Active ingredients: Filgrastim
Zarzio 30 MU / 0.5 ml solution for injection or infusion in a pre-filled syringe
Zarzio 48 MU / 0.5 ml solution for injection or infusion in a pre-filled syringe
Why is Zarzio used? What is it for?
Zarzio is a white blood cell growth factor (granulocyte colony stimulating factor) and belongs to a group of proteins called cytokines. Growth factors are proteins normally synthesized by the body, but which can also be produced with biotechnology and used as a medicine. Zarzio stimulates the bone marrow to produce more white blood cells.
The number of white blood cells can decrease (neutropenia) for several reasons, making the body's defenses less effective against infection. Zarzio stimulates the bone marrow to rapidly produce new white blood cells.
Zarzio can be used:
- to increase the number of white blood cells after chemotherapy and thus improve the prevention of infections;
- to increase the number of white blood cells after a bone marrow transplant and thus improve the prevention of infections;
- before high-dose chemotherapy to cause the bone marrow to produce more stem cells, which can be collected and given again after treatment. These cells can be taken from you or from a donor. The re-infused stem cells arrive in the bone marrow and produce blood cells;
- to increase the number of white blood cells in severe chronic neutropenia and thus improve the prevention of infections;
- in patients with advanced HIV infection to reduce the risk of infections.
Contraindications When Zarzio should not be used
Do not use Zarzio if you are allergic to filgrastim or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Zarzio
Talk to your doctor, pharmacist or nurse before using Zarzio.
Take special care with Zarzio if you have previously had an allergic reaction to latex.
Tell your doctor before starting treatment if you suffer from:
- osteoporosis (a bone disease);
- sickle cell anemia, because Zarzio can trigger a sickle cell crisis.
Tell your doctor immediately during treatment with Zarzio if:
- you experience pain in the left upper abdomen (abdominal pain), under the left rib arch or in the apex of the left shoulder [these may be symptoms of an enlarged spleen (splenomegaly) or a possible rupture of the spleen],
- you notice unusual bleeding or bruising [these may be symptoms of a reduction in blood platelets (thrombocytopenia), with reduced ability of the blood to clot],
- develop sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing, as these could be signs of an allergic reaction serious.
- you have swollen face or ankles, blood in your urine or brown colored urine, or notice that you urinate less than usual.
Loss of response to filgrastim
If you experience a loss of response or the inability to maintain the response with filgrastim treatment, your doctor will investigate the reasons, including the possibility that you have developed antibodies that neutralize the activity of filgrastim.
Your doctor may wish to monitor you with special care, see section 4 of the package leaflet.
If you are a patient with severe chronic neutropenia you may be at risk of developing blood cancer (leukemia, myelodysplastic syndrome [MDS]). Consult your doctor about the risk of developing blood cancers and the necessary tests. If you develop or are likely to develop blood cancers you should not use Zarzio unless directed by your doctor.
If you are a stem cell donor you must be between the ages of 16 and 60.
Take special care with other products that stimulate white blood cells.
Zarzio belongs to the group of medicines that stimulate the production of white blood cells. Your healthcare professional should always record the exact name of the medicine you are using.
Interactions Which drugs or foods can modify the effect of Zarzio
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, breastfeeding
Zarzio has not been studied 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 while taking Zarzio, please inform your doctor.
Unless your doctor advises you otherwise, if you use Zarzio you must stop breastfeeding.
Driving and using machines
Zarzio does not affect the ability to drive or use machines. However, you should wait and see how you feel after taking Zarzio before driving or using machines.
Zarzio contains sorbitol
Zarzio contains sorbitol (E420), if you have been told by your doctor that you have a reaction to some sugars, contact your doctor before taking this medicine.
Dosage and method of use How to use Zarzio: Dosage
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
How is Zarzio given and how much should I take?
Normally, Zarzio is given as a daily injection into the tissue located directly under the skin (subcutaneous injection). It can also be given as a slow daily injection into a vein (intravenous infusion). The usual dose depends on the disease you suffer from and your body weight. Your doctor will tell you what dose of Zarzio to take.
Bone marrow transplant patients after chemotherapy:
You will normally receive the first dose of Zarzio at least 24 hours after chemotherapy and at least 24 hours after a bone marrow transplant.
You or your caregivers can be taught how to perform subcutaneous injections so that you can continue the treatment at home. However, you should not try before you have received adequate training from the healthcare professional.
How long should I take Zarzio for?
You must take Zarzio until your white blood cell count has normalized. Blood tests will be done at regular intervals to check the number of white blood cells. Your doctor will tell you how long to take Zarzio for.
Use in children
Zarzio is used to treat children who are undergoing chemotherapy or who suffer from a severe reduction in their white blood cell count (neutropenia). The dose to be used in children undergoing chemotherapy is the same as in adults.
If you forget to use Zarzio
If you have missed an injection, or injected too little medicine, contact your doctor as soon as possible. Do not take a double dose to make up for a missed dose.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Overdose What to do if you have taken too much Zarzio
Do not increase the dose your doctor has given you. If you think you have injected more Zarzio than you should, contact your doctor as soon as possible.
Side Effects What are the side effects of Zarzio
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately during treatment
- if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), rash, itchy rash (hives), swelling of the lips, mouth, tongue or throat ( angioedema) and shortness of breath (dyspnoea). Hypersensitivity is common in patients who have cancer;
- if you experience cough, fever and difficulty breathing (dyspnoea), as this may be a sign of acute respiratory distress syndrome (ARDS). ARDS is not common in patients who have cancer;
- if you experience pain in the left upper abdomen (abdominal pain), pain in the left under the ribs or pain in the shoulder blade, 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). If you get this side effect or if you have protein in your urine (proteinuria), your doctor may do urinalysis at regular intervals.
- 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 could 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). Renal impairment has been observed in patients receiving filgrastim. See your doctor right away if you have swollen face or 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 from the use of filgrastim is pain in the muscles or bones (musculoskeletal pain), which can be relieved by taking normal pain relievers (analgesics). Graft versus host disease (GvHD), which is a reaction of the donor cells towards the patient receiving the transplant, can occur in patients undergoing a stem cell or bone marrow transplant; signs and symptoms include rash on the palms or soles and ulcers and lesions in the mouth, intestines, liver, skin or eyes, lungs, vagina and joints. In healthy stem cell donors, an increase in white blood cells (leukocytosis) and a decrease in platelets, which reduces the ability of the blood to clot (thrombocytopenia), are very commonly seen; your doctor will check for these reactions.
Very common side effects (may affect more than 1 in 10 people taking Zarzio)
in cancer patients
- changes in the chemical parameters of the blood
- increase in certain enzymes in the blood
- reduced appetite
- headache
- pain in the mouth and throat (oropharyngeal pain)
- cough
- diarrhea
- He retched
- constipation
- nausea
- rash
- unusual hair loss or thinning (alopecia)
- pain in the muscles or bones (musculoskeletal pain)
- generalized weakness (asthenia)
- tiredness (fatigue)
- lesions and swelling of the lining of the digestive tract between the mouth and the anus (inflammation of the mucosa)
- shortness of breath (dyspnoea)
- ache
in healthy stem cell donors
- decrease in platelets which reduces 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)
- low red blood cell count (anemia)
- changes in the chemical composition of the blood
- increase in certain enzymes in the blood
- headache
- nosebleed (epistaxis)
- diarrhea
- enlargement of the liver (hepatomegaly)
- rash
- pain in the muscles or bones (musculoskeletal pain)
- joint pain (arthralgia)
in patients with HIV
- pain in the muscles or bones (musculoskeletal pain)
Common side effects (may affect up to 1 in 10 people taking Zarzio)
in cancer patients
- allergic reaction (drug hypersensitivity)
- low blood pressure (hypotension)
- painful urination (dysuria)
- chest pain
- coughing up blood (hemoptysis)
in healthy stem cell donors
- increase in certain enzymes in the blood
- shortness of breath (dyspnoea)
- enlargement of the spleen (splenomegaly)
in patients with severe chronic neutropenia
- rupture of the spleen
- decrease in platelets which reduces the ability of the blood to clot (thrombocytopenia)
- changes in the chemical composition of the blood
- inflammation of the blood vessels in the skin (cutaneous vasculitis)
- unusual hair loss or thinning (alopecia)
- disease that makes bones less dense and therefore weaker, more fragile and prone to fractures (osteoporosis)
- blood in the urine (haematuria)
- pain at the injection site
- damage to the small filters inside the kidneys (glomerulonephritis)
in patients with HIV
- enlargement of the spleen (splenomegaly)
Uncommon side effects (may affect up to 1 in 100 people taking Zarzio)
in cancer patients
- rupture of the spleen
- enlargement of the spleen (splenomegaly)
- severe pain in the bones, chest, intestines or joints (sickle 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)
- insufficient function of the lungs, causing breathlessness (respiratory failure)
- swelling and / or accumulation of fluid in the lungs (pulmonary edema)
- inflammation of the lungs (interstitial lung disease)
- X-ray abnormalities of the lungs (pulmonary infiltration)
- purple, painful, raised lesions on the limbs and sometimes on the face and neck, with fever (Sweet's syndrome)
- inflammation of blood vessels in the skin (cutaneous vasculitis)
- worsening of rheumatoid arthritis
- unusual changes in urine
- ache
- liver damage caused by blockage of the small veins in the liver (veno-occlusive disease)
- bleeding from the lung (pulmonary haemorrhage)
- altered fluid regulation in the body, which can cause swelling
- damage to the small filters inside the kidneys (glomerulonephritis)
in healthy stem cell donors
- rupture of the spleen
- severe pain in the bones, chest, intestines or joints (sickle crisis)
- sudden life-threatening allergic reaction (anaphylactic reaction)
- changes in the chemical composition of the blood
- bleeding in the lung (pulmonary haemorrhage)
- coughing up blood (hemoptysis)
- X-ray abnormalities of the lungs (pulmonary infiltration)
- defective absorption of oxygen in the lung (hypoxia)
- increase in certain enzymes in the blood
- worsening of rheumatoid arthritis
- damage to the small filters inside the kidneys (glomerulonephritis)
in patients with severe chronic neutropenia
- severe pain in the bones, chest, intestines or joints (sickle crisis)
- excessive amount of protein in the urine (proteinuria)
in patients with HIV
- severe pain in the bones, chest, intestines or joints (sickle crisis)
Undesirable effects with frequency not known (frequency cannot be estimated from the available data)
- damage to the small filters inside the kidneys (glomerulonephritis)
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 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.
Do not use this medicine after the expiry date which is stated on the carton and syringe label after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C).
Keep the pre-filled syringe in the outer carton to protect the medicine from light.
Accidental freezing will not harm Zarzio.
The syringe can be kept out of the refrigerator and left at room temperature for one time only and for up to 72 hours (however, not above 25 ° C). At the end of this period, the product must not be put back in the refrigerator and must be discarded.
Do not use this medicine if you notice discolouration, a cloudy appearance or the presence of particles; the medicine should be presented as a clear colorless to pale yellow 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.
Deadline "> Other information
What Zarzio contains
The active ingredient is filgrastim.
- Zarzio 30 MU / 0.5 ml solution for injection or infusion in a pre-filled syringe.Each pre-filled syringe contains 30 MU of filgrastim in 0.5 ml, corresponding to 60 MU / ml.
- Zarzio 48 MU / 0.5 ml solution for injection or infusion in a pre-filled syringe. Each pre-filled syringe contains 48 MU of filgrastim in 0.5 ml, corresponding to 96 MU / ml.
The other ingredients are glutamic acid, sorbitol (E420), polysorbate 80 and water for injections. The syringe needle cap may contain dry rubber (latex).
Zarzio looks like and contents of the pack
Zarzio is a clear, colorless to pale yellow solution for injection or infusion in a pre-filled syringe.
Zarzio is available in packs containing 1, 3, 5 or 10 pre-filled syringes with injection needle, with or without a needle safety guard.
Not all pack sizes may be marketed.
Expiry "> Instructions for self-injection
This section contains information on how to inject Zarzio yourself. It is important that you do not try to inject the medicine yourself until you have been specially trained by your doctor or nurse. Zarzio is supplied with or without a needle safety device: your doctor or nurse will show you how to use it. if you have any questions or concerns about self-injection, ask your doctor or nurse.
- Wash your hands.
- Take a syringe out of the package and remove the protective cap from the injection needle. The syringes have a graduated scale that allows you to use only part of the contents if necessary. Each notch corresponds to a volume of 0.1 ml. If it is Partial use of the syringe is required, discard any unnecessary solution before injecting.
- Disinfect the skin at the injection site with an alcohol swab.
- Take a skin fold between your thumb and forefinger.
- With a quick, firm motion, insert the needle into the skin crease. Inject the Zarzio solution as you have been shown by your doctor. If you are unsure, consult your doctor or pharmacist.
Pre-filled syringe without needle safety guard
- Always holding the skin fold between your fingers, press down slowly and evenly on the plunger.
- After injecting the liquid, pull out the needle and let go of your skin.
- Throw away the used syringe in the special container. Each syringe should only be used for one injection.
Pre-filled syringe with needle safety guard
- Always holding the skin fold between your fingers, press the plunger slowly and evenly until the full dose is released and the plunger cannot be pushed further. Do not release the pressure on the plunger!
- After injecting the liquid, pull out the needle while maintaining pressure on the plunger and then let go of your skin.
- Let go of the plunger. The safety device will quickly cover the needle.
- Eliminate any product residues or waste. Each syringe should only be used for one injection.
Deadline "> Information for healthcare professionals
The solution should be visually inspected prior to use. Only clear, particle-free solutions should be used. Accidental exposure to freezer temperature has no adverse effect on the stability of Zarzio.
Zarzio does not contain preservatives: due to the risk of bacterial contamination, Zarzio syringes are for single use only.
The syringe needle cap may contain dry rubber (latex), which should not be handled by people sensitive to this substance.
Dilution before administration (optional)
If necessary, Zarzio can be diluted in 50 mg / ml (5%) glucose solution. Zarzio must not be diluted with sodium chloride solutions.
Dilution to final concentrations <0.2 MU / ml (2 µg / ml) is not recommended.
In patients treated with filgrastim diluted to concentrations <1.5 MU / ml (15 µg / ml), human serum albumin (HSA) should be added to a final concentration of 2 mg / ml.
Example: for a final volume of 20 ml, total doses of filgrastim below 30 MU (300 µg) must be added with 0.2 ml of human serum albumin solution Ph. Eur 200 mg / ml (20%).
Diluted with 50 mg / ml (5%) glucose solution, filgrastim is compatible with glass and with various plastic materials such as polyvinyl chloride, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
After dilution, the in-use chemical and physical stability of the diluted solution for infusion has been demonstrated for 24 hours at a temperature between 2 ° C - 8 ° C. From a microbiological point of view, the product should be used immediately. If the medicinal product is not used immediately, the user is responsible for the storage duration and conditions prior to use; the medicinal product can be stored for up to 24 hours at 2 ° C - 8 ° C, unless dilution has been carried out under controlled and validated aseptic conditions.
Using the pre-filled syringe with needle safety guard
The needle safety guard covers the needle after injection and prevents the operator from injuring himself.
The device does not interfere with normal use of the syringe. Push slowly and evenly on the plunger until the full dose is released and the plunger cannot be pushed further. Pull the syringe away from the patient while continuing to press down on the plunger. The safety device covers the needle as soon as the plunger is released.
Using the pre-filled syringe without a needle safety guard
Administer the dose according to the standard procedure.
Disposal
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
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 -
ZARZIO 30 MU / 0.5 ML SOLUTION FOR INJECTION OR FOR INFUSION IN PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each ml of solution contains 60 million units (MU) [equivalent to 600 mcg (mcg)] of filgrastim *.
Each pre-filled syringe contains 30 MU (equivalent to 300 mcg) of filgrastim in 0.5 ml.
* recombinant human methionine granulocyte colony stimulating factor (G-CSF) produced in E. coli with recombinant DNA technology.
Excipient: each ml of solution contains 50 mg of sorbitol (E420).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Solution for injection or infusion in pre-filled syringe
Clear, colorless to pale yellow solution.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
- Reduction of the duration of neutropenia and of the incidence of febrile neutropenia in patients treated with standard cytotoxic chemotherapy for malignant diseases (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) and reduction of the duration of neutropenia in patients undergoing myeloablative therapy followed marrow transplant patients considered to be at high risk for prolonged severe neutropenia.
The safety and efficacy of filgrastim are similar in adults and children undergoing cytotoxic chemotherapy.
- Mobilization of peripheral blood progenitor cells (PBPCs).
- In children and adults with severe congenital, cyclic or idiopathic neutropenia, with an absolute neutrophil count (ANC) ≤ 0.5 x 109 / l and a history of severe or recurrent infections, long-term administration of filgrastim is indicated for increase neutrophil counts and reduce the incidence and duration of infection-related events.
- Treatment of persistent neutropenia (ANC ≤ 1.0 x 109 / L) in patients with advanced HIV infection, to reduce the risk of bacterial infections when other treatment options are inadequate.
04.2 Posology and method of administration -
Filgrastim therapy should only be performed in conjunction with a cancer center experienced in the treatment with granulocyte colony stimulating factor (G-CSF) and in haematology, and which has the necessary diagnostic equipment.
The mobilization and apheresis procedures must be performed in collaboration with an oncology-hematology center with acceptable experience in the field and where the monitoring of hematopoietic progenitor cells can be correctly performed.
Zarzio is available in concentrations of 30 MU / 0.5 ml and 48 MU / 0.5 ml.
Standard cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MU / kg / day (5 mcg / kg / day). The first dose of filgrastim should not be administered earlier than 24 hours after cytotoxic chemotherapy.
Daily dosing of filgrastim should continue until the expected neutrophil nadir has been exceeded and the neutrophil count has returned to a normal level. After standard chemotherapy for solid tumors, lymphomas and lymphoid leukemias, the required duration of treatment to meet these criteria it can reach 14 days. After induction and consolidation treatment in acute myeloid leukemia, the duration of treatment can be considerably longer (up to 38 days) depending on the type, dose and pattern of cytotoxic chemotherapy used .
In patients undergoing cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1 - 2 days after initiation of filgrastim therapy. However, to achieve a prolonged therapeutic response, treatment with filgrastim should continue as long as the " expected neutrophil nadir has not been exceeded and the neutrophil count has not returned to a normal level. Premature discontinuation of filgrastim therapy before the expected neutrophil nadir is reached is not recommended.
Patients undergoing myeloablative therapy followed by bone marrow transplant
The recommended starting dose of filgrastim is 1.0 MU / kg / day (10 mcg / kg / day). The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and within 24 hours after bone marrow infusion.
Dosage adjustments: Once the neutrophil nadir has been passed, the daily dose of filgrastim should be titrated based on the neutrophil response as follows:
Mobilization of PBPCs
Patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation
The recommended dose of filgrastim for PBPC mobilization, when used alone, is 1.0 MU / kg / day (10 mcg / kg / day) for 5 to 7 consecutive days. Leukapheresis schedule: 1 or 2 leukaphereses are often sufficient on days 5 and 6. In other cases, additional leukapheresis may be required. Administration of filgrastim should be continued until the last leukapheresis.
The recommended dose of filgrastim for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU / kg / day (5 mcg / kg / day), given daily from the first day following the completion of chemotherapy until the expected nadir has not been exceeded and the neutrophil count has not returned to a normal level. Leukapheresis should be performed during the period when the ANC increases from 5.0 x 109 / L. In patients not undergoing extensive chemotherapy, a single leukapheresis is often sufficient. In other cases, further leukapheresis is recommended.
There are no prospective randomized comparative studies of the two recommended mobilization methods (filgrastim alone or filgrastim in combination with myelosuppressive chemotherapy) in the same patient population. The degree of variability between individual patients and between laboratory determination methods 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 take into account the general goals of treatment in each individual patient.
Healthy donors prior to allogeneic PBPC transplantation
For PBPC mobilization in healthy donors prior to allogeneic PBPC transplantation, filgrastim should be administered at doses of 1.0 MU / kg / day (10 μg / kg / day) for 4 to 5 consecutive days. Leukapheresis should begin on day 5 and continue as needed until day 6 to obtain 4 x 106 CD34 + cells / kg body weight (bw) of the recipient.
Severe chronic neutropenia (SCN)
Congenital neutropenia
The recommended starting dose is 1.2 MU / kg / day (12 mcg / kg / day) as a single dose or in divided doses.
Idiopathic or cyclic neutropenia
The recommended starting dose is 0.5 MU / kg / day (5 mcg / kg / day) as a single dose or in divided doses.
Dosage adjustments
Filgrastim should be administered daily until the neutrophil count has reached and can be maintained above 1.5 x 109 / l. When the response is obtained, the lowest effective dose to maintain this level should be determined. Long-term daily administration is required to maintain adequate neutrophil counts.
After 1 - 2 weeks of therapy, the starting dose can be doubled or halved based on the patient's response. Thereafter, the dose can be individually adjusted every 1 to 2 weeks to maintain a mean neutrophil count between 1.5 x 109 / l and 10 x 109 / l. In patients with severe infections, a more rapid schedule of progressive dose escalation may be considered. In clinical studies, 97% of responders achieved a complete response at doses ≤ 2.4 MU / kg / day (24 mcg / kg / day). The long-term safety of filgrastim administration at doses above 2.4 MU / kg / day (24 micrograms / kg / day) in SCN patients has not been demonstrated.
HIV infection
Reversal of neutropenia
The recommended starting dose of filgrastim is 0.1 MU / kg / day (1 mcg / kg / day) administered daily, with titration up to a maximum of 0.4 MU / kg / day (4 mcg / kg / day). until a normal neutrophil count (ANC> 2.0 x 109 / L) has been achieved and can be maintained. In clinical trials,> 90% of patients responded to these doses, achieving reversal of neutropenia over a median of 2 days.
In a small number of patients (
Maintaining a normal neutrophil count
When reversal of neutropenia has been achieved, the lowest effective dose to maintain a normal neutrophil count should be determined. An initial dose adjustment with alternate day dosing of 30 MU / day (300 mcg / day) is recommended. Further dose adjustments may be required, depending on the patient's ANC, in order to maintain neutrophil counts at> 2.0 x 109 / L. In clinical trials, doses of 30 MU / day (300 mcg / L) were required. day) from 1 to 7 days per week to maintain ANC> 2.0 x 109 / L, with a median frequency of administration of 3 days per week. Long-term administration may be required to maintain ANC> 2.0 x 109 / L.
Special patient populations
Patients with renal / hepatic insufficiency
Studies conducted with filgrastim in patients with severe renal or hepatic impairment show that its pharmacokinetic and pharmacodynamic profile is similar to that seen in healthy subjects. In these cases, no dosage adjustment is necessary.
Pediatric patients with SCN and malignant diseases
In clinical trials, 65% of patients treated for a SCN were under the age of 18. In this age group, including mainly patients with congenital neutropenia, efficacy has been demonstrated. No differences in the safety profiles of pediatric patients treated for SCN were observed compared to adults.
Data from clinical trials with pediatric patients indicate that the safety and efficacy of filgrastim are similar in adults and children undergoing cytotoxic chemotherapy.
The dosing recommendations in pediatric patients are identical to the recommendations valid for adults undergoing myelosuppressive cytotoxic chemotherapy.
Elderly patients
Only a small number of elderly patients were included in clinical trials with filgrastim. No specific studies have been performed in this patient population. Therefore, no specific dosage recommendations can be made for these patients.
Method of administration
Standard cytotoxic chemotherapy
Filgrastim can be given as a daily subcutaneous injection or alternatively as a daily 30 minute intravenous infusion. For more information regarding dilution with 50 mg / ml (5%) glucose solution prior to infusion, refer to section 6.6. In most cases, the subcutaneous route is preferable. There is evidence from a dosing study. that intravenous use may shorten the duration of the effect. The clinical relevance of this finding for multiple dose administration is unknown. The choice of route of administration should be based on the clinical condition of the individual patient. In randomized clinical trials Doses of 23 MU / m² / day (230 mcg / m² / day) or 0.4 - 0.84 MU / kg / day (4 - 8.4 mcg / kg / day) were used subcutaneously.
Patients undergoing myeloablative therapy followed by bone marrow transplant
Filgrastim is administered as a short 30-minute intravenous infusion, or as a 24-hour continuous subcutaneous or intravenous infusion, in both cases after dilution in 20 ml of 50 mg / ml (5%) glucose solution. For further information regarding dilution with 50 mg / ml (5%) glucose solution before infusion, please refer to section 6.6.
Mobilization of PBPCs
Subcutaneous injection.
For PBPC mobilization in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation, the recommended dose of filgrastim can also be administered by continuous 24-hour subcutaneous infusion. For infusions, filgrastim should be diluted in 20 ml of 50 mg / ml (5%) glucose solution. For further information regarding dilution with 50 mg / ml (5%) glucose solution prior to infusion, please refer to section 6.6.
NCG / HIV infection
Subcutaneous injection.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use -
Special warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond the standard dose regimen (see below).
Filgrastim should not be given to patients with severe congenital neutropenia (Kostmann syndrome) with cytogenetic abnormalities (see below).
Standard cytotoxic chemotherapy
Proliferation of malignant cells
It has been shown that G-CSF can promote the proliferation of myeloid cells in vitro; therefore, the following warnings must be kept in mind.
The safety and efficacy of administering filgrastim to patients with myelodysplastic syndrome or chronic myeloid leukemia have not been demonstrated. Therefore, the use of filgrastim is not indicated in such situations. Particular attention must be paid to the differential diagnosis between blast transformation in chronic myeloid leukemia and acute myeloid leukemia.
Due to limited data on safety and efficacy, filgrastim should be administered with caution in patients with secondary AML.
The safety and efficacy of filgrastim administration in patients of de novo age and favorable cytogenetics [t (8; 21), t (15; 17) and inv] have not been demonstrated.
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 were observed. However, in view of the potential risks associated with severe leukocytosis, regular monitoring of white blood cell counts should be performed during filgrastim therapy. Filgrastim treatment should be stopped immediately if the white blood cell count exceeds 50 x 109 / l after the expected nadir. During the period of administration of filgrastim for PBPC mobilization, treatment should be interrupted or the dose should be reduced if the white blood cell count exceeds 70 x 109 / l.
Risks associated with high-dose chemotherapy
Particular care should be taken in the treatment of patients with high-dose chemotherapy, because a more favorable tumor response has not been demonstrated and because the administration of high-dose chemotherapy can increase toxic effects, including cardiac, pulmonary, neurological and dermatological effects. (refer to the Summary of Product Characteristics of the chemotherapeutic agents used).
Treatment with filgrastim alone does not prevent thrombocytopenia and anemia following myelosuppressive chemotherapy. As a result of the possibility of receiving higher doses of chemotherapy (e.g. full doses according to the prescribed dosage regimen), the patient may be exposed to an increased risk of thrombocytopenia and anemia. Regular checks of platelet counts and hematocrit are therefore recommended. Particular attention should be paid during the administration, both alone and in combination, of chemotherapeutic agents known to induce severe thrombocytopenia.
The use of filgrastim-mobilized PBPCs has been shown to reduce the severity and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions
The effect of filgrastim in patients with significantly reduced myeloid progenitors has not been studied. To increase neutrophil counts, filgrastim acts primarily on neutrophil precursors. Therefore, in patients with low numbers of precursors (eg, patients treated with extensive radiotherapy or chemotherapy or patients with tumor infiltration of the bone marrow), the response of neutrophils may be reduced.
Cases of graft versus host disease (GvHD) and death have been reported in patients treated with G-CSF after allogeneic bone marrow transplantation (see section 5.1).
Mobilization of PBPCs
Previous exposure to cytotoxic agents
In patients extensively pretreated with myelosuppressive therapy, followed by administration of filgrastim for PBPC mobilization, PBPC mobilization may not be sufficient to achieve the recommended minimum cell count (≥ 2.0 x 106 CD34 + cells / kg) or that the acceleration of platelet recovery is less marked.
Some cytotoxic agents show particular toxicity on haematopoietic progenitor cells and can counteract their mobilization. Substances such as melphalan, carmustine (BCNU) and carboplatin, if given for an extended period before progenitor cell mobilization, can reduce the number of cells collected. However, administration of melphalan, carboplatin or BCNU in combination with filgrastim has been shown to be effective in mobilizing progenitor cells. If a PBPC transplant is planned, stem cell mobilization should be planned in the initial phase of the patient's intended treatment. Particular attention should be paid to the number of progenitor cells mobilized in such patients prior to the administration of high-dose chemotherapy. If cell collection is inadequate according to the previously indicated evaluation criteria, alternative treatments that do not require the use of progenitor cells should be considered.
Evaluation of the collection of progenitor cells
In the quantitative evaluation of progenitor cells obtained in patients treated with filgrastim, particular attention should be paid to the method of enumeration. The results of CD34 + cell count by flow cytometry vary according to the methodology used; therefore, numbers derived from studies conducted in other laboratories must be interpreted with caution.
Statistical analysis of the relationship between the number of reinfused CD34 + cells and the rate of platelet recovery after high-dose chemotherapy indicates a complex but constant relationship. The recommendation to collect a minimum of ≥ 2.0 x 106 CD34 + cells / kg is based on published experience, which indicates that haematological recovery is thus adequate, amounts higher than the minimum number indicated appear to be related to faster recovery, lower amounts to slower recovery.
Healthy donors prior to allogeneic PBPC transplantation
PBPC mobilization has no direct clinical benefit in healthy donors and should only be considered with the aim of allogeneic stem cell transplantation.
PBPC mobilization should only be considered in donors who meet the normal clinical and laboratory eligibility criteria for stem cell donation, paying particular attention to haematological parameters and the presence of infectious diseases.
The safety and efficacy of filgrastim have not been evaluated in healthy donors aged 60 years.
Transient thrombocytopenia (platelets
Leukapheresis should not be performed in donors on anticoagulant therapy or who have known changes in haemostasis.
Filgrastim administration should be discontinued or the dosage should be reduced if the white blood cell count reaches> 70 x 109 / L.
Donors receiving G-CSF for PBPC mobilization should be monitored until haematological parameters are normalized.
Transient cytogenic changes have been observed after use of G-CSF in healthy donors. The significance of these changes is unknown.
Long-term safety follow-up in donors is ongoing. However, the risk of developing a malignant myeloid cell clone cannot be excluded. It is recommended that the apheresis center carry out systematic registration and follow-up of stem cell donors for at least 10 years to ensure long-term safety monitoring.
Following administration of G-CSF, generally asymptomatic splenomegaly and, in very rare cases, rupture of the spleen has been commonly observed in healthy donors and patients. Some cases of ruptured spleen have been fatal. Therefore, the volume of the spleen should be carefully checked (e.g. by physical examination, ultrasound). The diagnosis of ruptured spleen should be considered in donors and / or patients with left upper abdominal pain or shoulder blade pain.
In post-marketing experience, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, pulmonary infiltrates, dyspnoea and hypoxia) have been reported very rarely in normal donors. In case of suspected or confirmed pulmonary adverse events, treatment discontinuation should be considered. with filgrastim the necessary medical assistance is provided.
Recipients of allogeneic PBPCs mobilized with filgrastim
Current data indicate that immunological interactions between allogeneic PBPCs and the recipient may be associated with an increased risk of acute and chronic GvHD compared to bone marrow transplantation.
NCG
Complete blood count
Platelet counts should be monitored frequently, particularly during the first few weeks of filgrastim therapy. Intermittent discontinuation of treatment or dose reduction of filgrastim should be considered in patients who develop thrombocytopenia, ie with platelets
Other changes in the blood picture may occur, including anemia and transient increases in myeloid progenitors, which require careful monitoring of blood counts.
Transformation into leukemia or myelodysplastic syndrome
Particular attention must be paid to the differential diagnosis between SCN and other haematological diseases such as aplastic anemia, myelodysplasia and myeloid leukemia. A complete blood count with differential and platelet counts, as well as an evaluation of bone marrow morphology and a karyotype should be done before starting treatment.
Myelodysplastic syndromes (MDS) or leukemia have been observed in a small number (approximately 3%) of SCN patients treated with filgrastim in clinical trials. This has only been observed in patients with congenital neutropenia. MDS and leukemia are natural complications of the disease and are not to be considered with certainty in relation to treatment with filgrastim. Abnormalities, including monosomy 7, were subsequently found in approximately 12% of patients with normal cytogenetics at baseline during routine repeat testing. If SCN patients develop cytogenetic abnormalities, the risks and benefits of continuing treatment with filgrastim should be carefully considered; Filgrastim administration should be discontinued if MDS or leukemia develops. It is currently unknown whether long-term treatment of SCN patients can predispose patients to cytogenetic abnormalities, MDS, or leukemic transformation. In these patients, morphological and cytogenetic analyzes of the bone marrow are recommended at regular intervals (approximately every 12 months).
Other special precautions
Causes of transient neutropenia, such as viral infections, must be excluded.
Splenomegaly is a direct effect of filgrastim treatment. Palpable splenomegaly was observed in 31% of patients in clinical studies. Volume increases, measured radiologically, were seen early during filgrastim therapy and showed a tendency to stabilize. Dose reductions were observed to slow or halt the progression of splenomegaly, and a splenectomy was required in 3% of patients. The volume of the spleen should be checked regularly. Abdominal palpation is sufficient to detect abnormal volume increases.
Haematuria / proteinuria occurred in a small number of patients. Urinalysis should be done at regular intervals in order to detect such events.
Safety and efficacy in neonates and in patients with autoimmune neutropenia have not been demonstrated.
HIV infection
Complete blood count
ANC should be monitored frequently, particularly during the first weeks of filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil counts to the starting dose of filgrastim. It is recommended that their ANC be determined daily during first 2 - 3 days of filgrastim administration. Thereafter, it is recommended that ANC be determined at least twice a week during the first 2 weeks and thereafter once a week or every other week during maintenance therapy. In case of intermittent dosing of 30 MU / day (300 mcg / die) of filgrastim, large fluctuations of ANC may occur over time. To determine the minimum or nadir value of a patient's ANC, it is recommended that blood samples intended for ANC determination be obtained immediately prior to the intended administration of filgrastim.
Risks associated with high doses of myelosuppressive drugs
Treatment with filgrastim does not prevent thrombocytopenia and anemia following myelosuppressive therapy. Since higher doses or a greater number of myelosuppressive agents can be administered with the use of filgrastim, the patient may be at increased risk of thrombocytopenia or anemia. Regular monitoring of hematocrit is recommended (see above).
Infections and malignancies causing myelosuppression
Neutropenia may be due to bone marrow infiltration from opportunistic infections, such as Mycobacterium avium complex, or to malignant neoplasms, such as lymphomas. In patients with known bone marrow infiltrating infections or malignancies, consideration should be given to adequate treatment of the underlying disease in addition to administration of filgrastim for the treatment of neutropenia. The effects of filgrastim on neutropenia due to bone marrow infiltrating malignancies or infections have not been conclusively demonstrated.
Other special precautions
Rare lung adverse reactions, in particular interstitial pneumonia, have been reported following administration of G-CSF (see section 4.8). Patients with a recent history of pulmonary infiltrates or pneumonia may be at increased risk. The appearance of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration of lung function may be preliminary signs of adult respiratory distress syndrome (ARDS). In these cases, administration of filgrastim should be stopped and appropriate treatment initiated.
Bone density monitoring may be indicated in patients with underlying osteoporosis who are on continuous filgrastim therapy for more than 6 months.
Sickle cell crises, in some cases fatal, have been reported in patients with sickle cell anemia treated with filgrastim. In patients with sickle cell anemia, physicians should exercise caution when evaluating the use of filgrastim, which should only be used after careful consideration of the potential benefits and risks.
Increased bone marrow hematopoietic activity in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone reports.
Excipients
Zarzio contains sorbitol. Patients with rare hereditary fructose intolerance should not use this medicine.
In order to improve the traceability of the granulocyte colony stimulating factor (G-CSFs) the trade name of the administered medicinal 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 filgrastim administered on the same day as myelosuppressive cytotoxic chemotherapy have not been conclusively demonstrated. Since rapidly dividing myeloid cells are sensitive to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended in the period included. three 24 hours before and 24 hours after chemotherapy. Preliminary data obtained in a small number of patients treated jointly with filgrastim and 5-fluorouracil indicate that neutropenia may worsen.
The possible interactions with other hematopoietic growth factors and cytokines have not yet been studied in clinical trials.
Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. Although this interaction has not been formally studied, there is no evidence that it is harmful.
04.6 Pregnancy and breastfeeding -
There are no adequate data regarding the use of filgrastim in pregnant women. Cases have been reported in the literature in which placental spread of filgrastim has been demonstrated in pregnant women. Studies in rats and rabbits have not shown a teratogenic effect. An increased incidence of embryo loss was observed in rabbits, but no malformations were observed.
In pregnancy, the possible risks to the fetus associated with the use of filgrastim must be weighed against the expected therapeutic benefit.
It is not known whether filgrastim is excreted in human breast milk; therefore, its use is not recommended during breastfeeding.
04.7 Effects on ability to drive and use machines -
Filgrastim does not affect the ability to drive or use machines.
04.8 Undesirable effects -
The most common adverse reaction due to filgrastim is mild to moderate musculoskeletal pain, occurring in more than 10% of patients. Musculoskeletal pain is usually controllable with conventional analgesics.
Adverse reactions listed below are classified by frequency and by system organ. Frequencies are defined according to the following conventions: very common (≥ 1/10), common (≥ 1/100,
Table 1. Adverse reactions observed in clinical studies in cancer patients
Table 2. Adverse reactions observed in clinical studies in healthy donors undergoing PBPC mobilization
Table 3. Adverse reactions observed in clinical studies in SCN patients
Table 4. Adverse reactions observed in clinical studies in HIV patients
In randomized, placebo-controlled clinical trials, filgrastim did not increase the incidence of undesirable effects associated with cytotoxic chemotherapy. Undesirable effects observed with equal frequency in patients treated with filgrastim / chemotherapy and placebo / chemotherapy were as follows: nausea and vomiting, alopecia, diarrhea, fatigue, anorexia, mucositis, headache, cough, rash, chest pain, general weakness, sore throat, constipation and unspecified pain.
Allergic reactions have been observed in patients treated with filgrastim during initial or subsequent treatment. In general, reports were more frequent after intravenous administration. In some cases the symptoms have recurred on subsequent use: this is indicative of a causal relationship. In patients who experience a severe allergic reaction to filgrastim, treatment should be permanently discontinued.
Cases of graft versus host disease (GvHD) and death have been reported in patients treated with G-CSF after allogeneic bone marrow transplantation (see section 5.1).
Vascular disorders have been observed in patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation. A causal relationship with filgrastim has not been demonstrated.
Pulmonary adverse reactions with respiratory failure or adult respiratory distress syndrome (ARDS) have been reported in some cases, which can be fatal. post-marketingpulmonary adverse events (haemoptysis, pulmonary haemorrhage, pulmonary infiltrates, dyspnoea and hypoxia) have been reported very rarely in normal donors (see section 4.4).
Occasional cases of Sweet's syndrome (acute febrile neutrophilic dermatosis) have been described in cancer patients. However, as a significant percentage of these patients were diagnosed with leukemia, a condition known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been demonstrated.
Isolated cases of sickle cell crises have been reported in patients with sickle cell anemia (see section 4.4). The frequency is unknown.
Cases of psudo-gout have been reported in cancer patients treated with filgrastim.
In all cases described in HIV patients, splenomegaly was mild or moderate on physical examination and the clinical course was benign; no patient was diagnosed with hypersplenism and no patient underwent splenectomy. filgrastim is not known as splenomegaly is common in HIV-infected patients and is present to varying degrees in most AIDS patients.
Immunogenicity
In four clinical studies, none of the healthy volunteers or cancer patients developed antibodies to rhG-CSF (neither binding nor neutralizing) following treatment with Zarzio.
04.9 Overdose -
The effects of filgrastim overdose have not been demonstrated.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: colony stimulating factors, ATC code: L03AA02
Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Zarzio, which contains r-metHuG-CSF (filgrastim), induces a marked increase in peripheral blood neutrophil counts and a less marked increase in monocytes within 24 hours. In some SCN patients, filgrastim may induce even a slight increase in the number of circulating eosinophils and basophils from baseline; some of these patients may present with eosinophilia or basophilia even before treatment. At recommended doses, the increase in the number of neutrophils is dose-dependent. As demonstrated in the analyzes conducted, neutrophils produced in response to filgrastim show normal or increased chemotactic and phagocytic properties. At the end of filgrastim treatment, the number of circulating neutrophils decreases by approximately 50% within 1 - 2 days and reaches normal levels within 1 - 7 days. As has been observed with other hematopoietic growth factors, G-CSF also shows in vitro a stimulating effect on human endothelial cells, equipped with specific receptors for G-CSF. Thus, G-CSF has been shown to induce angiogenesis-related endothelial cell functions. Furthermore, G-CSF increases neutrophil migration through the vascular endothelium.
The use of filgrastim in patients undergoing cytotoxic chemotherapy significantly reduces 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 in acute myeloid leukemia or myeloablative therapy followed by bone marrow transplantation. In both cases, the incidence of fever and documented infections was not reduced. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
The use of filgrastim alone or after chemotherapy mobilizes hematopoietic progenitor cells in peripheral blood. Such autologous PBPCs can be harvested and reinfused after high-dose cytotoxic chemotherapy, alternatively or in addition to bone marrow transplantation. PBPC infusion accelerates haematopoietic recovery and thus reduces the duration of the risk of bleeding complications and the need for thrombocyte transfusions.
A retrospective European study, in which the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemia was analyzed, indicated an increased risk of GvHD, treatment-related mortality (TRM) and mortality following administration of G-CSF. In another international retrospective study, conducted with patients with acute and chronic myeloid leukemias, no effect on the risk of GvHD, TRM and mortality was observed. In a meta-analysis of allogeneic transplant studies, including From the results of nine prospective randomized studies, 8 retrospective studies and 1 case-control study, no effects on the risk of acute GvHD, chronic GvHD or early treatment-related mortality were observed.
a L "analysis includes studies concerning BM transplantation in the period in question; GM-CSF was used in some studies
b The analysis includes patients who underwent BM transplant during the period in question
Use of filgrastim for PBPC mobilization in healthy donors prior to allogeneic PBPC transplantation
In healthy donors, a dose of 1 MU / kg / day (10 mcg / kg / day) administered subcutaneously for 4 - 5 consecutive days results in recovery of ≥ 4 x 106 CD34 + cells / kg bw. of the recipient after two leukaphereses in most donors.
Recipients of allogeneic PBPCs mobilized with filgrastim showed significantly faster haematological recovery compared to patients treated with allogeneic bone marrow transplantation, resulting in a significant reduction in natural thrombocyte recovery time.
The use of filgrastim in pediatric or adult patients with SCN (severe congenital neutropenia, cyclic neutropenia and idiopathic neutropenia) induces a prolonged increase in ANC in peripheral blood and a reduction in infectious episodes and related events.
The use of filgrastim in HIV-infected patients it maintains the neutrophil count at normal levels and thus allows the administration of antiviral and / or myelosuppressive drugs in the prescribed manner. There is no evidence that HIV replication is increased in HIV infected patients treated with filgrastim.
05.2 "Pharmacokinetic properties -
Randomized, double-blind, single and multiple dose studies in crossover, conducted on 146 healthy volunteers, demonstrated that the pharmacokinetic profile of Zarzio was comparable to that of the reference preparation after subcutaneous and intravenous administration.
Absorption
A single subcutaneous dose of 0.5 MU / kg (5 mcg / kg) induced peak serum concentrations after a t of 4.5 ± 0.9 hours (mean ± SD).
Distribution
The volume of distribution in the blood is approximately 150 ml / kg. After subcutaneous administration of the recommended doses, serum concentrations were maintained above 10 ng / ml for 8 - 16 hours. There is a positive linear correlation between filgrastim dose and serum concentration, both after intravenous and subcutaneous administration.
Elimination
Filgrastim elimination is non-linear with respect to dose, serum clearance decreases with increasing dose. Filgrastim is eliminated primarily via a neutrophil-mediated clearance mechanism, which becomes saturated at high doses. However, serum clearance increases with repeated dosing while neutrophil counts increase. The median serum elimination half-life (t½) of filgrastim after single subcutaneous doses ranged from 2.7 hours (1.0 MU / kg, 10 mcg / kg) to 5.7 hours (0.25 MU / kg, 2.5 mcg / kg) and increased, after 7 days of administration, up to 8.5 - 14 hours, respectively.
Continuous infusion of filgrastim for up to 28 days in patients recently undergoing autologous bone marrow transplantation showed no accumulation of the medicinal product; the elimination half-lives were comparable.
05.3 Preclinical safety data -
There are no preclinical data of relevance to the prescribing physician other than those already described in other sections of the Summary of Product Characteristics.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Glutamic acid
Sorbitol (E420)
Polysorbate 80
Water for injections
06.2 Incompatibility "-
Zarzio must not be diluted with sodium chloride solutions.
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
Diluted filgrastim can be absorbed by glass and plastics unless diluted with 50 mg / ml (5%) glucose solution (see section 6.6).
06.3 Period of validity "-
30 months.
After dilution: chemical and physical stability in use of the diluted solution for infusion has been demonstrated for 24 hours at a temperature between 2 ° C - 8 ° C. From a microbiological point of view, the product should be used immediately.If the medicinal product is not used immediately, the user is responsible for the storage duration and conditions prior to use; the medicinal product can be stored for up to 24 hours at 2 ° C - 8 ° C, unless dilution has been carried out under controlled and validated aseptic conditions.
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C).
Keep the pre-filled syringe in the outer carton to protect the medicine from light.
Within its shelf life and for outpatient use, the patient can remove the product from the refrigerator and store it at room temperature (not above 25 ° C) for one time and up to 72 hours. period, the product must not be put back in the refrigerator and must be discarded.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package -
Pre-filled syringe (type I glass) with injection needle (stainless steel), with or without needle safety guard, containing 0.5 ml of solution.
Packs of 1, 3, 5 or 10 pre-filled syringes.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
The solution should be visually inspected prior to use. Only clear, particle-free solutions should be used. Accidental exposure to freezer temperature has no adverse effect on the stability of Zarzio.
Zarzio does not contain preservatives: due to the risk of bacterial contamination, Zarzio syringes are for single use only.
Dilution before administration (optional)
If necessary, Zarzio can be diluted in 50 mg / ml (5%) glucose solution.
Dilution to final concentrations is not recommended
In patients treated with filgrastim diluted to human serum albumin (HSA) concentrations to a final concentration of 2 mg / ml.
Example: for a final volume of 20 ml, total filgrastim doses below 30 MU (300 mcg) must be added with 0.2 ml of human serum albumin solution Ph. Eur 200 mg / ml (20%).
Diluted with 50 mg / ml (5%) glucose solution, filgrastim is compatible with glass and with various plastic materials such as polyvinyl chloride, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
Using the pre-filled syringe with needle safety guard
The needle safety guard covers the needle after injection and prevents the operator from injuring himself. The device does not interfere with normal use of the syringe. Push slowly and evenly on the plunger until the full dose is released and the plunger cannot be pushed further. Pull the syringe away from the patient while continuing to press down on the plunger. The safety device covers the needle as soon as the plunger is released.
Using the pre-filled syringe without a needle safety guard
Administer the dose according to the standard procedure.
Disposal
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Sandoz GmbH
Biochemiestrasse 10
A-6250 Kundl
Austria
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/08/495/001
039125012
EU / 1/08/495/002
039125024
EU / 1/08/495/003
039125036
EU / 1/08/495/004
039125048
EU / 1/08/495/009
EU / 1/08/495/010
EU / 1/08/495/011
EU / 1/08/495/012
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
06/02/2009
