Active ingredients: Lenograstim
MYELOSTIM 34 million IU / ml - Powder and solvent for solution for injection / infusion
Indications Why is Myelostim used? What is it for?
The name of your medicine is Myelostim powder and solvent for injection / infusion (called Myelostim in this leaflet). Myelostim contains lenograstim, which belongs to the group of cytokines.
Myelostim works by helping your body to produce more blood cells that fight infection.
- These blood cells are produced by the bone marrow.
- Myelostim stimulates the bone marrow to produce more cells called 'blood stem cells'.
- It also helps transform these immature blood cells into fully functional cells.
- In particular, it helps produce more white blood cells called neutrophils. Neutrophils are important for fighting infections.
Myelostim is used:
After cancer therapy, if your white blood cell level is too low ("neutropenia")
Some cancer therapies (also called chemotherapies) damage the bone marrow. This can lower the number of your white blood cells. In particular, "neutrophil" white blood cells are affected and this condition is called "neutropenia". It lasts until your body is able to produce more white blood cells. When its neutrophil counts are low, it is easier to get infections. In some cases they can be very serious. Myelostim will help reduce the amount of time these cells are low. It does this by stimulating your body to make new white blood cells.
When you need to increase your blood stem cell count ("mobilization")
Myelostim can be used to stimulate the bone marrow to produce blood stem cells. This process is called "mobilization". This can occur on its own or possibly after chemotherapy. These blood stem cells are extracted from your blood and collected by special equipment. Blood stem cells can be stored and reintroduced into your body through a transfusion.
After a bone marrow or blood stem cell transplant
If you have a bone marrow or blood stem cell transplant, you will first receive a high dose of chemotherapy or total body radiation therapy. This is to eliminate diseased cells. Subsequently, a bone marrow or blood stem cell transplant is performed by means of a blood transfusion. It will take some time for your new bone marrow to start making new blood cells (including white blood cells). Myelostim will help your body speed up the formation of new white blood cells.
When he wants to donate his blood stem cells
Myelostim can also be used in healthy donors. In these people, it stimulates the bone marrow to produce additional blood stem cells. This process is called mobilization - see above.
These healthy donors will then be able to donate their blood stem cells to those in need.
Myelostim can be given to adults, adolescents and children over 2 years of age.
Contraindications When Myelostim should not be used
Do not take this medicine and tell your doctor
- If you are allergic (hypersensitive) to lenograstim or any of the other ingredients of Myelostim (listed in section 6 below). Symptoms of an allergic reaction include: redness of the skin, trouble swallowing or breathing, swelling of the lips, face, throat and tongue
- If you have a condition called "phenylketonuria"
- If you have a type of cancer called 'myeloid cancer'. However, if you have recently been diagnosed with "acute myeloid leukemia", you can, in certain cases, take Myelostim if you are over 55 years of age.
- If you are to have cancer chemotherapy on the same day.
Do not take this medicine if any of the above conditions apply to you. If you are not sure ask your doctor or pharmacist before you are given Myelostim.
Precautions for use What you need to know before taking Myelostim
Consult your doctor or pharmacist before taking this medicine if:
- you have had any illnesses in the past, especially allergies, infections, kidney or liver problems.
- suffer from sickle cell anemia or have a sickle cell trait, as Granocyte can cause sickle cell crisis
If you are not sure if this is the case, talk to your doctor or pharmacist before using Myelostim.
Children and adolescents
Consult your doctor before taking this medicine if:
- If you have a type of cancer called 'acute lymphocytic leukemia' and if you are under 18 years of age.
Interactions Which drugs or foods may change the effect of Myelostim
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription including herbal medicines.
If you want to donate your blood stem cells and are being treated with an anticoagulant (such as warfarin or heparin) make sure your doctor is aware of this before starting treatment with Myelostim. Also tell him if you have any other blood clotting problems.
If you are receiving cancer chemotherapy treatment, do not use Myelostim from 24 hours before starting treatment and up to 24 hours after ending therapy.
Warnings It is important to know that:
Pregnancy and breastfeeding
Myelostim has not been tested in pregnant or breastfeeding women. Do not take this medicine if you are pregnant, if you might get pregnant or if you are breastfeeding, unless your doctor tells you it is necessary.
Ask your doctor or pharmacist for advice before taking any medicine if you think you are pregnant.
Driving and using machines
The effects of Myelostim on the ability to drive, use machines or mechanical tools are not known. Please wait to know what effects Myelostim may have on you before driving, using machinery or mechanical tools.
Important information about some of the ingredients of Myelostim
Myelostim contains phenylalanine. This substance may be harmful to you if you have a disease called "phenylketonuria" (see the section above "Do not take this medicine").
Dose, Method and Time of Administration How to use Myelostim: Posology
Myelostim should be administered under supervision in a specialized Oncology or Hematology center. Normally, administration is performed by a doctor, nurse or pharmacist. It is administered by injection or infusion.
However, some patients may be taught how to inject themselves. If you have any questions about how to administer this medicine, ask your doctor, nurse or pharmacist.
How much Myelostim to take
If you are unsure why you are being given Myelostim or have any questions about how much Myelostim you should take, ask your doctor, nurse or pharmacist.
After a bone marrow transplant, chemotherapy or for blood stem cell mobilization after chemotherapy
- Your doctor will decide the dose to give you based on your body surface area. This is calculated using your weight and height. It is "measured in" square meters "which will be indicated as m2.
- The usual dose of Myelostim is 19.2 MIU (150 micrograms) per day for every m2 of body surface area. The dose in children over 2 years of age and adolescents is the same as in adults.
- Your doctor will decide how many days you need to take Myelostim for. Administration could last up to a maximum of 28 days.
- When Myelostim is given for blood stem cell mobilization after chemotherapy, your doctor will tell you when blood stem cell collection will be done.
For the mobilization of blood stem cells only with Myelostim
- Your doctor will work out how much medicine you need to take based on your weight.
- The usual dose of Myelostim is 1.28 MIU (10 micrograms) per day for each kg of body weight. The dose in children over 2 years of age and adolescents is the same as in adults.
- Myelostim will be given to you by injection under the skin for 4-6 days.
- The collection of your blood stem cells will take place 5-7 days later.
MYELOSTIM 34 million IU / ml can be used in patients with a body surface area up to 1.8 m2.
If you forget to take Myelostim
Do not take a double dose to make up for the injection you have forgotten. Always ask your doctor who will tell you what to do.
Blood tests
You need to be under medical supervision while taking this medicine. You will need regular blood tests. This will check the levels of different blood cells (neutrophils, other white blood cells, red blood cells, platelets).
Any other blood tests prescribed by other doctors may be changed while you are being treated with Myelostim. If you are having a blood test it is important that you tell your doctor that you are taking Myelostim. Your white blood cell count may rise, your platelet count may drop and your enzyme levels may rise. These changes usually improve after Myelostim is stopped. If you need to have blood tests it is important that you tell your doctor that you are taking Myelostim.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Myelostim
If this medicine is given to you by a doctor, nurse or pharmacist it is unlikely that they will give you too much. They will monitor your progress and check the dose. Always ask for an explanation if you are unsure about the dose of medicine that you are being given.
If you have taken too much Myelostim yourself, tell your doctor or go to a hospital straight away. Take the medicine pack with you so your doctor knows what you have taken. It could have particularly serious side effects if you have taken too much medicine. The most likely ailment you may have is pain in your muscles and bones.
Side Effects What are the side effects of Myelostim
Like all medicines, Myelostim can cause side effects, although not everybody gets them.
Stop taking Myelostim and tell your doctor immediately if:
- You have pain in the left upper left side of the abdomen or left shoulder. These could be symptoms of an increase in the size of the spleen. This is a common side effect, but very rarely it can cause rupture of the spleen.
- He has an allergic reaction. Symptoms include skin redness, trouble swallowing or breathing, swelling of the lips, face, throat or tongue. This is a very rare side effect.
- You have a very serious allergic reaction called "anaphylactic shock". Symptoms include feeling faint, weakness, difficulty in breathing or swelling of the face. This is a very rare side effect.
- You have trouble breathing. Symptoms include coughing, fever, or feeling short of breath easily. This is a rare side effect.
Tell your doctor or pharmacist as soon as possible if you experience any of the following side effects:
- A reaction at the injection site. This is a common side effect.
- Skin problems such as purplish-colored plaques on the arms, legs and sometimes on the face or neck with fever (symptoms of Sweet's syndrome). Red blisters may also appear with fever and headache (Lyell's syndrome symptoms). Other skin problems can be thickened red bruises on the legs or ulcers on the body with fever and joint pain. These are very rare side effects.
Other side effects include:
- Pain in the bones and muscles and headache. This is a common side effect. If this occurs, the pain can be controlled with normal pain relievers.
Blood stem cell donors
Like any medicine, Myelostim can cause side effects, although not everybody gets them. Some side effects may occur immediately, others may take a few days to appear.
Tell your doctor immediately if:
- You have pain in the left upper abdomen or left shoulder. These may be symptoms of an increase in the size of the spleen, a common side effect called splenomegaly. This condition can very rarely cause the spleen to rupture.
- You have signs of an allergic reaction, even after the first administration of Myelostim. Symptoms include skin rash, trouble swallowing or breathing, swelling of the lips, face, throat or tongue. This is a very rare side effect.
- You have a very rare and very serious allergic reaction called "anaphylactic shock". This is a sudden, life-threatening reaction. Symptoms include feeling faint, weakness, difficulty in breathing or swelling of the face.
- Has cough, fever and difficulty in breathing (dyspnoea). These can be symptoms of Acute Respiratory Distress Syndrome (ARDS) which is a very rare side effect.
- You experience any or a combination of the following side effects: edema or swelling, which may be associated with a decrease in urination, difficulty in breathing, abdominal bloating and a feeling of fullness, and a general feeling of tiredness. These symptoms usually develop quickly. These may be symptoms of 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 which requires urgent medical attention. .
Tell your doctor if you experience any of the following very common side effects:
- You may feel pain, pain in your bones and back, headache, fever and / or you may feel sick (feel nauseous);
- You may have temporary changes in blood test values, including those relating to liver function, but these generally do not require any additional precautions and tend to normalize after discontinuation of the drug.
- You may feel tired after donating blood stem cells. This is due to the drop in the number of red blood cells. You may also have a reduction in the number of platelets which can cause you to bleed or bruise more easily than normally.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep Myelostim out of the reach and sight of children.
Do not use any part of the Myelostim powder and solvent for solution kit after the expiry date (EXP).
The expiry date of Myelostim powder is indicated on the outer carton and on the label of each vial of Myelostim.
The expiration date of the solvent (water for injections) is indicated on the label of each ampoule of water for injections, on the label of the pre-filled syringe with water and on the paper sheet of the blister. The expiry date refers to the last day of the month indicated.
Do not store above 30 ° C. Do not freeze.
It is recommended to use the product immediately after reconstitution or dilution. If necessary, you can store the reconstituted or diluted solution for up to 24 hours between 2 ° C and 8 ° C (in the refrigerator).
Medicines should not be disposed of 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
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What Myelostim contains
- The active substance is lenograstim (rHuG-CSF) 33.6 million International Units (equivalent to 263 micrograms) per ml after reconstitution.
- The other ingredients contained in the powder are arginine, phenylalanine, methionine, mannitol (E421), polysorbate 20 and dilute hydrochloric acid.
- Excipients known to have a recognized "action or effect: phenylalanine.
- The solvent used to reconstitute the solution is water for injections
What Myelostim looks like and contents of the pack
Myelostim is presented as a powder and solvent for solution for injection / infusion.
Powder in a vial + 1 ml of solvent in a vial.
MYELOSTIM is available in packs of 1 or 5 units.
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
MYELOSTIM 34 MILLION IU / ML, POWDER AND SOLVENT FOR SOLUTION FOR INJECTION / INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lenograstim * (rHuG-CSF) 33.6 million International Units (equivalent to 263 mcg) per ml after reconstitution
* produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.
Excipients known to have a recognized effect or action: phenylalanine. For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection / infusion.
- White powder
- Solvent: clear, colorless solution
Solvent: clear, colorless solution
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Myelostim is indicated in adults, adolescents and children over 2 years of age for:
The reduction in the duration of neutropenia in patients (with non-myeloid malignancy) undergoing myeloablative therapy, followed by bone marrow transplant (BMT) and considered at increased risk of prolonged severe neutropenia.
The reduction of the duration of severe neutropenia and associated complications in patients undergoing cytotoxic chemotherapy regimens associated with a significant incidence of febrile neutropenia.
The mobilization of peripheral blood progenitor cells (PBPCs) in patients and also in healthy donors.
04.2 Posology and method of administration
The therapy should only be administered in a specialized oncology and / or haematology center. MYELOSTIM can be administered by subcutaneous injection or by intravenous infusion. Instructions for particular handling or preparation of the product are given in section 6.6.
The recommended dose of Myelostim is 19.2 MIU (150 mcg) per m 2 per day, therapeutically equivalent to 0.64 MIU (5 mcg) per kg per day for: peripheral stem cell or bone marrow transplantation, chemotherapy conventional cytotoxic, PBPC mobilization after chemotherapy.
Myelostim 34 million IU / ml can be used in patients with a body surface area up to 1.8 m2.
For PBPC mobilization with Myelostim alone, the recommended dose is 1.28 MIU (10 mcg) per kg per day.
Adults:
In peripheral stem cell or bone marrow transplantation
Myelostim should be administered daily at the recommended dose of 19.2 MIU (150 micrograms) per m2 per day as an intravenous infusion, lasting 30 minutes, diluted in isotonic saline or as a subcutaneous injection. The first dose should not be administered. in the 24 hours following the bone marrow implantation. Administration should be continued until the expected minimum concentration of neutrophils (nadir) is exceeded and the neutrophil count has returned to stable limits compatible with the interruption of treatment, up to a maximum, if necessary, of 28. consecutive days of therapy.
A normal level of neutrophils is expected to be achieved within 14 days of bone marrow transplantation in 50% of patients.
Ongoing conventional cytotoxic chemotherapy
Myelostim at the recommended dose of 19.2 MIU (150 micrograms) per m2 per day should be administered daily by subcutaneous injection. The first dose should not be administered within 24 hours following cytotoxic chemotherapy (see sections 4.4 and 4.5).
The daily administration of Myelostim should be continued until the expected nadir is exceeded and the neutrophil count has reached stable values compatible with the cessation of treatment, up to a maximum, if necessary, of 28 consecutive days of therapy.
Although a transient increase in neutrophils may occur within the first two days of therapy, treatment with Myelostim should not be interrupted as there is generally an earlier onset of the nadir and a more rapid return to normal with continued treatment.
In the mobilization of peripheral blood progenitor cells (PBPCs)
After chemotherapy, Myelostim should be administered daily at the recommended dose of 19.2 MIU (150 micrograms) per m2 per day by subcutaneous injection within a period of 1 - 5 days after completion of chemotherapy, according to the chemotherapy regimen given for mobilization. . Myelostim should be administered until the last leukapheresis.
Leukapheresis should be performed in the post-nadir period, when the white blood cell count is rising, or after determination of the CD34 + cell content in the blood by a validated method. In patients who have not received intensive chemotherapy, a single leukapheresis is often sufficient to achieve a minimal acceptable collection (≥ 2.0 x 106 CD34 + cells per kg).
In PBPC mobilization with Myelostim used alone, Myelostim should be administered daily at the recommended dose of 1.28 MIU (10 micrograms) per kg per day as a subcutaneous injection for 4-6 days. Leukapheresis should be performed between the 5th and 7th day. In patients who have not received intensive chemotherapy, a single leukapheresis is often sufficient to achieve a minimal acceptable collection (≥ 2.0 x 106 CD34 + cells per kg).
In healthy donors, a daily dose of 10 mcg / kg administered subcutaneously for 5-6 days allows collection of CD34 + 3 x 106 / kg body weight cells, with a single leukapheresis in 83% of subjects and with two leukaphereses in the 97% of subjects.
In the "elder
A small number of patients up to 70 years of age have been included in clinical trials with Myelostim but no targeted studies have been conducted in the elderly and therefore specific doses cannot be recommended.
In the child
In the reduction of the duration of neutropenia after myeloablative therapy followed by BMT or after cytotoxic chemotherapy, the dose in children over 2 years of age and adolescents is the same as in adults.
Very limited data are available for peripheral blood progenitor cell mobilization at adult doses.
The safety and efficacy of Myelostim in children less than 2 years of age have not been established. MYELOSTIM 34 million IU / ml can be used in patients with a body surface area up to 1.8 m2.
04.3 Contraindications
Myelostim should not be administered to patients with known hypersensitivity to lenograstim or to any of the excipients.
Myelostim should not be used to increase the dose intensity of cytotoxic chemotherapy beyond the established dosage and usual dosing regimens, as Myelostim may reduce the myelotoxicity but not the overall toxicity of cytotoxic drugs.
It must not be administered simultaneously with cytotoxic chemotherapy.
It must not be given to patients
- with myeloid neoplasia other than acute myeloid leukemia "de novo'
- with acute myeloid leukemia "de novo"under 55 years of age and / or with acute myeloid leukemia"de novo"with favorable cytogenetics, ie t (8; 21), t (15; 17) and inv.
04.4 Special warnings and appropriate precautions for use
Growth of malignant cells
Granulocyte colony stimulating factors can stimulate myeloid cell growth in vitro; similar effects were observed, again in vitro, in some non-myeloid cells.
The safety and efficacy of Myelostim administration in patients with myelodysplasia or secondary acute myeloid leukemia, or chronic myeloid leukemia have not been established. Therefore it should not be used in these indications. Particular care should be used in distinguishing the diagnosis of blast transformation of the chronic myeloid leukemia from acute myeloid leukemia. Clinical studies have not established whether Myelostim can influence the progression of myelodysplastic syndrome to acute myeloid leukemia. Particular caution should be exercised in its use in all pre-neoplastic myeloid conditions. Given that some cancers with non-specific characteristics may in exceptional cases express a G-CSF receptor, particular caution should be taken in the case of unexpected tumor recurrences observed in conjunction with rHuG-CSF therapy.
In children with ALL
An increased risk of secondary myeloid leukemia or myelodysplastic syndrome associated with CSFs has been reported in children with ALL. A similar risk was found in a systematic review of 25 randomized controlled trials involving 12,804 adult patients with solid tumors or lymphomas. This risk, however, had no negative impact on the long-term outcome in study adults. Therefore, Myelostim 34 million IU / ml should only be administered to children, and particularly those with a favorable long-term prognosis, only after careful evaluation. short-term benefits, based on long-term risks.
Leukocytosis
A white blood cell count greater than 50x109 / l was not observed in any of the 174 patients enrolled in clinical studies and treated with 5 mcg / kg / day (0.64 million Units / kg / day) following bone marrow transplantation. A white blood cell count equal to or greater than 70x10 9 / l has been observed in less than 5% of patients undergoing cytotoxic chemotherapy treated with Myelostim at a dose of 5 mcg / kg / day (0.64 million Units / kg / day ). No adverse events directly attributable to this degree of leukocytosis have been reported. Due to the potential risks associated with severe leukocytosis, white blood cell counts should still be performed at regular intervals during Myelostim therapy. If the number of leukocytes exceeds 50x10 9 / l after the expected nadir, Myelostim should be stopped immediately.
During PBPC mobilization, Myelostim should be discontinued if the white blood cell count increases to> 70 x 109 / L.
Pulmonary adverse events
After administration of G-CSF, rare pulmonary adverse events (> 0.01% and interstitial pneumonia have been reported.
Patients with a recent history of pulmonary infiltrates or pneumonia may be at high risk.
The appearance of pulmonary symptoms or signs such as cough, fever and dyspnoea, in association with radiological signs of pulmonary infiltrates and worsening of lung function may be preliminary signs of Acute Respiratory Distress Syndrom (ARDS).
Treatment with Myelostim should be stopped immediately and appropriate treatment given.
In peripheral stem cell or bone marrow transplantation
Particular attention should be paid to platelet recovery, since in double-blind placebo-controlled clinical trials the mean platelet count was lower in patients treated with Myelostim than in those treated with placebo.
The effect of Myelostim on the incidence and severity of acute and chronic Graft vs Host disease has not yet been well established.
In conventional cytotoxic chemotherapy
The use of Myelostim is not recommended in the period from 24 hours before to 24 hours after the end of chemotherapy (see section 4.5).
The safety of the use of Myelostim with antineoplastic agents characterized by cumulative or platelet-predominant myelotoxicity (nitrosurea, mitomycin) has not been established.
Administration of Myelostim could increase the toxicity of these agents, particularly towards platelets.
Risks associated with increasing the dose of chemotherapy
The safety and efficacy of Myelostim have not yet been verified in the course of intensification of chemotherapy. It should not be used to reduce the intervals between chemotherapy courses below established limits and / or to increase the dose of chemotherapy drugs. Non-myeloid cell load was a limiting factor in the phase II chemotherapy intensification studies with Myelostim.
Special precautions in the mobilization of peripheral blood progenitor cells
Choice of mobilization method
Clinical studies conducted in the same patient population showed that, as verified in the same laboratory, PBPC mobilization was higher when Myelostim was used after chemotherapy than when used alone. However, the choice between the two mobilization methods should be made in relation to the overall treatment goals for each individual patient.
Previous exposure to radiotherapy and / or cytotoxic agents
Patients who have undergone intensive myelosuppressive therapy and / or radiotherapy may not show sufficient PBPC mobilization to achieve the minimum acceptable collection (≥ 2.0 x 10 6 CD34 + / kg) and therefore adequate haematological recovery.
The PBPC transplant program should be defined early in the patient's treatment e first special attention should be paid to the number of mobilized PBPCs when administering high-dose chemotherapy. If the harvest is low, PBPC transplantation should be replaced by other forms of treatment.
Evaluation of the amount of progenitor cells collected
Particular attention should be paid to the method of quantifying the collected progenitor cells, since the results of the analysis of CD34 + cells obtained by flow cytometry vary from laboratory to laboratory.
The minimal collection of CD34 + cells is not well defined. The recommendation for a minimum collection of CD34 + ≥ 2.0 x 106 cells / kg is based on literature data in order to achieve adequate haematological reconstitution. Collections of CD34 + ≥ 2.0 x 106 cells / kg are associated with faster recovery, including that of platelets, while lower collections result in slower recovery.
In healthy donors
The mobilization of peripheral blood progenitor cells, a procedure that does not lead to direct benefits on the healthy population, must be taken into consideration only within the limits set by law, in accordance with local regulations for bone marrow donations, when applicable. .
The efficacy and safety of Myelostim have not been evaluated in donors over 60 years of age, therefore this procedure is not recommended for such subjects. Based on some local regulations and due to lack of specific studies, they should not be minors donors taken into consideration.
The PBPC mobilization procedure should be considered for donors who meet the clinical and laboratory criteria of suitability for bone marrow donation, especially with respect to normal haematological values.
Leukocytosis (WBC ≥ 50 x 109 / L) was observed in 24% of the subjects studied. Thrombocytopenia (platelets
Therefore leukapheresis should not be performed in donors treated with anticoagulants or with known haemostatic defects. If more than one leukapheresis is required, particular attention should be paid to donors with platelets.
If possible, a central venous catheter should not be inserted, taking into account the ease of venous access in the selection of donors.
Long-term follow-up data are available in a small number of subjects. No long-term sequelae have been reported for up to six years. However, there is a risk of developing a malignant myeloid clone. Therefore, it is recommended that apheresis centers keep records and systematic monitoring of stem cell donations.
During post-marketing experience, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, pulmonary infiltrates, dyspnoea and hypoxia) have been reported in healthy donors. In case of suspected or confirmed pulmonary adverse events, discontinuation of the treatment with Myelostim and appropriate medical care should be provided.
In recipients of allogeneic peripheral stem cells mobilized with Myelostim
Allogeneic stem cell transplantation may be associated with an increased risk of chronic GVH (Graft versus Host) and long-term data on graft function are scarce.
Other special precautions
There are insufficient data on the safety and efficacy of Myelostim in patients with severe renal or hepatic impairment.
In patients with substantially reduced myeloid progenitor cells, for example due to previous intensive exposure to radio / chemotherapy, the neutrophil response is sometimes reduced and the safety of Myelostim has not been established.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been observed in both healthy donors and patients following administration of granulocyte colony stimulating factors (G-CSF). Therefore, the size of the spleen must be carefully monitored (clinical examinations, ultrasound). If upper left abdominal pain or shoulder tip pain is reported, a diagnosis of ruptured spleen should be suspected.
Capillary leak syndrome has been reported following administration of G-CSF, and is characterized by hypotension, hypoalbuminemia, edema and haemoconcentration. In patients who develop capillary leak syndrome the administration of Lenograstim should be discontinued, such patients should be closely monitored and appropriate symptomatic treatment instituted, which may include the need for intensive care (see section 4.8).
In patients with sickle cell disease and in patients with sickle cell trait, the use of lenograstim may be associated with sickling seizures. Therefore, Myelostim should be prescribed with caution in patients with sickle cell disease or in patients with sickle cell trait MYELOSTIM contains phenylalanine which it can be harmful to people with phenylketonuria.
04.5 Interactions with other medicinal products and other forms of interaction
Given the sensitivity of rapidly multiplying myeloid cells to cytotoxic chemotherapy, the use of Myelostim is not recommended in the period from 24 hours before to 24 hours after the end of chemotherapy (see section 4.4). Possible interactions with other factors. growth pathways and cytokines have yet to be studied by specific clinical research.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data on the use of lenograstim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk in humans is unknown.
Myelostim should not be used during pregnancy unless clearly necessary.
Feeding time
It is not known whether lenograstim is excreted in human milk. The excretion of lenograstim in milk has not been studied in animals.
Breastfeeding should be discontinued during therapy with Myelostim.
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
The safety profile is similar in children, adolescents and adults.
In peripheral stem cell or bone marrow transplantation
In double-blind placebo-controlled clinical trials, mean platelet counts were lower in patients treated with Myelostim than in patients treated with placebo, with no increase in the incidence of haemorrhagic-type adverse reactions and the median number of days between bone marrow transplant and last platelet transfusion was similar in the two groups (see section 4.4).
In peripheral stem cell or bone marrow transplantation and in chemotherapy neutropenia
The most frequent adverse events reported in clinical trials (15%) were the same in patients treated with both Myelostim and placebo.
Adverse events were those generally seen during conditioning regimens and during chemotherapy in cancer patients.
The most frequently reported adverse events were oral infection / inflammation, sepsis and infections, fever, diarrhea, abdominal pain, vomiting, nausea, rash, alopecia, and headache.
In the mobilization of peripheral blood progenitor cells (PBPCs) in healthy donors
The most frequently reported undesirable effects are transient, mild to moderate: pain, bone pain, back pain, asthenia, fever, headache and nausea, increased ALAT / ASAT, alkaline phosphatase and LDH values.
Apheresis-related thrombocytopenia and leukocytosis were observed in 42% and 24% of study subjects, respectively.
Common but generally asymptomatic cases of splenomegaly and very rare cases of ruptured spleen have been reported.
Rare pulmonary adverse reactions, such as dyspnoea, hypoxia or haemoptysis, including, very rarely, acute respiratory distress syndrome (ARDS) have been reported (see section 4.4).
Allergic reactions, including anaphylaxis, arising after the first subcutaneous administration of lenograstim have been reported very rarely.
Post-marketing surveillance of life-threatening adverse reactions:
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported in post-marketing surveillance as an uncommon event (≥ 1/1000 to
Frequency of adverse reactions from clinical trials and from post-marketing data.
Very common (≥10%); common (≥1 / 100 and not known (cannot be estimated from the available data).
1 / The risk of pain is increased in people with high white blood cell counts, especially if white blood cells are ≥ 50x109 / l
2 / A transient increase in ASAT and / or ALAT was observed. In many cases the liver function abnormalities improved after discontinuation of lenograstim.
3 / Some of the respiratory cases reported have caused respiratory failure or acute respiratory distress syndrome (ADRS) which can be fatal.
4 / Sweet's syndrome, erythema nodosum and gangrenous pyoderma have been described mainly in patients with haematological malignancies, a condition known to be associated with neutrophilic dermatosis, but also in patients with non-tumor related neutropenia.
5 / Rupture of the spleen has been reported in both healthy volunteers and patients receiving G-CSF (see section 4.4).
6 / Cases of capillary leak syndrome have been reported in post-marketing surveillance (see section 4.4).
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 an overdose of Myelostim have not been identified (see section 5.3). Discontinuation of Myelostim therapy generally results in a 50% reduction in circulating neutrophils within 1-2 days, returning to normal levels in 1-7 days. A white blood cell count of approximately 50x10 9 / l has been described in one of the three patients who received the highest dose of Myelostim, equal to 40 micrograms / kg / day (5.12 million Units / kg / day) on the 5th day of treatment.
In humans, doses up to 40 mcg / kg / day have not been associated with toxic side effects, except musculoskeletal pain.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: cytokines.
ATC code L03AA10.
Lenograstim (rHuG-CSF) belongs to the group of cytokines, proteins that are biologically active in regulating cell differentiation and growth.
rHuG-CSF is a factor that stimulates the cellular precursors of neutrophils as demonstrated by the increase in the number of CFU-S and CFU-GM cells in the peripheral blood.
Myelostim induces a marked increase in the number of neutrophils in peripheral blood within 24 hours.
The increases in the number of neutrophils are dose-dependent in the range of 1 to 10 mcg / kg / day. At the recommended dose, repeated administrations induce an increase in the neutrophil response.
Neutrophils produced in response to Myelostim are found to function normally with regard to phagocytosis and chemotaxis.
Like other hematopoietic growth factors, G-CSF showed in vitro stimulating properties of human endothelial cells.
The use of Myelostim in patients undergoing bone marrow transplantation or treated with cytotoxic chemotherapies leads to a significant reduction in the duration of neutropenia and associated complications.
The use of Myelostim either alone or after chemotherapy mobilizes haematopoietic progenitor cells into the peripheral blood. These autologous Peripheral Blood Progenitor Cells (PBPCs) can be collected and reinfused after high-dose cytotoxic chemotherapy, either as a replacement or an adjunct. to bone marrow transplant.
It has been shown that reinfused PBPCs, obtained after mobilization with Myelostim, are able to reconstitute hematopoiesis and reduce the time required for engraftment, resulting in a marked decrease in the number of days of dependence on platelet transfusion in comparison. to autologous bone marrow transplant.
By analyzing data from 3 double-blind placebo-controlled studies in 861 patients (n = 411 55 years) a favorable benefit / risk ratio was demonstrated for the administration of lenograstim in patients over 55 years of age undergoing the conventional chemotherapy for acute myeloid leukemia "de novo", with the exception of acute myeloid leukemia with favorable cytogenetics ie t (8; 21), t (15; 17) and inv.. The benefit induced by lenograstim in the subgroup of patients over 55 years of age includes an" acceleration of the recovery of neutrophil values, an increase in the percentage of patients without episodes of infection, a reduction in the duration of infection, the duration of hospitalization, the duration of IV antibiotic therapy. However, these positive results are not associated with a decrease in the incidence of severe or fatal infections, nor with a decrease in infection-related mortality.
Data from a double-blind placebo-controlled study of 446 patients with acute myeloid leukemia "de novo"demonstrated that in the subgroup of 99 patients with favorable cytogenetics, event-free survival is significantly lower in the lenograstim arm than in the placebo arm; an overall lower trend towards survival was also observed in the lenograstim arm than in the subgroup data. with unfavorable cytogenetics.
05.2 Pharmacokinetic properties
The pharmacokinetics of Myelostim are dose and time dependent.
After repeated administration (i.v., s.c.) the maximum serum concentrations (immediately after intravenous infusion or after subcutaneous injection) are proportional to the injected dose.
Repeated doses of Myelostim administered by either route show no drug accumulation effects. At the recommended dose, the absolute bioavailability of Myelostim is 30%. The apparent volume of distribution (Vd) is approximately 1 L / kg body weight. The average residence time is close to 7 hours after subcutaneous administration.
In steady state after repeated administration, the apparent serum elimination half-life of Myelostim is approximately 3-4 hours after subcutaneous injection and shorter (1-1.5 hours) after intravenous infusion.
Plasma clearance of rHuG-CSF was increased threefold (50 to 150 mL / minute) after repeated subcutaneous administration.
Less than 1% of lenograstim is excreted unchanged in the urine and is therefore believed to be metabolised to peptides.
During multiple subcutaneous doses the maximum serum concentrations of lenograstim are close to 100 pg / ml / kg body weight at the recommended dose. There is a positive correlation between the dose and serum concentration of Myelostim and between the neutrophil response and the total amount of lenograstim in serum.
05.3 Preclinical safety data
In animals, acute toxicity studies (up to 1000 mcg / kg / day in mice) and subacute toxicity studies (up to 100 mcg / kg / day in monkeys) have shown that the effects of overdose are limited to reversible exacerbation of pharmacological effects.
In studies in rats and rabbits Myelostim did not show teratogenic activity. An increased incidence of abortions was observed in rabbits, but no malformations were found.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Dust
- Arginine
- Phenylalanine
- Methionine
- Mannitol (E421)
- Polysorbate 20
- Diluted hydrochloric acid (for pH adjustment)
Solvent
Water for injections
06.2 Incompatibility
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
06.3 Period of validity
2.5 years (30 months).
After reconstitution or dilution, immediate use is recommended.
However, the stability of the reconstituted / diluted medicinal product has been demonstrated for 24 hours at 2 ° C-8 ° C (in the refrigerator).
06.4 Special precautions for storage
Do not store above 30 ° C.
Do not freeze.
For storage conditions of the reconstituted / diluted product see section 6.3
06.5 Nature of the immediate packaging and contents of the package
263 mcg powder in vial (type I glass) with rubber stopper (type I butyl rubber)
+ 1 ml of solvent in ampoule (type I glass); Pack sizes of 1 or 5. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Any unused product / solution or any waste material must be disposed of in accordance with local regulations
Instructions for preparation
Myelostim vials are for single use only.
Myelostim must be reconstituted prior to subcutaneous or intravenous administration.
Preparation of the reconstituted solution of Myelostim
Using a graduated syringe fitted with a needle, aseptically withdraw the entire extractable content of a vial of solvent for Myelostim. Inject the entire content of the syringe into the corresponding vial of Myelostim.
Gently shake until completely dissolved. Do not shake vigorously. The reconstituted parenteral solution appears clear and free of particles.
The reconstituted solution should preferably be used immediately after preparation. For storage conditions of the reconstituted / diluted product, see section 6.3.
Preparation for subcutaneous administration
Prepare the reconstituted solution of Myelostim as described above.
While keeping the syringe needle inserted into the vial, withdraw the required volume of reconstituted solution from the vial. Replace the needle used for reconstitution and insert an appropriate needle for subcutaneous injection into the syringe.
Administer immediately by subcutaneous injection (for methods of administration see section 4.2).
Preparation of the infusion for intravenous administration:
For intravenous use Myelostim must be diluted after reconstitution. Prepare the reconstituted solution of Myelostim as described above.
While keeping the syringe needle inserted in the vial, withdraw the required volume of reconstituted solution from the vial. Dilute the reconstituted solution of Myelostim to the required concentration by injecting the required volume into 0.9% sodium chloride solution or dextrose solution to 5%.
Administer intravenously (for administration methods see section 4.2).
Myelostim is compatible with commonly used perfusion sets when diluted both in 0.9% physiological solution (polyvinyl chloride bags and glass bottles) and in 5% dextrose solution (glass bottles). Dilutions of Myelostim 34 million IU / mL at a final concentration below 0.32 million IU / mL (2.5 mcg / mL) are not recommended. A reconstituted vial of Myelostim 34 million IU / ml cannot be diluted in volumes greater than 100 ml.
07.0 MARKETING AUTHORIZATION HOLDER
Italfarmaco S.p.A. - Viale Fulvio Testi, 330 - 20126 Milan (Italy)
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 029059019 - 34 million IU / ml 1 vial of powder + 1 vial of solvent 1 ml
AIC n. 029059021 - 34 million IU / ml 5 vials of powder + 5 vials of solvent 1 ml
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First Authorization: February 13, 1995
Renewal of the Authorization: July 28, 2008
