Active ingredients: Filgrastim
Neupogen 30 MU (0.3 mg / ml) solution for injection
Neupogen 48 MU (0.3 mg / ml) solution for injection
Neupogen package inserts are available for pack sizes: - Neupogen 30 MU (0.3 mg / ml) solution for injection, Neupogen 48 MU (0.3 mg / ml) solution for injection
- Neupogen 30 MU (0.6 mg / ml) solution for injection in a pre-filled syringe, Neupogen 48 MU (0.96 mg / ml) solution for injection in a pre-filled syringe
Why is Neupogen used? What is it for?
Neupogen is a white blood cell growth factor (granulocyte colony-stimulating factor) and belongs to the group of drugs called cytokines. Growth factors are proteins naturally produced in the body, but they can also be produced with the help of biotechnology, for use as drugs. Neupogen stimulates the bone marrow to produce more white blood cells.
A reduction in the number of white blood cells (neutropenia) can occur for several reasons, reducing the body's ability to defend itself against infections. Neupogen stimulates the bone marrow to rapidly produce new white blood cells.
Neupogen can be used:
- to increase the number of white blood cells after chemotherapy treatment, thus helping to prevent infections;
- to increase the number of white blood cells after a bone marrow transplant, thus helping to prevent infections;
- before high-dose chemotherapy, to cause the bone marrow to produce more stem cells, which can be harvested and given back to the patient after treatment. These cells can be taken from you or from a donor. The stem cells will then return to the bone marrow and produce blood cells;
- to increase the number of white blood cells in case of severe chronic neutropenia, thus helping to prevent infections;
- in patients with advanced HIV infection, to help reduce the risk of infections.
Contraindications When Neupogen should not be used
Do not use Neupogen
- 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 Neupogen
Talk to your doctor, pharmacist or nurse before using Neupogen. Before starting Neupogen treatment, tell your doctor if you have:
- sickle cell anemia, as filgrastim can cause sickle cell crisis;
- osteoporosis (bone disease).
Tell your doctor immediately during Neupogen treatment if:
- you have pain in the left upper belly (abdominal pain), pain under the left rib cage or in the extremity of the left shoulder (these may be symptoms of an enlarged spleen (splenomegaly) or a possible rupture of the spleen).
- you notice uncommon bleeding or bruising (these may be symptoms of a decrease in the number of platelets (thrombocytopenia) with a reduced ability of the blood to clot).
- you have sudden signs of allergy such as rash, itching or bumps on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath or wheezing, as these may be signs of a severe allergic reaction.
- you experience swelling of your face or ankles, blood in your urine or brown colored urine or if you notice that you pass urine less than usual.
Loss of response to Filgrastim
If you experience a disappearance of response or the inability to maintain a response to treatment with filgrastim, your doctor will investigate the reasons including the possible development of antibodies that neutralize the activity of filgrastim.
The doctor may want to follow you closely.
If you are a patient with severe chronic neutropenia, you may be at risk of developing a blood cancer (leukemia, myelodysplastic syndrome (MDS). You should consult with your doctor about your risk of developing blood cancers and what tests you should If you develop or are likely to develop blood cancer, you should not use Neupogen, unless instructed by your doctor. If you are a stem cell donor, your age should be between 16 and 60 years.
Neupogen is part of a group of products that stimulate the production of white blood cells. The healthcare professional must always record the exact product you are using.
Take special care with other products that can stimulate white blood cells
Interactions Which drugs or foods may change the effect of Neupogen
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
Neupogen has not been tested in pregnant or breastfeeding women.
It is important that you tell your doctor if:
- you are pregnant;
- suspected pregnancy; or
- is planning a pregnancy.
If you become pregnant during Neupogen treatment, please inform your doctor. You may be encouraged to enroll in Amgen's Pregnancy Surveillance Program. Contact details of the local representative are given in section 6 of this leaflet.
Unless your doctor tells you otherwise, you should stop breastfeeding if you are using Neupogen.
If you are breastfeeding while taking Neupogen, you may be encouraged to enroll in Amgen's Lactation Surveillance program.
Driving and using machines
Neupogen is not expected to affect the ability to drive and use machines. However, it is recommended that you wait and see how you feel after taking filgrastim, before driving or using machines.
Neupogen contains sodium and sorbitol
Neupogen contains less than 1 mmol (23 mg) sodium per 0.3 mg / ml, i.e. essentially sodium-free.
Neupogen contains sorbitol (E420). If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Neupogen: Posology
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor, nurse or pharmacist.
How should Neupogen be given and how much should I take?
Neupogen is usually given as a daily injection into the tissue immediately beneath the skin (subcutaneous injection). It can also be given by slow daily injection into a vein (intravenous infusion). As a rule, the usual dose varies according to your disease and weight. Your doctor will tell you how much Neupogen to take.
Patients receiving bone marrow transplant after chemotherapy:
You will normally receive the first dose of Neupogen at least 24 hours after chemotherapy and at least 24 hours after the bone marrow transplant.
How long should I take Neupogen?
You will need to take Neupogen until the number of white blood cells has normalized. To monitor the number of white blood cells, you will have periodic blood tests. Your doctor will tell you how long to take Neupogen.
Use in children
Neupogen is used to treat children who are undergoing chemotherapy or who have a severe reduction in the number of white blood cells (neutropenia). The dosage in children undergoing chemotherapy is the same as in adults.
If you forget to use Neupogen
If you have missed an injection, contact your doctor as soon as possible. If you have any further questions on the use of this product, ask your doctor, nurse or pharmacist.
Overdose What to do if you have taken too much Neupogen
If you think you have injected more than you should, contact your doctor as soon as possible.
Side Effects What are the side effects of Neupogen
Tell your doctor immediately during treatment:
- if you experience allergic reactions, including weakness, drop in blood pressure, difficulty in breathing and swelling of the face (anaphylaxis), skin rashes and attacks of itching (hives), swelling of 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 (dyspnoea), as these can be symptoms of acute respiratory failure syndrome (ARDS); ARDS is not common in cancer patients;
- if you experience pain in the upper left (abdomen), pain under the left rib or pain in the extremity of the shoulder, as there may be a problem with the spleen (enlargement of the spleen (splenomegaly) or rupture of the spleen);
- if you are being treated for severe chronic neutropenia and have blood in your urine (haematuria). Your doctor may regularly evaluate your urine if you experience this side effect or if protein has been found in your urine (proteinuria);
- if you experience any or a combination of the following side effects:
- swelling or swelling, which may be associated with water passing less frequently, difficulty breathing, bloating and feeling of fullness, and a general feeling of tiredness. These symptoms usually develop quickly. These may be symptoms. an uncommon condition (may affect up to 1 in 100 people) called "capillary leak syndrome", which causes blood to leak from small blood vessels into the body and needs urgent medical attention.
- if you have kidney damage (glomerulonephritis). Kidney damage has been observed in patients taking filgrastim. Tell your doctor right away if you experience swelling of your face and ankles, blood in your urine or brown colored urine or if you notice that you pass urine less than usual.
A very common side effect with Neupogen use is pain in the muscles or bones (musculoskeletal pain) which can be relieved by taking common pain relievers (analgesics). graft versus host reaction (GvHD) - this is a reaction of the donor cells towards the person receiving the transplant; Signs and symptoms include rash of the palms or soles of the feet and ulcers and sores in the mouth, intestines, liver, skin or eyes, lungs, vagina and joints. It is seen very commonly. In healthy stem cell donors, the increase in white blood cells (leukocytosis) and the reduction in the number of platelets (thrombocytopenia), which lowers the blood's ability to clot, will be monitored by your doctor. Like all medicines, this medicine can cause side effects, although not everybody gets them.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects (seen in more than 1 in 10 people taking Neupogen):
in cancer patients
- changes in blood chemistry
- increase in the values of some enzymes in the blood
- decreased appetite
- headache
- pain in the mouth and throat (oropharyngeal pain)
- cough
- diarrhea
- He retched
- constipation
- nausea
- skin rashes
- unusual hair loss or thinning (alopecia)
- pain in the muscles or bones (musculoskeletal pain)
- generalized weakness (asthenia)
- tiredness (fatigue)
- ulceration and swelling of the cells lining the digestive tract, ie from the mouth to the anus (mucositis)
- shortness of breath (dyspnoea)
- pain in healthy stem cell donors
in healthy stem cell donors
- reduction in platelets which lowers the ability of the blood to clot (thrombocytopenia)
- increase in white blood cells (leukocytosis)
- headache
- pain in the muscles or bones (musculoskeletal pain)
in patients with severe chronic neutropenia
- enlargement of the spleen (splenomegaly)
- reduced number of red blood cells (anemia)
- changes in blood chemistry
- increase in some enzymes in the blood
- headache
- nosebleed (epistaxis)
- diarrhea
- enlarged liver (hepatomegaly)
- skin rashes
- pain in the muscles or bones (musculoskeletal pain)
- joint pain (arthralgia)
in patients with HIV infection
- pain in the muscles or bones (musculoskeletal pain).
Common side effects (seen in more than 1 in 100 people taking Neupogen):
in cancer patients
- allergic reactions (drug hypersensitivity)
- low blood pressure (hypotension)
- pain when urinating (dysuria)
- chest pain
- coughing up blood (hemoptysis)
in healthy stem cell donors
- increase in some enzymes in the blood
- breathing difficulties (dyspnoea)
- enlargement of the spleen (splenomegaly)
in patients with severe chronic neutropenia
- rupture of the spleen
- reduction in the number of platelets, which lowers the ability of the blood to clot (thrombocytopenia)
- changes in blood chemistry
- inflammation of the blood vessels in the skin (cutaneous vasculitis)
- unusual hair loss or thinning (alopecia)
- disease causing a reduction in bone density, making bones weaker, more fragile and more prone to fractures (osteoporosis)
- blood in the urine (haematuria)
- pain at the injection site
- damage to the kidney microfilters (glomerulonephritis)
in patients with HIV infection
- enlargement of the spleen (splenomegaly)
Uncommon side effects (seen in more than 1 in 1,000 people taking Neupogen):
in cancer patients
- rupture of the spleen
- enlargement of the spleen (splenomegaly)
- severe pain in the bones, chest, intestines or joints (sickle cell crisis)
- rejection of a bone marrow transplant (graft versus host disease)
- joint pain and swelling, similar to gout (pseudogout)
- severe inflammation of the lungs causing difficulty in breathing (acute respiratory distress syndrome)
- inadequate function of the lungs, which causes breathlessness (respiratory failure)
- swelling and / or fluid in the lungs (pulmonary edema)
- inflammation of the lungs (interstitial lung disease)
- abnormal x-ray examination of the lungs (pulmonary infiltrate)
- raised, painful purple lesions in the limbs, sometimes also in the face and neck with fever (Sweet's syndrome)
- inflammation of the blood vessels in the skin (cutaneous vasculitis)
- worsening of rheumatoid arthritis
- uncommon changes in urine
- liver damage caused by blockage of the small veins within the liver (veno-occlusive disease)
- bleeding from the lungs (pulmonary haemorrhage)
- a change in the regulation of fluids in the body which can lead to swelling
- damage to the kidney microfilters (glomerulonephritis)
in healthy stem cell donors
- rupture of the spleen
- severe pain in the bones, chest, intestines or joints (sickle cell crisis)
- sudden life-threatening allergic reaction (anaphylactic reaction)
- changes in blood chemistry
- bleeding in the lung (pulmonary haemorrhage)
- coughing up blood (hemoptysis)
- abnormal x-ray examination of the lungs (pulmonary infiltrate)
- loss of oxygen uptake in the lung (hypoxia)
- increase in some blood enzymes
- worsening of rheumatoid arthritis
- damage to the kidney microfilters (glomerulonephritis)
in patients with severe chronic neutropenia
- severe pain in the bones, chest, intestines or joints (sickle cell crisis)
- excess protein in the urine (proteinuria)
in patients with HIV infection
- severe pain in the bones, chest, intestines or joints (sickle cell crisis)
Not known side effects (frequency cannot be estimated from the available data)
- damage to the kidney microfilters (glomerulonephritis)
Reporting of side effects
If you get any side effects, talk to your doctor 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 at www.agenziafarmaco.it/it/responsabili. .
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Store in a refrigerator (2 ° C - 8 ° C).
Keep the container in the outer carton to protect it from light.
Accidental freezing will not harm Neupogen.
Do not use this medicine after the expiry date which is stated on the vial label (EXP) and on the carton after EXP. The expiry date refers to the last day of that month.
Do not use this medicine if you notice any abnormal coloration, cloudiness or particles, it must be a clear and colorless liquid.
Do not throw 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 Neupogen contains
- The active substance is filgrastim 30 million units in 1 ml (0.3 mg / ml) vial or 48 million units in 1.6 ml (0.3 mg / ml) vial.
- The other ingredients are sodium acetate, sorbitol (E420), polysorbate 80 and water for injections.
What Neupogen looks like and contents of the pack
Neupogen is a clear and colorless solution for injection (injection) / concentrate for solution for infusion (sterile concentrate) in a vial.
Neupogen is available in packs of one vial. Not all pack sizes may be marketed.
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
GRANULOKINE 30 MU (0.3 MG / ML) SOLUTION FOR INJECTION FILGRASTIM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 30 million units (MU) / 300 mcg (mcg) of filgrastim in 1 mL (0.3 mg / mL).
Filgrastim (recombinant human granulocyte colony stimulating methionylated factor) is produced by r-DNA technology in E. Coli (K12).
Excipient (s) with known effects:
Each ml of solution contains 0.0010 to 0.0022 mmol or 0.023 to 0.051 mg of sodium and 50 mg of sorbitol (E420).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
Concentrate for solution for infusion.
Clear, colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Neupogen is indicated to reduce the duration of neutropenia and the incidence of febrile neutropenia in patients treated with standard cytotoxic chemotherapy for malignancies (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) and to reduce the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplant considered to be at increased risk for prolonged severe neutropenia.
Neupogen safety and efficacy are similar in adults and children treated with cytotoxic chemotherapy.
Neupogen is indicated for the mobilization of peripheral blood progenitor cells (PBPCs).
In patients, children or adults, with severe congenital, cyclic or idiopathic neutropenia, with a CAN (absolute neutrophil count) ≤ 0.5 x 109 / l and a history of severe or recurrent infections, long-term administration of Neupogen is indicated. to increase neutrophil counts and to reduce the incidence and duration of infectious complications.
Neupogen is indicated for the treatment of persistent neutropenia (CAN equal to or less than 1.0 x 109 / L) in patients with advanced HIV infection to reduce the risk of bacterial infections when other options to control neutropenia are not appropriate.
04.2 Posology and method of administration
Neupogen therapy should only be performed in collaboration with cancer centers with experience in G-CSF treatment and in hematology and equipped with the necessary diagnostic equipment. The mobilization and apheresis procedures must be carried out in collaboration with an oncology-haematological center with adequate experience in this field and where the monitoring of hematopoietic progenitor cells can be correctly carried out.
Standard cytotoxic chemotherapy
Dosage
The recommended dose of Neupogen is 0.5 MU (5 mcg) / kg / day. The first dose of Neupogen should be given at least 24 hours after cytotoxic chemotherapy. In randomized clinical trials, a dose of 230 mcg / m2 / day (4.0-8.4 mcg / kg / day) was used subcutaneously.
Neupogen should be administered daily until the expected neutrophil nadir has been exceeded and the neutrophils have returned to a normal level. After standard chemotherapy for solid tumors, lymphomas and lymphoid leukemia, the duration of treatment required for meeting these criteria can reach up to 14. After induction and consolidation therapy for acute myeloid leukemia the duration of treatment can be substantially 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 the number of neutrophils is usually seen 1-2 days after initiation of Neupogen therapy. To achieve a prolonged therapeutic response, Neupogen therapy should not be discontinued before the nadir is exceeded. and before the neutrophil count has returned to normal. Premature discontinuation of Neupogen therapy before the expected neutrophil nadir is reached is not recommended.
Method of administration
Neupogen can be administered as a daily subcutaneous injection or as a daily intravenous infusion, diluted in 5% glucose solution, lasting 30 minutes (see section 6.6). The subcutaneous route is preferred in most cases. There is evidence from a single dose administration study that intravenous administration may reduce the duration of the effect. The clinical relevance of this compared to multidose administration is unclear. The choice of route of administration depends on the individual clinical circumstances.
Patients treated with myeloablative therapy followed by bone marrow transplant
Dosage
The recommended starting dose of Neupogen is 1.0 MU (10 mcg) / kg / day. The first dose of Neupogen 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 exceeded, the Neupogen daily dose should be adjusted to the neutrophil response as in the table below:
Method of administration
Neupogen can be given as a 30-minute or 24-hour 'intravenous infusion or given as a 24-hour continuous' subcutaneous infusion. Neupogen should be diluted in 20 ml of 5% glucose solution (see section 6.6).
For peripheral blood progenitor cell (PBPC) mobilization in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation
Dosage
The recommended dosage of Neupogen for PBPC mobilization when used alone is 1.0 MU (10 mcg) / kg / day for 5-7 consecutive days. Leukapheresis period: one or two leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukapheresis may be necessary. Neupogen dosage should be maintained until the last leukapheresis.
The recommended dose of Neupogen for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU (5 mcg) / kg / day from the first day following completion of chemotherapy until the expected neutrophil nadir is passed and until recovery. a normal neutrophil count. Leukapheresis must be performed in the period in which the CAN rises from
Method of administration
Neupogen when used alone for PBPC mobilization:
Neupogen can be given as a continuous 24-hour subcutaneous infusion or as a subcutaneous injection. Neupogen for infusion must be diluted in 20 ml of 5% glucose solution (see section 6.6).
Neupogen for PBPC mobilization after myelosuppressive chemotherapy:
Neupogen should be administered by subcutaneous injection.
For the mobilization of peripheral blood progenitor cells (PBPCs) in healthy donors prior to allogeneic peripheral blood progenitor cell transplantation
Dosage
For PBPC mobilization in healthy donors, Neupogen should be administered at a dose of 1.0 MU (10 mcg) / kg / day for 4-5 consecutive days. Leukapheresis should be started on day 5 and continued until day 6, if necessary, in order to collect a number of CD34 + cells equal to 4x106 per kg of recipient body weight.
Method of administration
Neupogen should be administered by subcutaneous injection.
Patients with severe chronic neutropenia (SCN)
Dosage
Congenital neutropenia: the recommended starting 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 in single or divided doses.
Dose adjustment: Neupogen should be administered daily by subcutaneous injection until a neutrophil count greater than 1.5 x 109 / l is achieved and can be maintained. Once the response is obtained, the minimum effective dose to maintain this level should be established. Daily administration is required for a long time in order to maintain an adequate neutrophil count. After 1-2 weeks of therapy the starting dose can be doubled or halved based on the patient's response. Thereafter, the dosage can be individually adjusted every 1-2 weeks in order to maintain a mean neutrophil count between 1.5 x 109 / l and 10 x 109 / l. A more rapid schedule of progressive dose escalation may be considered in patients with severe infections. In clinical studies, 97% of responders achieved a complete response at doses ≤ 24 micrograms / kg / day. The long-term safety of Neupogen administration at doses greater than 24 micrograms / kg / day in patients with severe chronic neutropenia has not been established.
Method of administration
Congenital or cyclic idiopathic neutropenia: Neupogen should be administered by subcutaneous injection.
Patients with HIV infection
Dosage
For the recovery of neutropenia:
The recommended starting dose of Neupogen is 0.1 MU (1 mcg) / kg / day, with increments up to a maximum of 0.4 MU (4 mcg) / kg / day, until it is reached, and it can be maintained, a normal neutrophil count (CAN> 2.0 x 109 / l). In clinical studies, more than 90% of patients responded to these dosages, achieving recovery from neutropenia with a median of two days.
In a small number of patients (
To maintain a normal neutrophil count:
Once recovery of neutropenia is achieved, the minimum effective dose to maintain a normal neutrophil count should be established. An initial dosage adjustment to 30 MU (300 mcg) / day every other day is recommended. Further dosage adjustments may be necessary, based on the patient's ANC, to maintain neutrophil counts> 2.0 x 109 / L. In clinical trials, dosages of 30 MU (300 mcg) / day, 1 to 7 days per week, with a median frequency of 3 days per week were required to maintain a CAN> 2.0 x 109 / L. Long-term administrations may be necessary to maintain CAN> 2.0 x 109 / L.
Method of administration
Recovery from neutropenia or maintenance of normal neutrophil counts: Neupogen should be administered by subcutaneous injection.
Elderly patients
A small number of elderly patients have been included in clinical studies with filgrastim, but no special studies have been performed for this group of subjects; therefore it is not possible to recommend a specific administration schedule.
Patients with reduced renal function
Studies with filgrastim in patients with severe renal or hepatic impairment have shown a pharmacokinetic and pharmacodynamic profile similar to that observed in normal individuals. No dosage adjustment is required under these conditions.
Pediatric use in severe chronic neutropenia (SCN) and neoplasms
Sixty-five percent of the patients studied in the NCG trials were under the age of 18. Treatment efficacy was evident for this age group, which for the majority included patients with congenital neutropenia. No differences were observed in the safety profiles of pediatric patients treated for severe chronic neutropenia.
Clinical studies in pediatric patients show that the safety and efficacy of Neupogen are similar in both adults and children treated with cytotoxic chemotherapy.
The posology for pediatric patients is the same as for adults treated with myelosuppressive cytotoxic chemotherapy.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Neupogen should not be used to increase the dose of cytotoxic chemotherapy beyond standard dosages.
Neupogen should not be given to patients with severe congenital neutropenia who develop leukemia or who develop leukemia.
Hypersensitivity reactions, including anaphylactic reactions, which occurred during initial or subsequent treatment, have been reported in patients treated with Neupogen. Permanently discontinue filgrastim in patients with clinically significant hypersensitivity. Neupogen should not be given to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.
As with all therapeutic proteins, there is a potential risk of immunogenicity. The frequency of antibody formation against filgrastim is generally low. Development of binding antibodies is expected with all biologics; however, to date they have not been associated with neutralizing activity.
Growth of cancer cells
Granulocyte colony growth factor may favor in vitro the growth of myeloid cells; the same effect was also noted in vitro on some non-myeloid cells.
The safety and efficacy of Neupogen administration in patients with myelodysplastic syndrome or chronic myeloid leukemia have not been established.
The use of Neupogen is not indicated in these diseases. Particular attention should be paid to distinguish the diagnosis of blast transformation of chronic myeloid leukemia from that of acute myeloid leukemia.
As there are limited safety and efficacy data for patients with secondary acute myeloid leukemia, Neupogen should be administered with caution in this patient group.
The safety and efficacy of Neupogen administration in newly diagnosed acute myeloid leukemia patients with age
Other special precautions
Patients with osteoporosis, if treated with filgrastim for longer than 6 months, should undergo bone density checks.
Cases of pulmonary adverse events, in particular interstitial lung disease, have been reported following administration of G-CSF. Patients with a recent history of pulmonary infiltrates or pneumonia may be at increased risk. The onset of pulmonary symptoms such as cough, fever and dyspnoea in association with radiological evidence of pulmonary infiltrates and deterioration of lung function may be the initial symptoms of acute respiratory distress syndrome (ARDS). Neupogen therapy should be discontinued and initiated. suitable treatment.
Capillary leak syndrome has been reported following administration of granulocyte colony-stimulating factors, 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).
Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Events of glomerolunephritis generally resolved after dose reduction or discontinuation of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Special precautions in cancer patients
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.
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 undesirable effects directly attributable to this degree of leukocytosis have been reported. However, in anticipation of the potential risks associated with marked leukocytosis, the number of white blood cells should be checked at regular intervals during treatment with Neupogen. If the white blood cell count exceeds 50 x 109 / l after the expected nadir, Neupogen administration should be stopped immediately. However, during the PBPC mobilization period with Neupogen Neupogen administration should be discontinued or its dosage reduced if the leukocyte count exceeds 70 x 109 / L.
Risks associated with increasing chemotherapy doses
Particular attention should be paid in the treatment of patients with high-dose chemotherapy, since a more favorable outcome of the tumor disease has not been demonstrated and the intensification of the doses of chemotherapeutic agents can lead to an increase in toxicities, including cardiac, pulmonary, neurological and dermatological (consult the information contained in the Summary of Product Characteristics of the specific chemotherapeutic agents used).
Treatment with Neupogen alone does not avoid thrombocytopenia and anemia due to myelosuppressive chemotherapy. Due to the possibility of receiving higher doses of chemotherapy (eg, full dosages according to the planned schedule) the patient may be exposed to a greater risk of thrombocytopenia. and anemia Regular checks of platelet counts and hematocrit are recommended. Particular attention should be paid when administering single or combination chemotherapeutic agents that cause severe thrombocytopenia.
The use of Neupogen-mobilized PBPCs has been shown to reduce the severity and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions
The effect of Neupogen in patients with a significant reduction in myeloid progenitors has not been studied. Neupogen acts primarily on neutrophil precursors to perform its effect in increasing the neutrophil count.Therefore, in patients with low numbers of neutrophil precursors (such as those treated with extensive radiotherapy or chemotherapy or those with tumor infiltration of the bone marrow) the response may be less.
Vascular disorders, including veno-occlusive disease and fluid volume changes, have occasionally been reported in patients receiving high-dose chemotherapy followed by transplantation.
Cases of graft versus host reaction disease (GvHD) and fatal events have been reported in patients receiving G-CSF following allogeneic bone marrow transplantation (see sections 4.8 and 5.1).
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transiently abnormal bone radiographic images. This should be considered when interpreting radiological data.
Special precautions in patients undergoing peripheral blood progenitor cell mobilization
Mobilization
There are no prospective randomized comparisons between the two recommended mobilization methods (Neupogen alone or in combination with myelosuppressive chemotherapy) in the same patient population. The degree of variability between individual patients and between laboratory tests for the evaluation of CD34 + cells makes direct comparison between different studies difficult. It is therefore difficult to recommend an optimal method. The choice of the mobilization method must be weighed for each individual patient in relation to the general objectives of the treatment.
Previous exposure to cytotoxic agents
Patients who have been very heavily pre-treated with myelosuppressive therapy may not achieve sufficient PBPC mobilization to achieve the minimum recommended cell count (≥ 2.0 x 106 CD34 + cells / kg) or, to the same degree, accelerated recovery of platelets.
Some cytotoxic agents exhibit particular toxicity on the hematopoietic progenitor cell pool and may counteract progenitor mobilization. Drugs such as melphalan, carmustine (BCNU) and carboplatin, if given for an extended period before attempting to mobilize progenitor cells, can reduce progenitor cell collection. However, administration of melphalan, carboplatin or BCNU, together with filgrastim, has been shown to be effective for the mobilization of progenitor cells. When planning a peripheral blood progenitor cell transplant, it is advisable to plan the stem cell mobilization procedure early in 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 collections, according to the previously indicated evaluation criteria, are inadequate, alternative treatments that do not require the support of progenitor cells should be considered.
Evaluation of progenitor cell collections
In evaluating the number of progenitor cells collected in patients treated with Neupogen, particular attention should be paid to the method of counting. The results of CD34 + cell counts by flow cytometry vary according to the specific methodology used and numbers from studies conducted in different laboratories should 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 ongoing relationship.
The recommendation for a minimum collection of CD34 + cells ≥ 2.0 x 106 / kg is based on published experience indicating adequate haematological recovery. slow.
Special precautions in healthy donors undergoing peripheral blood progenitor cell mobilization
PBPC mobilization does not result in 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 have normal clinical and laboratory eligibility criteria for stem cell donation, with particular attention to haematological values and the presence of infectious diseases.
The safety and efficacy of Neupogen have not been evaluated in healthy donors aged 60 years.
Thrombocytopenia has been very commonly reported in patients receiving filgrastim. Therefore the platelet count must be closely monitored.
Transient thrombocytopenia (platelets
If more than one leukapheresis is required, special care should be taken in donors with platelets
A leukapheresis should not be performed in donors on anticoagulant therapy or who have known haemostasis alterations.
Neupogen administration should be discontinued or its dosage reduced if the leukocyte count exceeds 70 x 109 / l.
Donors receiving G-CSF for PBPC mobilization must be monitored until complete recovery of haematological parameters.
Transient cytogenetic abnormalities have been observed in healthy donors after use of G-CSF. The significance of these changes is unknown.
However, a risk of developing a malignant myeloid cell clone cannot be excluded. It is recommended that the apheresis center perform systematic recording and follow-up of stem cell donors over time for at least 10 years to ensure long-term safety monitoring.
Common but generally asymptomatic cases of splenomegaly and uncommon cases of ruptured spleen in healthy donors (and patients) have been reported following administration of granulocyte colony growth factors (G-CSF). Some cases of ruptured spleen have been fatal. Therefore, the size of the spleen must be carefully monitored (for example, by clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and / or patients presenting with pain in the left upper abdomen or extremity of the shoulder.
In healthy donors, dyspnoea was commonly reported and other pulmonary adverse events (haemoptysis, pulmonary haemorrhage, pulmonary infiltrates and hypoxia) were reported uncommonly. In the event of suspected or confirmed pulmonary adverse events, discontinuation of Neupogen treatment and appropriate medical therapy should be considered.
Special precautions in patients receiving allogeneic peripheral blood progenitor cells mobilized with Neupogen
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 compared to bone marrow transplantation.
Special precautions in patients with severe chronic neutropenia (SCN)
Blood cell count
Thrombocytopenia has been commonly reported in patients receiving filgrastim. Platelet counts should be monitored closely, especially during the first few weeks of Neupogen therapy. Intermittent interruption or dose reduction of Neupogen should be considered in patients who develop thrombocytopenia, ie with platelets constantly 3.
Other changes in the blood picture may occur, including anemia and transient increases in myeloid progenitors, which require careful monitoring of cell counts.
Transformation into leukemia or myelodysplastic syndrome
Special attention should be paid to the diagnosis of severe chronic neutropenias to distinguish them from other haematological disorders such as aplastic anemia, myelodysplasia and myeloid leukemia. Differential blood cell counts and platelet counts should be performed before starting treatment. as well as an assessment of bone marrow morphology and karyotype.
A low incidence (approximately 3%) of myelodysplastic syndromes (MDS) or leukemia has been observed in clinical trial patients with severe chronic neutropenia treated with Neupogen. This has only been observed in patients with congenital neutropenia. MDS and leukemia are natural complications of the disease and are not to be posed with certainty in relation to Neupogen therapy. In about 12% of patients who had normal baseline cytogenetic evaluations, abnormalities were subsequently found, including monosomy 7, in the course of repeated routine evaluations. It is currently unclear whether long-term treatment of patients with severe chronic neutropenia predisposes patients to cytogenetic abnormalities, MDS, or transformation to leukemia. It is recommended that morphological examinations be performed in patients. and bone marrow cytogenetics at regular intervals (approximately every 12 months).
Other special precautions
Causes of transient neutropenia, such as viral infections, must be excluded.
Cases of splenomegaly have been reported very commonly and cases of splenic rupture have been reported commonly following administration of filgrastim. Individuals receiving filgrastim and reporting left upper abdominal pain and / or shoulder extremity pain should be evaluated for splenic enlargement or splenic rupture.
Splenomegaly is a direct effect of Neupogen treatment. In studies, palpable splenomegaly was observed in 31% of patients. Increases in volume, measured radiographically, were found early during Neupogen therapy and tended to plateau. Dose reductions have been observed to slow or stop the progression of splenomegaly, and in 3% of patients, a splenectomy was required. The volume of the spleen should be checked regularly. Abdominal palpation is sufficient to detect abnormal increases in splenic volume.
Hematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis should be done to monitor for these events.
Safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
Special precautions in HIV infected patients
Cases of splenomegaly have been commonly reported following administration of filgrastim. Individuals receiving filgrastim and reporting left upper abdominal pain and / or shoulder extremity pain should be evaluated for splenic enlargement or splenic rupture.
Blood cell count
Absolute neutrophil count (CAN) should be closely monitored, especially during the initial weeks of Neupogen therapy. Some patients may respond very quickly and with a marked increase in neutrophil counts at the starting dose of Neupogen. It is recommended that CAN be measured daily during the first 2-3 days of Neupogen administration. Thereafter, it is recommended that CAN be measured at least twice a week, during the first two weeks, and then once a week or every other week, during maintenance therapy. During intermittent administration of Neupogen at 30 MU (300 mcg) / day, large fluctuations in the patient's ANC may occur over time. To determine the minimum or nadir value of a patient's CAN, it is recommended that blood draws be taken for CAN measurement immediately prior to each scheduled administration of Neupogen.
Risks associated with dose increases of myelosuppressive drugs
Treatment with Neupogen alone does not preclude thrombocytopenia and anemia due to myelosuppressive drugs. The patient may be at increased risk of developing thrombocytopenia and anemia if he is given increased doses or more of these drugs while on Neupogen therapy. Regular monitoring of blood counts is recommended (see above).
Myelosuppression caused by infections and neoplasms
Neutropenia may be due to bone marrow infiltration from opportunistic infections, for example from Mycobacterium avium complex, or from neoplasms, such as lymphomas. In patients in whom bone marrow infiltration by infection or malignancy is known, adequate treatment of the underlying disease should be considered, in addition to administration of Neupogen for the treatment of neutropenia. The effects of Neupogen have not been established. Neupogen on neutropenia due to infections or neoplasms infiltrating the bone marrow.
Special precautions in sickle cell tract and sickle cell disease
In patients with sickle cell trait or sickle cell disease, episodes of disease crisis, in some cases fatal, have been observed following the use of filgrastim. sickle cell.
All patients
Neupogen contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this drug.
Neupogen contains less than 1 mmol (23 mg) sodium per 0.3 mg / ml, i.e. essentially sodium-free.
To improve the traceability of granulocyte colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient's medical record.
04.5 Interactions with other medicinal products and other forms of interaction
The safety and efficacy of Neupogen given on the same day as myelosuppressive cytotoxic chemotherapy have not been definitively established. Since rapidly dividing myeloid cells are sensitive to myelosuppressive cytotoxic chemotherapy, use of Neupogen in the previous 24 hours is not recommended. and subsequent to chemotherapy. Preliminary data from a small number of patients treated concurrently with filgrastim and 5-fluorouracil indicate that neutropenia may be aggravated.
Possible interactions with other hematopoietic growth factors and cytokines have not yet been studied.
Since lithium promotes the release of neutrophils, it may 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
Data from the use of filgrastim in pregnant women do not exist or are limited in number. Animal studies have shown reproductive toxicity. An increased incidence of abortions has been observed in rabbits following exposure to high multiples of clinical doses and in the presence of maternal toxicity (see section 5.3) There are published data in the literature demonstrating the transplacental passage of filgrastim in pregnant women.
Neupogen is not recommended during pregnancy.
Women who are found to be pregnant during Neupogen treatment should be encouraged to enroll in Amgen's Pregnancy Surveillance Program. Contact details are given in section 6 of the Package Leaflet.
Feeding time
It is unknown whether filgrastim / metabolites are excreted in human milk. A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from Neupogen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Women who are breastfeeding during treatment should be encouraged to enroll in Amgen's Lactation Surveillance program. Contact details are provided in section 6 of the Package Leaflet.
Fertility
Filgrastim does not affect reproductivity or fertility performance in male or female rats (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
to. Summary of the safety profile
In clinical trials in cancer patients the most frequent undesirable effect 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 section c below).
In the mobilization of circulating peripheral stem cells (PBPCs) in healthy donors, the most commonly reported undesirable effect was musculoskeletal pain. Leukocytosis was observed in donors and thrombocytopenia was observed in donors following filgrastim and leukapheresis. also reported splenomegaly and splenic rupture.Some cases of splenic rupture have been fatal.
In patients with Severe Chronic Neutropenia (SCN) the most frequent undesirable effects attributable to Neupogen were bone pain, general musculoskeletal pain and splenomegaly. Myelodysplastic syndromes (MDS) or leukemia have developed in patients with congenital neutropenia treated with Neupogen (see section 4.4).
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 undesirable effects that were considered uniquely related to Neupogen administration were musculoskeletal pain, bone pain and myalgia.
b. Tabular summary of adverse reactions
The data in the tables below describe adverse reactions reported from clinical studies and spontaneous reports.Within each frequency class, undesirable effects are reported in decreasing order of severity. The data are presented separately for neoplastic patients, PBPC mobilization in healthy donors, SCN patients and HIV patients, reporting the different reaction profiles adverse in these populations.
Cancer patients
a See section c
b GvHD and deaths have been reported in patients after allogeneic bone marrow transplantation (see section c)
c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain
d Cases have been observed in post-marketing experience in patients undergoing bone marrow transplantation or PBPC mobilization
e Cases have been observed in clinical trial experience
PBPC mobilization in healthy donors
a See section c
b Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain
NCG patients
a See section c
b Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain
Patients with HIV infection
a See section c
b Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain
c. Description of selected adverse reactions
GvHD and deaths have been reported in patients receiving G-CSF following allogeneic bone marrow transplantation (see sections 4.4 and 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 malignant disease, sepsis, taking multiple chemotherapy drugs or undergoing apheresis (see paragraph 4.4).
Cancer patients
In randomized, placebo-controlled studies, Neupogen did not increase the incidence of undesirable effects associated with cytotoxic chemotherapy. In those clinical trials, undesirable effects that occurred with equal frequency in patients treated with Neupogen / chemotherapy and placebo / chemotherapy included nausea. and vomiting, alopecia, diarrhea, fatigue, anorexia (decreased appetite), mucosal inflammation, headache, cough, rash, chest pain, asthenia, pharyngolaryngeal pain (oropharyngeal pain) and constipation.
Cutaneous vasculitis has been reported in post-marketing experience in patients treated with Neupogen. The mechanism of vasculitis in patients receiving Neupogen is not known. Frequency is estimated to be uncommon from clinical trial data.
Cases of Sweet's Syndrome (acute febrile dermatosis) have been reported in post-marketing experience. The frequency was estimated as uncommon from clinical trial data.
Pulmonary adverse reactions including interstitial lung disease, pulmonary edema and pulmonary infiltrate, in some cases resulting in respiratory failure or acute respiratory distress syndrome (ARDS), which can be fatal ( see section 4.4).
Cases of splenomegaly and splenic rupture have been uncommonly reported following administration of filgrastim. Some cases of splenic rupture have been fatal (see section 4.4).
In clinical trials and post-marketing experience, hypersensitivity reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension have been reported at initiation of therapy or during subsequent treatments. In general, reports were more common after intravenous administration. In some cases, symptoms re-occurred after re-administration, suggesting a causal relationship. Neupogen should be permanently discontinued in patients who have experienced a severe allergic reaction.
In post-marketing experience, isolated cases of sickle cell crises have been observed in patients with sickle trait or sickle cell disease (see section 4.4). The frequency was estimated as uncommon from clinical trial data.
In neoplastic patients treated with filgrastim, pseudogout has been reported. The frequency is estimated as uncommon from clinical trial data.
Mobilization of peripheral blood progenitor cells (PBPCs) in healthy donors
Common, but generally asymptomatic, cases of splenomegaly and uncommon cases of splenic rupture in healthy donors and patients have been reported following administration of filgrastim. Some cases of splenic rupture have been fatal (see section 4.4).
Adverse pulmonary events (haemoptysis, pulmonary haemorrhage, pulmonary infiltrate, dyspnoea and hypoxia) have been reported (see section 4.4).
Worsening of arthritic symptoms was observed uncommonly.
Leukocytosis (leukocytes> 50 x 109 / l) in 41% of donors and transient thrombocytopenia (platelets
Patients with severe chronic neutropenia (SCN)
Adverse effects observed include splenomegaly, which may be progressive in a minority of cases, splenic rupture and thrombocytopenia (see section 4.4).
Adverse events, possibly related to Neupogen administration and generally found in less than 2% of SCN patients, were: injection site reactions, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and rash.
Cutaneous vasculitis was observed in 2% of SCN patients during prolonged administration.
Patients with HIV infection
Neupogen-related splenomegaly has been reported in less than 3% of patients. In all cases it was mild to moderate on physical examination and, course benign; no patient was diagnosed with hypersplenism and no patient underwent splenectomy. The relationship to Neupogen is unclear, as splenomegaly occurs. commonly diagnosed in HIV-infected patients and present to varying degrees in most AIDS patients (see section 4.4).
d. 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 for further evaluation of Neupogen use in pediatric subjects.
And. 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 Neupogen use in geriatric individuals for the other approved Neupogen indications.
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 Neupogen. 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 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. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
The effects of filgrastim overdose have not been established. Interruption of Neupogen treatment generally results in a 50% decrease in the number of circulating neutrophils within 1-2 days, with a return to physiological levels in 1-7 days.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: cytokines.
ATC code: L03AA02.
Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Neupogen, which contains r-metHuG-CSF (filgrastim), causes a significant increase in the number of peripheral neutrophils within 24 hours and a minor increase in monocytes. In some patients with severe chronic neutropenia, filgrastim may also induce a smaller increase in the number of circulating eosinophils and basophils compared to baseline values; some of these patients may present with eosinophilia or basophilia even before treatment. In the recommended dosage range, the increase in the number of neutrophils is dose-dependent. Neutrophils produced in response to filgrastim exhibit normal or increased function, as demonstrated by chemotaxis and phagocytic properties studies. At the end of treatment with filgrastim, the number of circulating neutrophils decreases by 50% in 1-2 days returning to physiological levels in 1-7 days.
The use of filgrastim in patients undergoing cytotoxic chemotherapy leads to a significant reduction in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalization after induction chemotherapy for acute myeloid leukemia or myeloablative therapy followed by bone marrow transplant. The incidence of fever and documented infections was not reduced in either of these situations. Fever duration was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
The use of filgrastim, alone or after chemotherapy, is able to mobilize hematopoietic progenitor cells in peripheral blood. These autologous peripheral blood progenitor cells (PBPCs) can be harvested and reinfused, after high-dose cytotoxic therapy, as an alternative or in addition to bone marrow transplantation. PBPC infusion accelerates haematopoietic recovery by reducing the duration of the risk of bleeding complications and the need for platelet transfusions.
Patients who received filgrastim mobilized allogeneic peripheral blood progenitor cells showed much faster haematological recovery; this led to a significant decrease in platelet recovery time, without additional interventions, compared to allogeneic bone marrow transplantation.
A European retrospective study, which evaluated the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemia, indicated an increased risk of GvHD, treatment-related mortality (TRM) and mortality, when it is G-CSF was administered. In another international retrospective study, conducted in patients with acute or chronic myeloid leukemia, no effects on the risk of GvHD, TRM and mortality were observed. A meta-analysis of allogeneic transplant studies, which included the results of 9 prospective randomized clinical trials, 8 retrospective studies and 1 case-control study, showed no effects on the risk of acute GvHD, chronic GvHD and treatment-related early mortality.
a The analysis includes studies involving bone marrow transplantation during this period; some studies used GM-CSF.
b Analysis includes patients receiving bone marrow transplantation during this period.
Use of filgrastim for peripheral blood progenitor cell mobilization in healthy donors prior to allogeneic peripheral blood progenitor cell transplantation
In healthy donors, subcutaneous administration of 10 mcg / kg / day for 4-5 consecutive days resulted in the collection of CD34 + cells ≥ 4 x 106 per kg of recipient body weight in the majority of donors after two leukaphereses.
The use of filgrastim in adult or pediatric patients with severe chronic neutropenia (severe congenital, cyclic and idiopathic neutropenia) induces a prolonged increase in absolute peripheral blood neutrophil counts and a reduction in infectious episodes and their consequences.
Use of filgrastim in HIV-infected patients maintains neutrophil counts at normal levels to allow for the administration of antiviral and / or myelosuppressive drugs at scheduled dosages. There is no evidence that HIV-infected patients treated with filgrastim have a increased HIV replication.
As with other hematopoietic growth factors, G-CSF showed in vitro stimulating properties on human endothelial cells.
05.2 Pharmacokinetic properties
After both subcutaneous and intravenous administration, the elimination of filgrastim has been shown to follow first-order kinetics. The elimination half-life of filgrastim is approximately 3.5 hours, with a clearance of approximately 0.6 ml / min. / kg. In patients undergoing autologous bone marrow transplantation, the continuous infusion of Neupogen for up to 28 days showed no drug accumulation and resulted in a comparable half-life.There is a positive linear correlation between dose and plasma concentration of filgrastim administered both subcutaneously and intravenously. Following subcutaneous administration of the recommended doses, plasma concentrations were maintained above 10 ng / mL for 8-16 hours. The volume of distribution 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 to 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 to filgrastim, similar results were observed in addition to "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 of approximately 3-5 times the exposure observed in patients treated with 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
Sodium acetate *
Sorbitol (E420)
Polysorbate 80
Water for injections
* Sodium acetate is formed by titration of glacial acetic acid with sodium hydroxide
06.2 Incompatibility
Neupogen should not be diluted with saline solutions.
Once diluted filgrastim can be adsorbed by glass and plastic materials.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
30 months.
Chemical and physical 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 not be longer than 24 hours at 2 ° C to 8 ° C, unless dilution is in conditions aseptic controlled and validated.
06.4 Special precautions for storage
Store at a temperature between 2 ° C and 8 ° C.
For storage conditions after dilution of the medicinal product, see section 6.3.
Accidental exposure to freezing temperatures does not affect the stability of Neupogen.
Keep the container in the outer carton to protect it from light.
06.5 Nature of the immediate packaging and contents of the package
Carton of one or five 1 ml vials of Neupogen solution for injection.
The vials are type I glass with a rubber stopper.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
If necessary, Neupogen can be diluted in 5% glucose solution.
In any case, a dilution leading to a final concentration of less than 0.2 MU (2 mcg) per ml should be avoided.
The solution should be visually inspected prior to use. Only clear, particle-free solutions should be used.
For patients treated with filgrastim, diluted to concentrations below 1.5 MU (15 mcg) per ml, human serum albumin should be added to the solution until a final concentration of 2 mg / ml is reached.
For example: in a final volume to be injected of 20 ml, at a total filgrastim dose of less than 30 MU (300 mcg), 0.2 ml of 20% human albumin solution (Ph. Eur.) Should be added.
Neupogen does not contain preservatives. Considering a possible risk of microbial contamination, Neupogen syringes are for single use only.
When Neupogen is diluted with 5% glucose solution it is compatible with glass and with numerous plastics including PVC, polyolefin (copolymer of polypropylene and polyethylene) and polypropylene.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Amgen Europe B.V. - Minervum 7061 - NL-4817 ZK Breda (Netherlands).
08.0 MARKETING AUTHORIZATION NUMBER
"30 MU (0.3 mg / ml) solution for injection", 1 vial of 1 ml: AIC n. 027772033
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: May 2003
Date of most recent renewal: February 23, 2009
10.0 DATE OF REVISION OF THE TEXT
07 June 2016
