plunger is released.

Use of the pre-filled syringe without a safety needle guard

Administer the dose following the standard protocol.

Never use a pre-filled syringe that has fallen onto a hard surface.

Disposal

The disposal of unused medicinal product and all materials that have been in contact with it will be carried out in accordance with local regulations.