Active ingredients: Filgrastim
Nivestim 12 MU / 0.2 ml solution for injection / infusion
Nivestim 30 MU / 0.5 ml solution for injection / infusion
Nivestim 48 MU / 0.5 ml solution for injection / infusion
Why is Nivestim used? What is it for?
What is Nivestim
Nivestim contains the active substance filgrastim which belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocyte colony stimulating factor [G-CSF]) produced by the human body. Filgrastim stimulates the bone marrow (the tissue that makes new blood cells) to produce more blood cells, especially some types of white blood cells.White blood cells are important because they help the body fight infections.
What Nivestim is used for
Your doctor has prescribed Nivestim for you to help your body make more white blood cells. Your doctor will explain why you have been prescribed Nivestim. Nivestim is useful in a number of different clinical conditions such as:
- chemotherapy
- bone marrow transplant,
- severe chronic neutropenia (neutropenia is an abnormal low number of a certain type of white blood cell also known as neutrophils),
- neutropenia in patients with HIV infection,
- mobilization of peripheral blood stem cells.
Contraindications When Nivestim should not be used
Do not use Nivestim
- if you are allergic to filgrastim or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Nivestim
Talk to your doctor, pharmacist or nurse before taking Nivestim: - if you have any other illness (especially if you think you have an "infection),
- if you have cough, fever and difficulty in breathing. They could be secondary to lung problems (see also section 4 "POSSIBLE ADVERSE EVENTS"),
- if you have sickle cell anemia (an inherited blood disorder affecting red blood cells),
- if you have abdominal pain in the upper left or if you have shoulder pain. It could be a consequence of a spleen disease (see section 4 "POSSIBLE ADVERSE EVENTS"),
- if you suffer from specific blood disorders (e.g. Kostmann's syndrome, myelodysplastic syndrome, different types of leukemia),
- if you suffer from osteoporosis. Your doctor may check the density of your bones regularly.
If you need to have a bone scan, please tell your doctor or nurse that you are being treated with Nivestim.
Tell your doctor or nurse straight away 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 during treatment with Nivestim because these these could be signs of a severe allergic reaction.
While you are being treated with Nivestim, you may need to have regular blood tests to check the number of neutrophils and other white blood cells in your blood. With these data, the doctor determines the effectiveness of the treatment and whether it should continue.
Loss of response to filgrastim
If you have decreased response or failure to maintain response to filgrastim treatment, your doctor will investigate the reasons, including the possibility that you have developed antibodies that neutralize the activity of filgrastim.
Interactions Which drugs or foods may change the effect of Nivestim
You must not be treated with Nivestim in the 24 hours before and 24 hours after treatment with chemotherapy.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Filgrastim has not been studied in pregnant women. It is important that you tell your doctor if you are pregnant, if you think you may be making a pregnancy or if you are planning to become pregnant, as your doctor may decide that you cannot use this medicine. Filgrastim may have adverse effects on your ability to get pregnant or lead to end a pregnancy.
It is not known whether filgrastim passes into breast milk. Therefore, your doctor may decide that you cannot use this medicine if you are breastfeeding.
Driving and using machines
Filgrastim has modest effects on the ability to drive and use machines. If you feel tired, you should be careful when driving or using machines.
Nivestim contains sorbitol
This medicine contains sorbitol (E420). If you have been told by your doctor that you have an intolerance to some sugars (fructose), contact your doctor before taking this medicinal product. This medicine also contains sodium in less than 1 mmol (23 mg) per dose and is therefore essentially "sodium-free".
Dose, Method and Time of Administration How to use Nivestim: Posology
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are unsure.
This medicine is given by injection, either by intravenous infusion (drip) or subcutaneously into the tissue located directly under the skin.
If you are using this medicine by subcutaneous injection, your doctor may consider it appropriate for you to inject it yourself. Your doctor or nurse will show you how to inject (instructions on self-injection are given at the end of this leaflet). Do not try to inject the medicine yourself unless you have been specially trained. Some information you need is reported at the bottom of this leaflet, however for the appropriate treatment of your disease it is necessary a "careful and constant cooperation with the doctor.
The amount of Nivestim you need depends on the disease you are taking Nivestim for and your body weight.
Nivestim and chemotherapy-associated neutropenia
The usual dose in adults and children is 0.5 million units (5 micrograms) per kilogram of body weight per day. For example, if you weigh 60 kg your daily dose is 30 million units (300 micrograms). The treatment can last up to 14 days. For some diseases, prolonged treatment for up to about a month may be required.
Nivestim and bone marrow transplant
The usual starting dose is 1 million units (10 micrograms) per kilogram of body weight per day by infusion. For example, if you weigh 60 kg, your daily dose is 60 million units (600 micrograms). You will usually receive the first dose at least 24 hours after chemotherapy, but within 24 hours of a bone marrow transplant. The doctor will then carry out blood tests to check the effect of the treatment and establish its duration.
Nivestim and severe chronic neutropenia
The usual starting dose is between 0.5 million (5 micrograms) and 1.2 million (12 micrograms) units per kilogram of body weight per day, as a single or divided dose. Your doctor will then carry out blood tests to check the effect of the treatment and determine the most suitable dose for you. In case of neutropenia, prolonged treatment with Nivestim is necessary.
Nivestim and neutropenia in patients with HIV infection
The usual starting dose is between 0.1 (1 microgram) and 0.4 million units (4 micrograms) per kilogram of body weight per day. Your doctor will carry out blood tests at regular intervals to check the effect of the treatment. Once the white blood cell count has returned to normal, the frequency of dosing can be reduced to less than once a day. maintaining normal white blood cell counts may require prolonged treatment with Nivestim.
Nivestim and peripheral blood stem cell transplantation
If you are donating stem cells for yourself, the usual dose is 0.5 million (5 micrograms) to 1 million units (10 micrograms) per kilogram of body weight per day. Treatment with Nivestim lasts up to 2 weeks. Your doctor will carry out blood tests to determine the best time to collect the stem cells.
If you donate stem cells for another person, the usual dose is 1 million units per kilogram of body weight per day. Treatment with Nivestim will last for 4 to 5 days.
If you forget to use Nivestim
If you have forgotten to inject a dose, contact your doctor or pharmacist and ask them when to inject the next dose. Do not use a double dose to make up for a forgotten injection.
How Nivestim treatment ends
Your doctor will tell you when to stop using Nivestim. It is quite normal to have several courses of treatment with Nivestim.
If you have any further questions on the use of the medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Nivestim
If you use more Nivestim than you should, contact your doctor or pharmacist as soon as possible.
Side Effects What are the side effects of Nivestim
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Allergic-type reactions to filgrastim, including rash, raised itchy skin areas and anaphylaxis (weakness, drop in blood pressure, difficulty breathing and swallowing and swelling of the face) have been reported. If you think you have these types of reactions, stop taking Nivestim injections and seek medical help immediately.
Increased size of the spleen and very rare cases of rupture of the spleen have been reported. Some cases of ruptured spleen have been fatal. It is important that you contact your doctor immediately if you experience pain in the left upper abdomen or shoulder blade as this may be a sign of problems with the spleen.
Tell your doctor immediately if you experience one or more of the following adverse events during treatment:
- swelling or swelling, which may be related to decreased urination, difficulty in breathing, bloating and feeling full, and a general feeling of tiredness. These symptoms usually come on quickly.
These may be symptoms of an uncommon disease (may affect up to 1 in 100 people) known as "Capillary Leak Syndrome" which causes blood to leak into the body from small blood vessels and which requires urgent medical attention.
It is also very important to tell your doctor if you think you have an "infection. There are many ways an" infection can manifest itself. You must check that the temperature is not and does not exceed 37.8 ° C, chills or other signs of infection such as skin redness, sore throat, diarrhea, ear pain, difficulty or pain in breathing or problems such as cough and asthma These symptoms may be due to severe pulmonary adverse effects, such as pneumonia and respiratory distress syndrome in adults which can cause death. If you have fever or any other symptoms, contact your doctor immediately and go straight to a hospital.
If you have sickle cell anemia, be sure to inform your doctor before starting therapy with Nivestim. Crises of sickle cell anemia have been reported in some patients with this disease treated with filgrastim.
Very common adverse events (affects more than 1 in 10 patients)
- Feeling or being sick
- Pain in the bones and muscles. Ask your doctor which medicine to take to relieve this
- Nosebleed
- Drop in blood glucose levels which could cause you to feel hungry, sick, weak, tired, shaky or confused or cause sweating, headaches, blurred vision or increased heart rate
- Increase in liver enzyme values or changes in blood tests. Your doctor will do blood tests to check for this
- Increased uric acid which could manifest with gout
- Chest pain
Common adverse events (affects up to 1 in 10 patients)
- Weakness
- Generalized fatigue
- Headache
- Constipation or diarrhea
- Loss of appetite
- Inflammation and ulceration of the mouth and the inner lining of the intestine
- Cough
- Sore throat
- Hair loss
- Rash
- Enlarged liver
- Thinning of the bones
- Pain at the injection site
- Inflammation of the blood vessels
- Drop in platelets (cells involved in clotting) - with an increased risk of bleeding or bruising
Uncommon adverse events (affects up to 1 in 100 patients)
- Unspecified pain
- Presence of blood or protein in the urine
Rare adverse events (affects up to 1 in 1,000 patients)
- Liver damage caused by blockage of the small veins within the liver (veno-occlusive disease)
- A change in the regulation of fluids in the body which can lead to swelling
Very rare adverse events (affects up to 1 in 10,000 patients)
- Abnormal x-ray radiography of the lungs (pulmonary infiltration)
- Violet-colored, raised and painful lesions on the limbs and sometimes on the face and neck, associated with fever (Sweet's syndrome)
- Inflammation of the skin blood vessels (cutaneous vasculitis) • Aggravation of rheumatoid arthritis already present
- Unusual change in urine
Frequency not known (frequency cannot be estimated from the available data)
- Swelling and pain in the joints, as in gout (pseudogout).
In patients undergoing stem cell donation or bone marrow transplantation, graft-versus-host reaction disease (GvHD) may occur - this is a reaction of the donor cells towards the person receiving the transplant; signs and symptoms they include rash on the palms or soles and ulcers and sores in the mouth, intestines, liver, skin or eyes, lungs, vagina and joints. Some cases of GvHD have been fatal.
Adverse events you may experience if you are a stem cell donor for another person are:
Very common adverse events (affects more than 1 in 10 patients)
- Headache
- Pain in the bones or muscles. Ask your doctor which medicine to take to relieve this
- Changes in white blood cells or platelets (your doctor will check them with blood tests)
Common adverse events (affects up to 1 in 10 patients)
- Increase in the levels of some liver enzymes (your doctor will monitor them)
Uncommon adverse events (affects up to 1 in 100 patients)
- Severe allergic reaction
- Problems with the spleen
- Increased levels of uric acid which can occur with gout
- Worsening of rheumatoid arthritis
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the outer carton and on the syringe label after the abbreviation EXP / EXP. The expiry date refers to the last day of the month.
Store and transport refrigerated (2 ° C - 8 ° C). Do not freeze. Keep the pre-filled syringe in its original package to protect the medicine from light.
The syringe can be kept out of the refrigerator and left at room temperature for a single period of up to 7 days (however, not above 25 ° C).
Do not use Nivestim if you notice that it is cloudy or there are particles in it.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Nivestim contains
- The active ingredient is filgrastim. Each milliliter contains 60 million units [MU] (600 micrograms) or 96 million units [MU] (960 micrograms) of filgrastim.
- Nivestim 12 MU / 0.2 ml solution for injection / infusion: each pre-filled syringe contains 12 million units (MU), 120 micrograms of filgrastim in 0.2 ml (corresponding to 0.6 mg / ml).
- Nivestim 30 MU / 0.5 mL solution for injection / infusion: Each pre-filled syringe contains 30 million units (MU), 300 micrograms of filgrastim in 0.5 mL (corresponding to 0.6 mg / mL).
- Nivestim 48 MU / 0.5 mL solution for injection / infusion: Each pre-filled syringe contains 48 million units (MU), 480 micrograms of filgrastim in 0.5 mL (corresponding to 0.96 mg / mL).
- The other ingredients are acetic acid (glacial), sodium hydroxide, sorbitol E420, polysorbate 80, and water for injections.
What Nivestim looks like and contents of the pack
Nivestim is a clear, colorless solution for injection / infusion in a pre-filled syringe with a protective (stainless steel) injection needle. There may be 1, 5, 8 or 10 syringes in each pack.
Patient instructions for self-injection
This section contains information on how to inject Nivestim yourself. It is important that you do not try to inject the medicine yourself until you have been specially trained by your doctor or nurse.
It is also important that you dispose of the syringe in a needle-prick-proof container. If you have any questions or concerns about self-injection, ask your doctor or nurse.
How do I inject myself?
Normally, Nivestim is given twice a day by injection, into the tissues located under the skin, also known as a subcutaneous injection.
Learning the self-injection procedure means avoiding waiting at home for the nurse to arrive, much less having to go to the hospital or clinic every day to receive the injection.
You will need to inject yourself at the same time each day. The most suitable sites to inject are:
- the front of the thigh,
- the abdomen, except for the area around the navel.
It is best to always change the injection site every day to avoid pain in a certain area.
Equipment required for administration
The following equipment is required when performing a "subcutaneous self-injection:"
- A new Nivestim pre-filled syringe.
- A sharps container (needle puncture proof) to safely dispose of used syringes.
- Antiseptic wipes (if recommended by your doctor or nurse).
How do I give Nivestim subcutaneous self-injection?
- Try to inject yourself at about the same time every day.
- Remove the Nivestim syringe from the refrigerator and allow it to reach room temperature (approximately 25 ° C). This will take 15-30 minutes. Check the date on the package to make sure the medicine has not expired. have the container for the collection of sharp waste materials nearby.
- Look for a well-lit work site for your injection and to check your prescribed dose.
- Wash your hands thoroughly with soap and water.
- Remove the syringe from the blister and check that the solution it contains is clear, colorless and practically free from visible particles. Do not use the Nivestim syringe if the liquid has floating particles in it or if some of the liquid has leaked out of the syringe.
- Hold the syringe with the needle pointing up. Remove the protective cap from the needle. The syringe is now ready for use. There may be a small air bubble in the syringe. You do not have to remove the air bubble before injecting. Injecting the solution in the presence of an air bubble is not dangerous.
- Decide where to inject Nivestim - find a spot on the front of the abdomen or a front of the thighs. Select a different injection site each time. Do not choose a painful, red, bruised, or scarred area. If your nurse or doctor recommends it, clean the skin surface with a disinfectant.
- Take a "wide skin fold between your thumb and forefinger, taking care not to touch the area you just cleaned."
- With your other hand, insert the needle under the skin at an angle of approximately 45 °.
- Pull the plunger lightly to check that no blood enters the syringe. If you see blood in the syringe, pull out the needle and insert it somewhere else. Slowly push down on the plunger until the entire contents of the syringe have been emptied.
- After injecting the solution, remove the needle from the skin.
- By following the instructions below for the active or passive needle guard device, make sure that the device covers the needle.
- Return the syringe to the sharps container. Do not try to replace the protective cap.
- Keep used syringes out of the reach and sight of children.
- NEVER throw syringes into your household waste container.
Remember
Most people can learn about subcutaneous self-injection, but if you have a lot of difficulty, don't be afraid to ask your doctor or nurse for help and advice.
Using the Active Ultrasafe Needle Guard for Nivestim 12 MU / 0.2 ml solution for injection / infusion
The pre-filled syringe is equipped with a needle safety device, UltraSafe Needle Guard, which protects against accidental needle sticking. When handling the pre-filled syringe, keep your hands behind the needle.
- Carry out the injection according to the technique described above.
- When you have finished your injection, slide the needle guard forward until the needle is completely covered (the device snaps into place).
Using the Ultrasafe Passive Needle Guard for Nivestim 30 MU / 0.5 ml solution for injection / infusion and Nivestim 48 MU / 0.5 ml solution for injection / infusion
The pre-filled syringe is equipped with a needle safety guard, UltraSafe Needle Guard, which protects against accidental needle sticking. When handling the pre-filled syringe, keep your hands behind the needle.
- Carry out the injection according to the technique described above.
- While holding the syringe with your fingers resting on its support edge, apply pressure on the plunger until the injection of the entire dose is complete. The passive needle guard system will NOT activate if the FULL dose has not been administered.
- Remove the needle from your skin, then release the plunger and the syringe will move forward until the shield has covered the needle and snaps into place.
THE FOLLOWING INFORMATION IS INTENDED FOR DOCTORS OR HEALTHCARE PROFESSIONALS ONLY
Nivestim does not contain any preservatives. Due to the risk of bacterial contamination, Nivestim syringes are for single use only.
Accidental exposure to freezing temperatures for up to 24 hours has no adverse effect on the stability of Nivestim. The frozen pre-filled syringe can be thawed and returned to the refrigerator for later use. If exposure to low temperatures is greater than 24 hours or if frozen for more than once then Nivestim must NOT be used anymore.
Nivestim must not be diluted in sodium chloride solution. This medicinal product must not be mixed with other medicinal products except those described below. If not diluted as described below, diluted filgrastim may absorb to glass and plastic materials.
If required, Nivestim can be diluted in 50 mg / ml (5%) glucose solution for infusion. Dilution to final concentrations <0.2 MU (2 micrograms) per ml is never recommended. The solution should be visually inspected prior to use. Only clear solutions with no visible particles should be used. For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 micrograms) per mL, human serum albumin ( HSA) to a final concentration of 2 mg / ml.
Example: In a final volume to be injected of 20 mL, total filgrastim doses below 30 MU (300 micrograms) should be administered by adding 0.2 mL of a 200 mg / mL (20%) human albumin solution. Diluted with 50 mg / ml (5%) glucose solution for infusion, Nivestim is compatible with glass and various plastic materials such as PVC, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
After dilution: Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours at 2 ° C to 8 ° C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not exceed 24 hours at 2 ° C to 8 ° C, unless dilution has taken place under conditions aseptic controlled and validated.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NIVESTIM 12 MU / 0.2 ML SOLUTION FOR INJECTION / INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution for injection or infusion contains 60 million units [MU] (600 mcg) of filgrastim *.
Each pre-filled syringe contains 12 million units (MU) (120 mcg) of filgrastim in 0.2 mL (0.6 mg / mL).
* recombinant methionine granulocyte colony stimulating factor [GCSF]) produced in Escherichia Coli (BL21) with recombinant DNA technology.
Excipient (s) with known effect
Each ml of solution contains 50 mg of sorbitol.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection / infusion.
Clear, colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Filgrastim is indicated for the reduction of the duration of neutropenia and the incidence of febrile neutropenia in patients treated with standard cytotoxic chemotherapy for malignant diseases (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) and reduction of the duration of neutropenia in patients undergoing to myeloablative therapy followed by bone marrow transplant considered to be at high risk for prolonged severe neutropenia.
The safety and efficacy of filgrastim are similar in adults and children undergoing cytotoxic chemotherapy.
Filgrastim is indicated for the mobilization of peripheral blood progenitor cells (PBPCs).
In patients, children or adults with severe congenital, cyclic or idiopathic neutropenia, with an absolute neutrophil count (ANC) ≤ 0.5 x 109 / L, and a history of severe or recurrent infections, long-term administration of filgrastim is indicated for increasing neutrophil counts and reducing the incidence and duration of infection-related events.
Filgrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109 / l) in patients with advanced HIV infection to reduce the risk of bacterial infections when other treatment options are inadequate.
04.2 Posology and method of administration
Filgrastim therapy should only be performed in conjunction with a cancer center with
experience in G-CSF treatment and haematology, and who has the necessary diagnostic equipment. The mobilization and apheresis procedures must be performed in collaboration with an oncology-hematology center with acceptable experience in the field and where the monitoring of hematopoietic progenitor cells can be correctly performed.
Dosage
Standard cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MU (5 mcg) / kg / day. The first dose of filgrastim should be given at least 24 hours after cytotoxic chemotherapy.
Daily dosing of filgrastim should continue until the expected neutrophil nadir has been exceeded and the nuetrophil count has returned to a normal level. After standard chemotherapy for solid tumors, lymphomas and lymphoid leukemias, the required duration of treatment to meet these criteria could reach 14 days. After induction and consolidation treatment in acute myeloid leukemia, the duration of treatment can be considerably longer (up to 38 days) depending on the type, dose and pattern of cytotoxic chemotherapy used. .
In patients undergoing cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1-2 days after initiation of filgrastim therapy. expected neutrophil nadir has not been exceeded and the neutrophil count has not returned to a normal level. Premature discontinuation of filgrastim therapy before the expected neutrophil nadir is reached is not recommended.
Patients undergoing myeloablative therapy followed by bone marrow transplant
The recommended starting dose of filgrastim is 1.0 MU (10 mcg) / kg / day.
The first dose of Filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.
Once the neutrophil nadir has been passed, the daily dose of Filgrastim should be titrated based on the neutrophil response as follows:
Mobilization of PBPCs
For the mobilization of peripheral blood progenitor cells (PBPCs) in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation
The recommended dose of filgrastim for PBPC mobilization, when used alone, is 1.0 MU (10 mcg) / kg / day for 5 to 7 consecutive days. Leukapheresis planning: 1 or 2 leukapheresis on days 5 and 6 are often sufficient. In other cases, additional leukapheresis may be required. Filgrastim administration should be continued until the last leukapheresis.
The recommended dose of filgrastim for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU (5 mcg) / kg / day to be administered daily from the first day following completion of chemotherapy until the expected neutrophil nadir has been exceeded and the neutrophil count has not returned to a normal level. Leukapheresis should be performed during the period when the ANC increases from 5.0 x 109 / L. In patients not undergoing extensive chemotherapy, a single leukapheresis is often sufficient. In other cases, further leukapheresis is recommended.
For the mobilization of peripheral blood progenitor cells (PBPCs) in healthy donors prior to allogeneic peripheral blood progenitor cell transplantation
For PBPC mobilization in healthy donors, filgrastim should be administered by subcutaneous injection at a dose of 10 mcg / kg / day for 4 to 5 consecutive days. Leukapheresis should start on day 5 and continue as needed until day 6 to achieve 4 x 106 CD34 + cells / kg body weight of the recipient.
In patients with severe chronic neutropenia
Congenital neutropenia: the recommended dose is 1.2 MU (12 micrograms) / kg / day in single or divided doses.
Idiopathic or cyclic neutropenia: the recommended starting dose is 0.5 MU (5 mcg) / kg / day as a single dose or in divided doses.
Dosage adjustments: Filgrastim should be administered daily until the neutrophil count has reached and can be maintained above 1.5 x 109 / l. When the response is obtained, the lowest effective dose to maintain this level should be determined. Long-term daily administration is required to maintain adequate neutrophil counts. After one to two weeks of therapy, the starting dose can be doubled or halved based on the patient's response. Thereafter, the dose can be individually adjusted every 1-2 weeks to maintain a mean neutrophil count between 1.5 x 109 / L and 10 x 109 / L. In patients with severe infections, a more rapid schedule of progressive dose escalation may be considered. In clinical studies, 97% of responders achieved a complete response at doses ≤ 24 mcg / kg / day. The long-term safety of filgrastim administration at doses above 24 micrograms / kg / day in patients with severe chronic neutropenia has not been demonstrated.
In patients with HIV infection
Reversal of neutropenia
The recommended starting dose of filgrastim is 0.1 MU (1 microgram) / kg / day administered daily with titration up to a maximum of 0.4 MU (4 mcg) / kg / day until it has been reached and can a normal nuetrophile count (ANC> 2.0 x109 / l) be maintained. In clinical trials,> 90% of patients responded to these doses, achieving reversal of neutropenia over a median of 2 days.
In a small number of patients (
Maintaining a normal neutrophil count
When reversal of neutropenia has been achieved, the lowest effective dose to maintain a normal neutrophil count should be determined. An initial dose adjustment with alternate day dosing of 30 MU (300 mcg) / day is recommended. Further dose adjustments may be required, depending on the patient's ANC, in order to maintain neutrophil counts at> 2.0 x 109 / L. In clinical trials, doses of 30 MU (300 mcg) / day were required. 1 to 7 days per week to maintain ANC> 2.0 x 109 / L, with a median frequency of administration of 3 days per week. Long-term administration may be required to maintain ANC> 2.0 x 109 / L.
Special populations
Elderly patients
Only a small number of elderly patients were included in clinical trials with filgrastim. No specific studies have been performed in this patient population. Therefore, no specific dosage recommendations can be made for these patients.
Patients with renal or hepatic insufficiency
Studies conducted with filgrastim in patients with severe renal or hepatic impairment show that its pharmacokinetic and pharmacodynamic profile is similar to that seen in healthy subjects. In these cases, no dosage adjustment is necessary.
Pediatric patients with severe chronic neutropenia (SCN) and malignant diseases
In clinical trials, sixty-five percent of patients treated for a SCN were under the age of 18. In this age group, mainly including patients with congenital neutropenia, efficacy has been demonstrated. No differences were observed in the safety profiles of pediatric patients treated for severe chronic neutropenia.
Data from clinical trials with pediatric patients indicate that the safety and efficacy of filgrastim are similar in adults and children undergoing cytotoxic chemotherapy.
The dosing recommendations in pediatric patients are identical to the recommendations valid for adults undergoing myelosuppressive cytotoxic chemotherapy.
Method of administration
Standard cytotoxic chemotherapy
Filgrastim can be administered by daily subcutaneous injection or daily intravenous infusion diluted in 50 mg / ml (5%) glucose solution for injection over 30 minutes (see section 6.6 on dilution instructions). In most cases, the subcutaneous route is preferable. There is evidence from a single dose study that intravenous use may reduce the duration of effect. The clinical relevance of this finding for multiple dose administration is unclear. The choice of route of administration should be based on the clinical condition of the individual patient. In randomized clinical trials, subcutaneous doses of 230 mcg / m2 / day (4.0 to 8.4 mcg / kg / day) were used.
Patients undergoing myeloablative therapy followed by bone marrow transplant
Filgrastim is administered by intravenous infusion lasting 30 minutes or by intravenous infusion or by continuous 24 hour subcutaneous infusion. Filgrastim must be diluted in 20 ml of a 50 mg / ml (5%) glucose solution for infusion (see section 6.6).
Mobilization of PBPCs
For peripheral blood progenitor cell (PBPC) mobilization in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation, the recommended dose of filgrastim by continuous subcutaneous infusion can be administered over 24 hours or by single daily subcutaneous injection for 5 - 7 consecutive days. For infusion filgrastim must be diluted in 20 ml of a 50 mg / ml (5%) glucose solution for injection (see section 6.6).
NCG / HIV infection
Subcutaneous injection.
For instructions on handling the medicinal product before use refer to section 6.6.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients mentioned in section 6.1.
04.4 Special warnings and appropriate precautions for use
Special warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond the standard dose regimen.
Filgrastim must not be given to patients with severe congenital neutropenia (Kostman's syndrome) with cytogenetic abnormalities.
Hypersensitivity reactions, including anaphylactic reactions, occurring at initiation or subsequent to treatment, have been reported in patients treated with filgrastim. Permanently discontinue treatment with filgrastim in patients with clinically significant hypersensitivity.Do not administer filgrastim to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.
As with all therapeutic proteins, there is a potential risk of immunogenicity. The likelihood of generating antibodies against filgrastim is generally low. Development of binding antibodies is expected with all biologics; however, to date they have not been associated with activity. neutralizing.
Proliferation of malignant cells
GCSF can promote the proliferation of myeloid cells in vitro and similar effects can be seen in vitro on some non-myeloid cells.
The safety and efficacy of administering Filgrastim to patients with myelodysplastic syndrome or chronic myeloid leukemia have not been demonstrated.
Filgrastim is not indicated in such situations. Particular attention must be paid to the differential diagnosis between blast transformation in chronic myeloid leukemia and acute myeloid leukemia.
Due to limited data on safety and efficacy, filgrastim should be administered with caution in patients with secondary AML.
The safety and efficacy of filgrastim administration in patients of de novo age and favorable cytogenetics [t (8; 21), t (15; 17), and inv] have not been demonstrated.
Other special precautions
Bone density monitoring may be indicated in patients with underlying osteoporosis who are on continuous filgrastim therapy for more than 6 months.
Rare lung adverse reactions (> 0.01% and interstitial pneumonia have been reported following administration of G-CSF. Patients with a recent history of pulmonary infiltration or pneumonia may be at increased risk. The appearance of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltration and deterioration of lung function may be preliminary signs of adult respiratory distress syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment initiated.
Capillary leak syndrome has been reported following administration of granulocyte colony stimulating factor and is characterized by hypotension, hypoalbuminaemia, edema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment which may include the need for intensive care (see section 4.8).
Special precautions in cancer patients
Leukocytosis
White blood cell counts of 100 x 109 / L or greater have been observed in less than 5% of patients treated with filgrastim at doses above 0.3 MU / kg / day (3 mcg / kg / day). No adverse reactions directly attributable to this degree of leukocytosis were observed. However, in view of the potential risks associated with severe leukocytosis, regular monitoring of white blood cell counts should be performed during filgrastim therapy. Filgrastim treatment should be stopped immediately if the white blood cell count exceeds 50 x 109 / l after the expected nadir. However, during the period of administration of filgrastim for PBPC mobilization, treatment should be stopped or the dose should be reduced if the white blood cell count exceeds 70 x 109 / l.
Risks associated with high-dose chemotherapy
Particular care should be taken in the treatment of patients with high-dose chemotherapy, because a more favorable tumor response has not been demonstrated and because the administration of high-dose chemotherapy can increase toxic effects, including cardiac, pulmonary, neurological and dermatological effects. (refer to the summary of product characteristics of the chemotherapeutic agents used).
Treatment with filgrastim alone does not prevent thrombocytopenia and anemia following myelosuppressive chemotherapy. As a result of the possibility of receiving higher doses of chemotherapy (e.g. full doses according to the prescribed dosage regimen), the patient may be exposed to an increased risk of thrombocytopenia and anemia. Regular checks of platelet counts and hematocrit are therefore recommended. Particular attention should be paid during the administration, both alone and in combination, of chemotherapeutic agents known to induce severe thrombocytopenia.
The use of filgrastim-mobilized PBPCs has been shown to reduce the severity and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Splenomegaly
Cases of splenomegaly and splenic rupture have been uncommonly reported following administration of filgrastim. Some cases of splenic rupture have been fatal. Subjects receiving filgrastim and reporting left upper abdominal pain and / or shoulder extremity pain should be evaluated for splenic enlargement or splenic rupture.
Other special precautions
The effect of filgrastim in patients with significantly reduced myeloid progenitors has not been studied. To increase neutrophil counts, filgrastim acts primarily on neutrophil precursors. Therefore, in patients with low numbers of precursors (for example in patients treated with radiotherapy or extensive chemotherapy or patients with tumor infiltration of the bone marrow), the response of neutrophils may be reduced.
Cases of graft versus host disease, GvHD and death have been reported in patients treated with G-CSF after allogeneic bone marrow transplantation (see section 5.1).
The effect of filgrastim on GvHD disease has not been defined.
Increased bone marrow hematopoietic activity in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone reports.
Special precautions in patients undergoing peripheral blood progenitor cell mobilization.
Mobilization
There are no prospective radiological studies comparing the two recommended mobilization methods (filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patient population. The degree of variability between individual patients and between laboratory tests of CD34 + cells demonstrates the difficulty of comparing different studies, therefore it is difficult to recommend an optimal method.The choice of the mobilization method should be evaluated in relation to the treatment goals for the individual patient.
Previous exposure to cytotoxic agents
In patients extensively pre-treated with myelosuppressive therapy it is possible that PBPC mobilization is not sufficient to obtain the minimum recommended number of cells (2.0 x 106 CD34 + cells / kg) or that the acceleration of platelet recovery is less marked.
Some cytotoxic agents show particular toxicity on haematopoietic progenitor cells and can counteract their mobilization. Substances such as melphalan, carmustine (BCNU) and carboplatin, if given for an extended period before progenitor cell mobilization, can reduce the number of cells collected. However, administration of melphalan, carboplatin or BCNU in combination with filgrastim has been shown to be effective in mobilizing progenitor cells. If a peripheral blood progenitor cell transplant is planned, stem cell mobilization should be planned in the initial phase of the patient's intended treatment. Particular attention should be paid to the number of progenitor cells mobilized in such patients prior to the administration of high-dose chemotherapy. If cell collection is inadequate according to the previously indicated evaluation criteria, alternative treatments that do not require the use of progenitor cells should be considered.
Evaluation of the collection of progenitor cells
In the quantitative evaluation of progenitor cells obtained in patients treated with filgrastim, particular attention should be paid to the method of enumeration. The results of CD34 + cell count by flow cytometry vary according to the methodology used; therefore, numbers derived from studies conducted in other laboratories must be interpreted with caution.
Statistical analysis of the relationship between the number of CD34 + cells reinfused and the rate of platelet recovery after high-dose chemotherapy indicates a complex but constant relationship.
The recommendation to collect a minimum number of 2.0 x 106 CD34 + cells / kg is based on published experience, which indicates that haematological recovery is thus adequate. Amounts greater than the minimum number indicated appear to be related to faster recovery, smaller amounts to slower recovery.
Special precautions in healthy donors undergoing peripheral blood progenitor cell mobilization
PBPC mobilization has no direct clinical benefit in healthy donors and should only be considered with the aim of allogeneic stem cell transplantation.
PBPC mobilization should only be considered in donors who meet the normal clinical and laboratory eligibility criteria for stem cell donation, paying particular attention to haematological parameters and the presence of infectious diseases.
The safety and efficacy of filgrastim have not been evaluated in healthy donors aged 60 years.
Transient thrombocytopenia (platelets
If more than one leukapheresis is required, donors with platelets
Leukapheresis should not be performed in donors on anticoagulant therapy or who have known changes in haemostasis.
Filgrastim administration should be discontinued or the dosage should be reduced if the white blood cell count reaches> 70 x109 / l.
Donors receiving G-CSF for PBPC mobilization should be monitored until haematological parameters are normalized.
Transient cytogenic changes have been observed after use of G-CSF in healthy donors. The significance of these changes is unknown.
Long-term safety follow-up in donors is ongoing. However, the risk of developing a malignant myeloid cell clone cannot be excluded. It is recommended that the apheresis center carry out systematic registration and screening of stem cell donors to ensure long-term safety monitoring.
Following administration of G-CSF, generally asymptomatic splenomegaly and, in very rare cases, rupture of the spleen has been commonly observed in healthy donors (and patients). Some cases of ruptured spleen have been fatal. Therefore, the volume of the spleen should be carefully checked (e.g. by physical examination, ultrasound). The diagnosis of ruptured spleen should be considered in donors and / or patients with left upper abdominal pain or shoulder blade pain.
In post-marketing experience, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, pulmonary infiltration, dyspnoea and hypoxia) have been reported very rarely in normal donors after use of other medicinal products containing filgrastim. In case of suspected pulmonary adverse events or established, discontinuation of filgrastim treatment should be considered and necessary medical assistance provided.
Special precautions in recipients of allogeneic peripheral blood progenitor cells mobilized with filgrastim
Current data indicate that immunological interactions between allogeneic PBPCs and the recipient may be associated with an increased risk of acute and chronic graft versus host disease (GvHD) compared to bone marrow transplantation.
Special precautions in patients with severe chronic neutropenia (SCN)
Complete blood count
Platelet counts should be monitored frequently, particularly during the first few weeks of filgrastim therapy. Intermittent discontinuation of treatment or dose reduction of filgrastim should be considered in patients who develop thrombocytopenia, ie with platelets
Other changes in the blood picture may occur, including anemia and transient increases in myeloid progenitors, which require careful monitoring of blood counts.
Transformation into leukemia or myelodysplastic syndrome
Particular attention must be paid to the differential diagnosis between severe chronic neutropenia and other haematological diseases such as aplastic anemia, myelodispalsia and myeloid leukemia. A complete blood count with differential and platelet counts, as well as an assessment of bone marrow morphology and a karyotype, should be performed prior to initiation of treatment.
Myelodysplastic syndromes (MDS) or leukemia have been observed in a small number (approximately 3%) of patients with severe chronic neutropenia treated with filgrastim in clinical trials. This has only been observed in patients with congenital neutropenia. MDS and leukemia are natural complications of the disease and are not to be considered with certainty in relation to treatment with filgrastim. Abnormalities, including monosomy 7, were subsequently found in approximately 12% of patients with normal cytogenetics at baseline during routine repeat testing. If patients with severe chronic neutropenia develop cytogenetic abnormalities, the risks and benefits of continuing treatment with filgrastim should be carefully considered; Filgrastim administration should be discontinued if MDS or leukemia develops. It is currently unknown whether long-term treatment of patients with severe chronic neutropenia can predispose patients to cytogenetic abnormalities, MDS, or leukemic transformation. In these patients, morphological and cytogenetic analyzes of the bone marrow are recommended at regular intervals (approximately every 12 months).
Splenomegaly
Cases of splenomegaly and splenic rupture have been uncommonly reported following administration of filgrastim. Some cases of splenic rupture have been fatal. Individuals receiving filgrastim and reporting left upper abdominal pain and / or shoulder extremity pain should be evaluated for splenic enlargement or splenic rupture.
Other special precautions
Causes of transient neutropenia, such as viral infections, must be excluded.
Splenomegaly is a direct effect of filgrastim treatment. Palpable splenomegaly was observed in 31% of patients in clinical studies. Volume increases, measured radiologically, were seen early during filgrastim therapy and showed a tendency to stabilize. Dose reductions were observed to slow or halt the progression of splenomegaly, and a splenectomy was required in 3% of patients. The volume of the spleen should be checked regularly. Abdominal palpation is sufficient to detect abnormal volume increases.
Haematuria / proteinuria occurred in a small number of patients. Urinalysis should be done at regular intervals in order to detect such events.
Safety and efficacy in neonates and in patients with autoimmune neutropenia have not been demonstrated.
Special precautions in HIV infected patients
Complete blood count
Absolute neutrophil count (ANC) should be monitored frequently, particularly during the first few weeks of filgrastim therapy. Some patients may respond very quickly and with a marked increase in neutrophil counts at the starting dose of filgrastim. It is recommended that the ANC be determined daily during the first 2-3 days of filgrastim administration. Thereafter, it is recommended that the ANC be determined at least twice a week during the first 2 weeks and once a week or every other week thereafter. during maintenance therapy. With intermittent administration of 30 MU (300 mcg) / day of filgrastim, large fluctuations over time of the ANC may occur. To determine the minimum or nadir value of a patient's ANC, it is recommended that blood samples be taken. intended for ANC determination immediately prior to the intended administration of filgrastim.
Risks associated with high doses of myelosuppressive medicinal products
Treatment with filgrastim alone does not prevent thrombocytopenia and anemia following myelosuppressive therapy. Since higher doses or more of these medicinal products can be administered with the use of filgrastim, the patient may be at increased risk of thrombocytopenia or anemia. Regular monitoring of hematocrit is recommended (see above).
Infections and malignancies causing myelosuppression
Neutropenia may be due to bone marrow infiltration from opportunistic infections, such as Mycobacterium avium complex, or to malignant neoplasms, such as lymphomas. In patients with known bone marrow infiltrating infections or malignancies, consideration should be given to adequate treatment of the underlying disease in addition to administration of filgrastim for the treatment of neutropenia. The effects of filgrastim on neutropenia due to bone marrow infiltrating infections or malignancies have not been conclusively demonstrated.
Splenomegaly
Cases of splenomegaly and splenic rupture have been uncommonly reported following administration of filgrastim. Some cases of splenic rupture have been fatal. Individuals receiving filgrastim and reporting left upper abdominal pain and / or shoulder extremity pain should be evaluated for splenic enlargement or splenic rupture.
Special precautions in sickle cell or sickle cell anemia
Sickle cell crises, in some cases fatal, have been reported in patients with sickle cell or sickle cell anemia treated with filgrastim. In patients with sickle trait or sickle cell anemia, physicians should exercise caution when evaluating the use of filgrastim which should only be used after careful consideration of the potential benefits and risks.
Excipients
Nivestim contains sorbitol. Patients with rare hereditary fructose intolerance should not use this medicine. It also contains less than 1 mmol sodium (23 mg) per dose, ie essentially "sodium-free".
04.5 Interactions with other medicinal products and other forms of interaction
The safety and efficacy of filgrastim administered on the same day as myelosuppressive cytotoxic chemotherapy have not been conclusively demonstrated. Since rapidly dividing myeloid cells are sensitive to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended in the period. between 24 hours before and 24 hours after chemotherapy. Preliminary data obtained in a small number of patients treated jointly with filgrastim and 5-Fluorouracil indicate that neutropenia may worsen.
The possible interactions with other hematopoietic growth factors and cytokines have not yet been studied in clinical trials.
Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. Although this interaction has not been formally studied, there is no evidence that it is harmful.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no or limited data from the use of filgrastim in pregnant women.
Animal studies have shown reproductive toxicity. An "increased incidence of miscarriages following exposure" to high multiples of clinical doses was observed in rabbits
and in the presence of maternal toxicity (see section 5.3). Cases have been described in the literature in which placental spread of filgrastim has been demonstrated in pregnant women. Filgrastim is not recommended during pregnancy.
Feeding time
It is not known whether filgrastim is excreted in human breast milk; therefore, filgrastim is not recommended in women who are breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from filgrastim therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Filgrastim had no effect on reproduction or fertility in male or female rats (see section 5.3).
04.7 Effects on ability to drive and use machines
Filgrastim has modest effects on the ability to drive and use machines. If the patient feels tired, care should be taken when driving or using machines.
04.8 Undesirable effects
Summary of the safety profile
During clinical trials, 183 cancer patients and 96 healthy volunteers were exposed to Nivestim.
The safety profile of filgrastim observed in these clinical studies was consistent with that reported for the reference product used in these studies.
In clinical studies in cancer patients the adverse reaction attributable to filgrastim at the most frequent recommended dose was musculoskeletal pain, mild or moderate in 10% and severe in 3% of patients.
Graft versus host reaction disease (GvHD) has also been reported (see below).
In the mobilization of circulating peripheral stem cells (PBPCs) in healthy donors, the most common reported adverse reaction was musculoskeletal pain. Leukocytosis was observed in donors and thrombocytopenia following filgrastim and leukapheresis was also observed in donors. Splenomegaly and splenic rupture have also been reported. Some cases of splenic rupture have been fatal.
In patients with severe chronic neutropenia (SCN) the most frequent adverse reactions attributable to filgrastim were bone pain, general musculoskeletal pain and splenomegaly.
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported uncommonly (≥1 / 1000 to
In clinical trials in HIV patients, the only adverse reactions that were considered uniquely related to filgrastim administration were musculoskeletal pain, mild to moderate bone pain and myalgia. The incidence of these reactions was similar to that reported in cancer patients.
Table of adverse reactions
The adverse reactions listed below and their frequency were observed after treatment with filgrastim according to published data.
Frequencies of adverse reactions are defined according to the following conventions:
Very common: ≥1 / 10
Common: ≥1 / 100 y
Uncommon: ≥1 / 1,000 y
Rare: ≥1 / 10,000 y
Very rare:
Not known: cannot be estimated from the available data
Within each frequency group, adverse reactions are presented in descending order of severity.
In cancer patients
Healthy donors undergoing peripheral blood progenitor cell mobilization
In patients with severe chronic neutropenia (SCN)
In patients with HIV
Description of selected adverse reactions
GvHD and deaths have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation (see section 5.1).
Cases of capillary leak syndrome have been reported post-marketing with the use of granulocyte colony stimulating factors. These have generally occurred in patients with advanced malignancy, sepsis, who were taking multiple chemotherapy drugs or undergoing apheresis ( see section 4.4).
In cancer patients
Musculoskeletal pain is usually controlled with standard analgesics. Less frequent adverse reactions include urinary abnormalities with predominantly mild or moderate dysuria.
In randomized, placebo-controlled trials, filgrastim did not increase the incidence of adverse events associated with cytotoxic chemotherapy. Adverse reactions observed with equal frequency in patients treated with filgrastim chemotherapy and placebo / chemotherapy were nausea, vomiting, alopecia, diarrhea, fatigue, anorexia, headache, cough rash, chest pain, general weakness, sore throat, constipation and unspecified pain.
Reversible, dose-dependent and usually mild to moderate increases in lactate dehydrogenase, alkaline phosphatase, uric acid have been reported in 50%, 35%, 25%, and 10% of patients treated with filgrastim at recommended doses, respectively. serum and gamma-glutamyltranspeptidase.
Transient increases in blood pressure have also occasionally been reported, requiring no clinical treatment.
Vascular disorders including veno-occlusive disease and fluid volume changes have occasionally been reported in patients treated with high doses of chemotherapy followed by autologous bone marrow transplantation. A causal relationship with filgrastim has not been demonstrated.
Rare adverse events of cutaneous vasculitis have been reported in patients treated with filgrastim. The mechanism of vasculitis in patients treated with filgrastim is not known.
Occasional cases of Sweet's syndrome (acute febrile dermatosis) have been described. However, as a significant percentage of these patients were diagnosed with leukemia, a condition known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been demonstrated.
In individual cases an "exacerbation of" rheumatoid arthritis has been reported.
There have been rare reports of pulmonary adverse events including interstitial pneumonia, pulmonary edema and pulmonary infiltrations with respiratory failure or adult respiratory distress syndrome (ARDS), which can be fatal (see section 4.4).
Allergic reactions: Allergic-type reactions, including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension, occurring in patients on first or subsequent filgrastim treatment, have been reported. Overall, reports were more frequent after administration. In some cases, symptoms have recurred upon resumption of treatment, suggesting a causal relationship In patients who experience a severe allergic reaction to filgrastim, treatment should be permanently discontinued.
Isolated cases of sickle cell crises have been reported in patients with sickle cell anemia or sickle trait (see section 4.4). From clinical data the frequency is estimated as uncommon.
Pseudogout has been reported in cancer patients treated with filgrastim.
Healthy donors undergoing peripheral blood progenitor cell mobilization
Leukocytosis (white blood cell count (WBC)> 50 x 109 / l) was reported in 41% of donors and thrombocytopenia (platelet
Transient and mild elevations in alkaline phosphatase, LDH, SGOT and uric acid have been reported in healthy donors treated with filgrastim who had no clinical sequelae.
An "exacerbation of arthritic symptoms has been reported very rarely.
Severe allergic reactions have been reported very rarely.
Headache, believed to be triggered by filgrastim, has been reported in studies with healthy PBPC donors.
Asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been commonly reported in healthy donors and in patients following administration of granulocyte colony stimulating factors (G-CSFs) (see section 4.4).
Pulmonary adverse events in healthy donors (haemoptysis, pulmonary haemorrhage, pulmonary infiltrates, dyspnoea and hypoxia) have been reported very rarely in post-marketing experience of other filgrastim medicinal products (see section 4.4).
In patients with severe chronic neutropenia (SCN)
Adverse reactions related to filgrastim therapy have been reported in SCN patients and for some of them their frequency tends to decrease over time.
Adverse reactions include splenomegaly which may be progressive in a minority of cases and thrombocytopenia. Headache and diarrhea have usually been reported in less than 10% of patients soon after initiation of filgrastim therapy. Anemia and epistaxis have also been reported.
Transient increases in serum without any clinical symptoms have been reported for uric acid, lactate dehydrogenase and alkaline phosphatase. Transient and moderate drops in non-fasting blood glucose have also been reported.
Among the adverse reactions likely related to filgrastim therapy that normally occurred in arthralgia, alopecia, osteoporosis and rash.
Cutaneous vasculitis was reported in 2% of SCN patients after prolonged use. There have been only a few cases of proteinuria / hematuria.
In patients with HIV
Splenomegaly was reported to be secondary to filgrastim therapy in hypersplenism and no patient underwent splenectomy. The relationship to filgrastim treatment is unknown as splenomegaly is common in HIV-infected patients and is present to varying degrees in most AIDS patients.
Pediatric population
Data from clinical trials in pediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy, suggesting that there are no age-related differences in the pharmacokinetics of filgrastim. The only adverse reaction consistently reported was musculoskeletal pain which is no different from the experience in the adult population.
There are insufficient data to further evaluate the use of filgrastim in pediatric subjects.
Other special populations
Geriatric use
In general, no differences in safety or efficacy were observed between subjects over 65 years of age and younger adults (> 18 years of age) receiving cytotoxic chemotherapy and clinical experience has identified no differences in responses. between older and younger adult patients. There are insufficient data to evaluate the use of filgrastim in geriatric individuals for the other approved indications of filgrastim.
Pediatric patients with severe chronic neutropenia (SNG)
Cases of decreased bone density and osteoporosis have been reported in pediatric patients with severe chronic neutropenia receiving chronic treatment with filgrastim. The frequency is estimated as "common" from data from clinical trials.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows for continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "Annex V.
04.9 Overdose
The effects of filgrastim overdose have not been demonstrated.
Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1-2 days and return to normal within 1-7 days.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunostimulant, colony stimulating factors.
ATC code: L03AA02.
Nivestim is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency www.ema.europa.eu
Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Nivestim, which contains r-metHuG-CSF (filgrastim), induces a marked increase in peripheral blood neutrophil counts and a less marked increase in monocytes within 24 hours. In some patients with severe chronic neutropenia, filgrastim may induce even a slight increase in the number of circulating eosinophils and basophils from baseline; some of these patients may present with eosinophilia or basophilia even before treatment. At recommended doses, the increase in the number of neutrophils is dose-dependent.As demonstrated in the analyzes conducted, neutrophils produced in response to filgrastim show normal or increased chemotactic and phagocytic properties. Upon completion of filgrastim treatment, the number of circulating neutrophils decreases by approximately 50% within 1-2 days and reaches normal levels within 1-7 days.
The use of filgrastim in patients undergoing cytotoxic chemotherapy significantly reduces the incidence, severity and duration of nuetropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalization after induction chemotherapy in acute myeloid leukemia or myeloablative therapy followed by bone marrow transplant. In both cases, the incidence of fever and documented infections was not reduced. Fever duration was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
The use of filgrastim, either alone or after chemotherapy, mobilizes haematopoietic progenitor cells into peripheral blood. These autologous peripheral blood progenitor cells (PBPCs) can be collected and reinfused after high-dose cytotoxic chemotherapy, as an alternative to or in addition to transplantation of bone marrow. PBPC infusion accelerates haematopoietic recovery and thus reduces the duration of the risk of bleeding complications and the need for thrombocyte transfusions.
Recipients of peripheral allogeneic blood progenitor cells mobilized with filgrastim, compared to allogeneic bone marrow transplant recipients, reported a significant rapid haematological recovery with consequent significant recovery of time without supply of thrombocytes.
A retrospective European study, which analyzed the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemia, indicated an increased risk of GvHD, and mortality following administration of G-CSF (TRM In another international retrospective study, conducted with patients with acute and chronic myeloid leukemias, no effect on the risk of GvHD, TRM and mortality was observed. In a meta-analysis of allogeneic transplant studies, including the results of nine prospective randomized studies, 8 retrospective studies and 1 case-control study, no effects on the risk of acute GvHD, chronic GvHD or early treatment-related mortality were observed.
a The analysis includes studies concerning bone marrow transplantation in the period in question; GM-CSF was used in some studies
b The analysis includes patients who underwent bone marrow transplant during the period in question
Use of filgrastim for PBPC mobilization in healthy donors prior to allogeneic PBPC transplantation results in recovery of 4 x 106 CD34 + cells / kg per recipient body weight in most donors after two leukaphereses. Normal donors are given a dose of 10 mcg / kg / day, subcutaneously for 4-5 consecutive days.
The use of filgrastim in patients, adults and children, with severe chronic neutropenia (severe congenital, cyclic and idiopathic neutropenia) induces a marked increase in absolute peripheral blood neutrophil counts and a reduction in infectious episodes and related events.
The use of filgrastim in HIV-infected patients maintains neutrophil counts at normal levels and thus allows the antiviral and / or myelosuppressive drugs to be administered as intended. There is no evidence that HIV-infected patients and treated with filgrastim show increased HIV replication.
As has been observed with other hematopoietic growth factors, G-CSF also shows in vitro a stimulating effect on human endothelial cells.
The efficacy and safety of Nivestim have been studied in randomized, controlled phase III studies in breast cancer. No relevant differences were found between Nivestim and the reference product with regard to the duration of severe neutropenia and the incidence of febrile neutropenia.
05.2 Pharmacokinetic properties
A randomized, unencrypted, single-dose, comparator-controlled trial, in duplicate crossover conducted on 46 healthy volunteers showed that the pharmacokinetic profile of Nivestim was comparable to that of the reference product after subcutaneous and intravenous treatment.
In another randomized, double-blind, multiple-dose, comparator-controlled, double-crossover study in 50 healthy volunteers showed that the pharmacokinetic profile of Nivestim was comparable to that of the reference product after subcutaneous treatment.
The clearance of filgrastim has been demonstrated to follow first-order pharmacokinetics after both subcutaneous and intravenous treatment. The serum elimination half-life of filgrastim is approximately 3.5 hours, with an elimination rate of approximately 0.6 ml / min / kg. Continuous infusion of filgrastim over a period of 28 days in patients with recovery phase from autologous bone marrow transplantation, did not show any accumulation of the drug with a comparable half-life. Therefore, there is a positive linear correlation between the dose and serum concentration of filgrastim, regardless of whether it is administered intravenously or subcutaneously. After subcutaneous administration of the recommended doses, serum concentrations were maintained above 10 ng / ml for 8 - 16 hours. The volume of distribution in the blood is approximately 150 ml / kg.
05.3 Preclinical safety data
Filgrastim has been studied in repeat dose toxicity studies up to 1 year duration which revealed changes attributable to expected pharmacological effects including increased leukocytes, myeloid bone marrow hyperplasia, extramedullary granulocytopoiesis and splenic enlargement.
These changes are all reversible after stopping treatment.
The effects of filgrastim on prenatal development were studied in rats and rabbits. Intravenous administration (80 micrograms / kg / day) of filgrastim in rabbits during the period of organogenesis showed maternal toxicity and an increase in spontaneous abortions, post-implantation loss and decrease in mean live litter size and fetal weight.
Based on data reported for another filgrastim product, similar results were observed beyond "increased fetal malformations at a dose of 100 mcg / kg / day, a maternal toxicity dose corresponding to a" systemic exposure of approximately 50-90. times the exposure observed in patients treated with the clinical dose of 5 mcg / kg / day. The level at which no adverse effect was observed for embryo-fetal toxicity in this study was 10 mcg / kg / day, which corresponded to a systemic exposure approximately 3-5 times the exposure observed in patients treated with the clinical dose.
In pregnant rats, no maternal or fetal toxicity was observed at doses above 575 mcg / kg / day. Administration of filgrastim to offspring of rats during the peri-natal and lactation periods showed a delay in external differentiation and growth retardation (≥ 20 mcg / kg / day) and a slightly reduced survival rate (100 mcg / kg / day). day).
No effects on fertility were observed in male or female rats for filgrastim.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Acetic acid, glacial
Sodium hydroxide
Sorbitol (E420)
Polysorbate 80
Water for injections
06.2 Incompatibility
Nivestim must not be diluted with sodium chloride solutions.
Diluted filgrastim can be absorbed by glass and plastics unless diluted in a 50 mg / ml (5%) glucose solution for infusion (see section 6.6).
This medicinal product must not be mixed with other medicinal products except those listed in section 6.6.
06.3 Period of validity
Pre-filled syringe
30 months.
After dilution
Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours at 2 ° C to 8 ° C. From a microbiological point of view, the product should be used immediately. If the medicinal product is not used immediately, the user is responsible for the storage duration and conditions prior to use; the medicinal product can be stored for up to 24 hours at a temperature between 2 ° C and 8 ° C, unless dilution takes place in controlled and validated aseptic conditions.
06.4 Special precautions for storage
Store and transport refrigerated (2 ° C - 8 ° C).
Do not freeze.
Keep the pre-filled syringes in the outer carton to protect them from light.
Accidental exposure to freezing temperatures for up to 24 hours has no adverse effect on the stability of Nivestim. The frozen pre-filled syringe can be thawed and returned to the refrigerator for later use. If exposure to low temperatures is greater than 24 hours or if frozen for more than once then Nivestim must NOT be used anymore.
Within its shelf life and for outpatient use, the patient can remove the product from the refrigerator and store it at room temperature (not above 25 ° C) for one time and up to 7 days. period, the product must no longer be placed in the refrigerator and must be discarded.
For storage conditions of the medicinal product after dilution, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Pre-filled syringe (type I glass) with injection needle (stainless steel) with needle safety guard, containing 0.2 ml of solution for injection / infusion.
Pack size of 1, 5 or 10 pre-filled syringes.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
If necessary, Nivestim can be diluted in 50 mg / ml (5%) glucose solution for injection.
Dilution to a final concentration below 0.2 MU (2 mcg) per ml is never recommended.
The solution should be visually inspected prior to use. Only clear, particle-free solutions should be used.
In patients treated with filgrastim diluted to concentrations below 1.5 MU (15 mcg) per ml, human serum albumin (HSA) should be added at a final concentration of 2 mg / ml.
Example: In a final volume to be injected of 20 ml, total doses of filgrastim below 30 MU (300 mcg) should be administered by adding 0.2 ml of 20% human albumin solution.
Filgrastim diluted in glucose solution at 50 mg / ml (5%) is compatible with glass and many plastics including PVC, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
Nivestim does not contain preservatives. Due to the risk of bacterial contamination, Nivestim syringes are for single use only. Unused medicinal product and waste derived from this medicinal product should be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire CV31 3RW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/631/001
040158014
EU / 1/10/631/002
040158026
EU / 1/10/631/003
040158038
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 08 June 2010
10.0 DATE OF REVISION OF THE TEXT
D.CCE May 2015
