Active ingredients: Pegfilgrastim
Neulasta 6 mg solution for injection in a pre-filled syringe
Indications Why is Neulasta used? What is it for?
Neulasta contains the active substance pegfilgrastim. Pegfilgrastim is a protein produced with a biotechnological technique in a bacterial cell called Escherichia coli. It belongs to a group of proteins called cytokines and is very similar to a natural protein (granulocyte colony stimulating factor) produced by our body.
Neulasta is used to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with fever) which can be caused by cytotoxic chemotherapy (medicines that destroy rapidly growing cells). White blood cells are important because they help the body fight infections. These cells are very sensitive to the effects of chemotherapy, which can cause a decrease in the number of these cells in the body. If your white blood cell count falls to a low level, there may not be enough left to fight the bacteria and you may be at greater risk of getting an infection.
Your doctor has prescribed Neulasta to stimulate your bone marrow (the part of bone that makes blood cells) to make more white blood cells to help your body fight infections.
Contraindications When Neulasta should not be used
Do not use Neulasta if you are allergic to pegfilgrastim, filgrastim, proteins derived from Escherichia coli or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Neulasta
Talk to your doctor or pharmacist or nurse before using Neulasta:
- if you have an allergic reaction including weakness, drop in blood pressure, difficulty in breathing, swelling of the face (anaphylaxis), redness and redness, skin rash and itchy areas of skin
- if you have a latex allergy. The needle cap of the pre-filled syringe contains a derivative of latex which can cause severe allergic reactions
- if you have cough, fever and difficulty in breathing. This can be a sign of Acute Respiratory Distress Syndrome (ARDS).
- if you have one or more of the following side effects:
- swelling or swelling, which may be associated with less fluid passing, difficulty breathing, abdominal bloating and a feeling of fullness and a general feeling of tiredness These could be symptoms of a condition called "Capillary Leak Syndrome" causing perfusion blood from small vessels in the body. See paragraph 4.
- if you have pain in the left upper abdomen or pain in the extremity of the shoulder. These could be signs of a spleen problem (splenomegaly)
- if you have recently had a "severe lung infection (pneumonia), fluid in the lungs (pulmonary edema), inflammation of the lungs (interstitial lung disease) or an" abnormality found on X-rays (lung infiltration)
- if you know that you have abnormal blood cell counts (eg increased white blood cells or anemia) or a decrease in platelet levels, which reduces the body's ability to clot (thrombocytopenia). Your doctor may want to monitor you closely
- if you have sickle cell anemia. Your doctor may want to monitor you closely
- if you suddenly have signs of allergy such as a rash, hives or itchy skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing these could be signs of a serious allergic reaction .
Your doctor will check your blood and urine regularly as Neulasta can damage the tiny filters inside your kidneys (glomerulonephritis).
You should talk to your doctor about the risks of developing blood cancer. If you have or may have blood cancer, you should not use Neulasta unless your doctor tells you to do so.
Loss of response to pegfilgrastim
If you have decreased response or failure to maintain response to treatment with pegfilgrastim, your doctor will investigate the reasons, including the possibility that you have developed antibodies that neutralize the activity of pegfilgrastim.
Interactions Which drugs or foods can modify the effect of Neulasta
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine. Neulasta has not been tested in pregnant women. It is important to tell your doctor if:
- you are pregnant;
- suspected pregnancy; or
- is planning a pregnancy.
If you become pregnant during treatment with Neulasta, please inform your doctor. You may be encouraged to enroll in Amgen's Pregnancy Surveillance Program. Contact details of the local representative are given in section 6 of this leaflet.
Unless your doctor tells you otherwise, you must stop breastfeeding if you use Neulasta.
If you are breastfeeding while taking Neulasta, you may be encouraged to enroll in Amgen's Lactation Surveillance program. Contact details for your local representative are provided in section 6 of this leaflet.
Driving and using machines
Neulasta has no or negligible influence on the ability to drive or use machines.
Neulasta contains sorbitol (E420) and sodium acetate
Neulasta contains sorbitol (a type of sugar). If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicine.
This medicinal product contains less than 1 mmol (23 mg) sodium per 6 mg dose, it is essentially sodium-free.
Dose, Method and Time of Administration How to use Neulasta: Posology
Neulasta is indicated in adults aged 18 or over.
Always take Neulasta exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. The usual dose is a subcutaneous injection (injection under the skin) of 6 mg using a pre-filled syringe, which must be administered at least 24 hours after the last dose of chemotherapy at the end of each chemotherapy cycle.
Do not shake Neulasta vigorously as this can compromise its activity.
How to inject yourself with Neulasta
Your doctor may feel that it is best for you to inject Neulasta yourself. Your doctor or nurse will show you how to inject Neulasta. Do not try to inject yourself if you have not been told how to inject. .
Read the section at the end of this leaflet for instructions on how to inject Neulasta yourself.
If you forget your Neulasta injection
If you have forgotten a dose of Neulasta, you should contact your doctor to determine when to have the next injection.
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 Neulasta
If you use more Neulasta than you should, you should contact your doctor, pharmacist or nurse.
Side Effects What are the side effects of Neulasta
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately 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 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 needs urgent medical attention. .
Very common side effects (which may affect more than 1 in 10 people):
- bone pain. Your doctor will tell you what to take to relieve bone pain.
- nausea and headache.
Common side effects (which may affect up to 1 in 10 people):
- pain at the injection site.
- general aches and pains in the joints and muscles.
- some changes may occur in the blood, but these will be detected during routine blood tests. Levels of white blood cells may rise for a short period of time. Platelet levels may drop causing bruising.
Uncommon side effects (which may affect up to 1 in 100 people):
- allergic-type reactions, including redness and flushing, skin rash (redness of the skin) and itchy swelling of the skin.
- severe allergic reactions including anaphylaxis (weakness, drop in blood pressure, difficulty in breathing, swelling of the face).
- increase in the volume of the spleen.
- rupture of the spleen. Some cases of ruptured spleen have been fatal. It is important that you contact your doctor immediately if you feel pain in the upper left side of the abdomen or left shoulder as this may indicate problems with the spleen.
- breathing problems. If you have a cough, fever and difficulty breathing contact your doctor.
- there have been cases of Sweet's syndrome (purplish, raised and painful lesions on the limbs and sometimes on the face and neck, associated with fever), but other factors may have contributed
- cutaneous vasculitis (inflammation of the skin blood vessels).
- damage to the tiny filters inside the kidneys (glomerulonephritis).
- redness at the injection site.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the 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).
You can take Neulasta out of the refrigerator and keep it at room temperature (no more than 30 ° C) for no more than 3 days. Once the syringe has been removed from the refrigerator and has reached room temperature (not above 30 ° C) it must either be used within 3 days or thrown away.
Do not freeze. Neulasta can be used if it has been accidentally frozen once for less than 24 hours.
Keep the container in the outer carton to protect the medicine from light.
Do not use this medicine if you notice it is cloudy or you see particles.
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 Neulasta contains
- The active ingredient is pegfilgrastim. Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution.
- The other ingredients are sodium acetate, sorbitol (E420), polysorbate 20 and water for injections. See paragraph 2.
What Neulasta looks like and contents of the pack
Neulasta is a clear, colorless solution for injection in a pre-filled syringe (6 mg / 0.6 ml).
Each pack contains 1 type I glass pre-filled syringe with stainless steel needle and needle cap. The syringes are packed with blister or without blister.
Expiry "> Instructions for the injection of the Neulasta pre-filled syringe
This section contains information on how to inject Neulasta yourself.
It is important that you do not try to inject yourself if you have not been told how to do it by your doctor, nurse or pharmacist. If you have any questions about how to inject, ask your doctor, nurse or pharmacist for assistance.
How to use, by you, or by the person giving you the injection, of Neulasta in a pre-filled syringe
You will need to inject yourself just under the skin. This injection is called subcutaneous.
What is needed
To give yourself a "subcutaneous injection, you will need:
- one pre-filled syringe of Neulasta; And
- alcohol wipes or similar disinfectants.
What should I do before giving myself a "subcutaneous injection of Neulasta?
- Take the medicine out of the refrigerator.
- Do not shake the pre-filled syringe.
- Do not remove the needle cap from the syringe until you are ready to inject.
- Check the expiry date on the pre-filled syringe label (EXP). Do not use it after the last day of the month shown.
- Check the appearance of Neulasta. It must be a clear, colorless liquid. If you see particles, you should not use it.
- For a more comfortable injection, leave the pre-filled syringe out of the refrigerator for half an hour to reach room temperature or hold it gently in your hand for a few minutes. Do not heat Neulasta in any other way (e.g. do not heat it in a microwave oven or hot water).
- Wash your hands thoroughly.
- Find a comfortable, well-lit and clean surface and keep everything you need close at hand.
How do I prepare the injection of Neulasta?
Before giving yourself the injection of Neulasta you must do the following:
- Take the syringe in your hand and gently remove the cap from the needle without bending it. Pull horizontally. Do not touch the needle or push the plunger.
- You may notice a small air bubble in the pre-filled syringe. You must not remove the air bubble before injecting. Injecting the solution with the air bubble is harmless.
- You can now use the pre-filled syringe.
Where should I give myself the injection?
The most suitable places to inject yourself are:
- the upper part of the thighs; And
- the abdomen, except the area around the navel.
If someone else gives you the injection, you can also use the back of your arms.
How do I give myself the injection?
- Clean your skin using an alcohol wipe.
- Lift the skin between your thumb and forefinger (without squeezing it). Push the needle into your skin.
- Push the plunger down with slow, steady pressure. Push the plunger all the way in until all the liquid has been injected.
- After injecting the liquid, pull out the needle and let go of your skin.
- If you notice a small drop of blood at the injection site, gently wipe it off with a cotton swab or gauze. Do not rub the injection site. If necessary, you can cover the injection site with a patch.
- Do not reuse the leftover Neulasta in the syringe.
To remember
Only use each syringe for one injection. If you have any problems, do not hesitate to consult your doctor or nurse for help and advice.
Disposal of used syringes
- Do not put the cap back on used needles.
- Keep used syringes out of the sight and reach of children.
- Used syringes should be disposed of in accordance with local requirements. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
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 -
NEULASTA 6 MG SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each pre-filled syringe contains 6 mg of pegfilgrastim * in 0.6 ml of solution for injection. The concentration is 10 mg / ml considering only the protein portion **.
* Pegfilgrastim is produced in cells of Escherichia coli with recombinant DNA technology and subsequent conjugation with polyethylene glycol (PEG).
** The concentration is 20 mg / ml if the PEG portion of the molecule is included.
The potency of this product should not be compared with that of any other pegylated or non-pegylated protein belonging to the same therapeutic class.
For further information, see section 5.1.
Excipient (s) with known effects:
Each pre-filled syringe contains 30 mg of sorbitol (E420)
Each pre-filled syringe contains less than 1 mmol (23 mg) sodium (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Injectable solution.
Clear and colorless solution for injection.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for cancer (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).
04.2 Posology and method of administration -
Neulasta therapy should be initiated and supervised by physicians experienced in oncology and / or hematology.
Dosage
A 6 mg dose (a single pre-filled syringe) of Neulasta is recommended for each chemotherapy cycle, administered at least 24 hours after cytotoxic chemotherapy.
Method of administration
Neulasta is injected subcutaneously. The injection should be given in the thigh, abdomen or upper arm. For instructions on handling of the medicinal product before administration, see section 6.6.
Pediatric population
The safety and efficacy of Neulasta in children has not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.
Patients with renal impairment
No dose adjustments are recommended in patients with renal impairment, including those with end stage renal disease.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use -
Limited clinical data suggest a comparable effect of pegfilgrastim compared to filgrastim on time to remission from severe neutropenia in patients with acute myeloid leukemia. de novo (see section 5.1). However, the long-term effects of Neulasta in acute myeloid leukemia have not been established; therefore the product should be used with caution in this patient population.
The granulocyte colony stimulating factor can promote the growth of myeloid cells in vitro and similar effects can be observed in vitro in some non-myeloid cells.
The safety and efficacy of Neulasta have not been studied in patients with myelodysplastic syndrome, chronic myeloid leukemia and in patients with secondary acute myeloid leukemia (AML); therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukemia from that of acute myeloid leukemia.
The efficacy and safety of the administration of Neulasta in patients with AML de novo of age
The safety and efficacy of Neulasta in patients receiving high-dose chemotherapy have not been studied. This medicinal product should not be used to increase the doses of cytotoxic chemotherapy beyond standard dose regimens.
Pulmonary adverse events
Uncommon pulmonary adverse reactions (≥ 1 / 1,000, interstitial pneumonia, have been reported following administration of G-CSF. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8).
The onset of pulmonary symptoms such as cough, fever and dyspnoea at the same time as a radiological picture of pulmonary infiltrates and deterioration of lung function, associated with an elevated white blood cell count, may be the initial signs of acute respiratory distress syndrome (Acute Respiratory Distress Syndrome, ARDS). In such circumstances, at the physician's discretion, Neulasta therapy should be discontinued and appropriate treatment instituted (see section 4.8).
Glomerulonephritis
Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, glomerolunephritis events resolved after dose reduction or discontinuation of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.
Capillary leak syndrome
Capillary leak syndrome has been reported following administration of granulocyte colony-stimulating factors, and is characterized by hypotension, hypoalbuminaemia, edema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include the need for intensive care (see section 4.8).
Splenomegaly and splenic rupture
Uncommon, but generally asymptomatic, cases of splenomegaly and uncommon cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, the volume of the spleen should be carefully monitored (e.g. by clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients presenting with left upper quadrant abdominal or shoulder pain.
Thrombocytopenia and anemia
Treatment with Neulasta alone does not preclude thrombocytopenia and anemia caused by maintaining full doses of myelosuppressive chemotherapy as scheduled. Regular monitoring of platelet counts and hematocrit are recommended. Particular attention should be paid when administering single or combination chemotherapeutic agents that cause severe thrombocytopenia.
Sickle cell anemia
Sickle cell seizures have been associated with the use of pegfilgrastim in patients with sickle cell trait or with sickle cell disease (see section 4.8). Therefore, the physician should exercise caution when prescribing Neulasta to patients with sickle cell trait or sickle cell disease, and should be monitored. appropriate clinical and laboratory parameters and you should pay attention to the possible association between this medicine and an enlarged spleen and a vaso-occlusive crisis.
Leukocytosis
White blood cell values (White Blood Cell, WBC) equal to or greater than 100 x 109 / l have been observed in less than 1% of patients treated with Neulasta. No adverse events directly attributable to this degree of leukocytosis have been reported. This increase in white blood cell count is transient , is typically observed 24 - 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the possibility of leukocytosis, a white blood cell count (WBC) should be performed at regular intervals during therapy If the white blood cell count exceeds 50 x 109 / L after the expected nadir, administration of this medicinal product should be stopped immediately.
Hypersensitivity
Hypersensitivity reactions, including anaphylactic reactions, occurring at initiation or subsequent to treatment have been reported in patients treated with Neulasta. Permanently discontinue treatment with Neulasta in patients with clinically significant hypersensitivity. Do not administer Neulasta to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a severe allergic reaction occurs, appropriate therapy should be given, followed by careful follow-up of the patient for several days.
Immunogenicity
As with all therapeutic proteins, there is a potential risk of immunogenicity. The probability of generating antibodies against pegfilgrastim is generally low. Development of binding antibodies is expected with all biologics; however, to date they have not been associated with activity. neutralizing.
The safety and efficacy of Neulasta in haematopoietic progenitor cell mobilization in healthy patients or donors have not been adequately evaluated.
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may cause allergic reactions.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transiently positive bone radiological findings. This should be considered when interpreting radiological data.
Neulasta contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Neulasta contains less than 1 mmol (23 mg) sodium in a 6 mg dose, ie it is essentially "sodium free".
In order to improve the traceability of granulocyte colony stimulating factors (G-CSF), the trade name of the administered product should be clearly recorded in the patient record.
04.5 Interactions with other medicinal products and other forms of interaction -
Given the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, Neulasta should be administered at least 24 hours after the administration of cytotoxic chemotherapy. In clinical studies, administration of Neulasta 14 days before chemotherapy was shown to be safe. The use of Neulasta concomitantly with any chemotherapy has not been evaluated in patients. In animal models, the concomitant administration of Neulasta and 5-fluorouracil (5-FU) or other antimetabolites has been shown to worsen myelosuppression..
Clinical studies did not specifically investigate possible interactions with other haematopoietic growth factors and cytokines.
The potential interaction with lithium, which also promotes the release of neutrophils, has not been specifically studied. There is no evidence that this interaction can be harmful.
The safety and efficacy of Neulasta have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, such as nitrosoureas.
No specific studies on interactions or metabolism have been performed; however, clinical studies have not shown any interactions of Neulasta with other medicinal products.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no or limited data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Neulasta is not recommended during pregnancy and in women of childbearing potential. who do not use contraceptive measures.
Women who are found to be pregnant during treatment with Neulasta are encouraged to enroll in Amgen's Pregnancy Surveillance Program. Contact details are given in section 6 of the Package Leaflet.
Feeding time
There is insufficient information on excretion of Neulasta / metabolites in human milk. A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from Neulasta therapy taking into account the benefit breastfeeding for the baby and the benefit of therapy for the woman.
Breastfeeding women during treatment with Neulasta are encouraged to enroll in Amgen's Lactation Surveillance Program. Contact details are provided in section 6 of the Package Leaflet.
Fertility
Pegfilgrastim had no effect on reproductive performance or fertility in male or female rats at the cumulative weekly dose of approximately 6 to 9 times the highest recommended human dose (based on body surface area) (see section 5.3).
04.7 Effects on ability to drive and use machines -
Neulasta has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects -
Summary of the safety profile
The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common). Bone pain was generally mild to moderate, transient, and was controllable with common analgesics in most patients.
Cases of hypersensitivity reactions, including skin rash, urticaria, angioedema, dyspnoea, erythema, flushing and hypotension, have been reported with the first or subsequent administrations of Neulasta (uncommon [≥ 1 / 1,000, anaphylaxis, may occur in patients receiving Neulasta (uncommon) (see section 4.4).
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1 / 1,000 to
Splenomegaly, usually asymptomatic, is uncommon.
Uncommon cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.4).
Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary edema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommon cases have resulted in respiratory failure or acute respiratory distress syndrome (Acute Respiratory Distress Syndrome, ARDS) which can be fatal (see section 4.4).
Isolated cases of sickle cell crises (uncommon in such patients) have been reported in patients with sickle trait or sickle cell disease (see section 4.4).
Table of adverse reactions
The data in the table below describe the adverse reactions reported in clinical studies and spontaneous reports. Within each frequency class, undesirable effects are reported in descending order of severity.
¹ See section "Description of selected adverse reactions" below.
² This adverse reaction was identified through post-marketing surveillance but was not observed in randomized controlled trials in adults. The frequency class was determined with a statistical calculation based on 1,576 patients treated with Neulasta in nine randomized clinical trials.
Description of selected adverse reactions
Uncommon cases of Sweet's syndrome have been reported, although the underlying presence of haematological malignancies may have contributed in some cases.
Uncommon events of cutaneous vasculitis have been reported in patients treated with Neulasta. The mechanism causing vasculitis in patients treated with Neulasta is unknown.
Injection site reactions, including injection site erythema (uncommon (≥ 1 / 1,000,
Common cases (≥ 1/100, 100 x 109 / l) have been reported (see section 4.4).
In patients treated with Neulasta after cytotoxic chemotherapy, reversible, mild or moderate elevations, not accompanied by clinical symptoms, in uric acid and alkaline phosphatase are uncommon; Reversible, mild or moderate elevations, not accompanied by clinical symptoms, in lactate dehydrogenase are uncommon.
Nausea and headache were observed very commonly in patients receiving chemotherapy.
Uncommon cases of elevated liver function tests (LFT) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase) have been observed in patients who received pegfilgrastim after cytotoxic chemotherapy. These increases are transient and reversible.
Common cases of thrombocytopenia have been reported.
Cases of capillary leak syndrome have been reported post-marketing with the use of granulocyte colony stimulating factors. These have generally occurred in patients with advanced malignant disease, sepsis, who are taking multiple chemotherapy drugs or are undergoing apheresis ( see section 4.4).
Pediatric population
Experience in children is limited. A higher frequency of serious adverse reactions was observed in children aged 0-5 years (92%) compared to older children aged 6-11 and 12-21 years respectively (80 % and 67%) and adults. The most common adverse event reported was bone pain (see sections 5.1 and 5.2).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicine is important as it allows for continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system ( Italian Medicines Agency - Website: www.agenziafarmaco.gov.it/it/responsabili).
04.9 Overdose -
A single dose of 300 mcg / kg was administered subcutaneously to a limited number of healthy volunteers and in patients with non-microcytoma lung cancer, without serious adverse reactions. Adverse events were similar to those in subjects who received lower doses of pegfilgrastim.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: immunostimulants, colony stimulating factor.
ATC code: L03AA13.
Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein that regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is composed of a recombinant human G-CSF molecule (r-metHuG-CSF) covalently linked to a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a long-lasting form of filgrastim due to reduced renal clearance. Pegfilgrastim and filgrastim have identical mechanisms of action, causing a marked increase in the number of peripheral neutrophils within 24 hours, with negligible increases in monocytes and / or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim exhibit normal or increased function, as demonstrated by assessments of chemotactic and phagocytic activity. Like other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth in vitro of myeloid cells, even malignant and similar effects can be detected in vitro on some non-myeloid cells.
In two randomized, double-blind, pivotal studies in patients with high-risk stage II-IV breast cancer undergoing myelosuppressive chemotherapy, including doxorubicin and docetaxel, the use of pegfilgrastim as a single dose once per cycle reduced the duration of neutropenia and the incidence of febrile neutropenia similar to that observed with daily dosing of filgrastim (median of 11 dosing days). In the absence of growth factor support, this pattern has been reported to result in a mean duration of grade 4 neutropenia of 5-7 days, with an incidence of febrile neutropenia of 30-40%. In one study (n = 157 ) using a 6 mg fixed dose of pegfilgrastim, the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.8 days, compared with 1.6 days in the filgrastim group (difference 0.23 days, 95% CI : -0.15, 0.63). During the entire study, the febrile neutropenia rate was 13% of patients treated with pegfilgrastim compared to 20% of patients treated with filgrastim (difference 7%, 95% CI: - 19%, 5%). In a second study (n = 310), using a weight-adjusted dose (100 mcg / kg), the mean duration of grade 4 neutropenia in the pegfilgrastim group was 1.7 days, compared with 1.8 days in the filgrastim group. (difference 0.03 days, 95% CI: -0.36, 0.30). The overall rate of febrile neutropenia was 9% of patients treated with pegfilgrastim and 18% of patients treated with filgrastim (difference 9%, 95% CI: -16.8%, -1.1%).
In a double-blind, placebo-controlled study in breast cancer patients, the effect of pegfilgrastim on the incidence of febrile neutropenia was evaluated following administration of a chemotherapy regimen associated with a 10-20% incidence of febrile neutropenia (docetaxel 100 mg / m² every 3 weeks for 4 cycles). Nine hundred twenty-eight patients were randomized to receive a single dose of pegfilgrastim or placebo approximately 24 hours after chemotherapy in each cycle (day 2). The incidence of febrile neutropenia was lower in randomized patients. to receive pegfilgrastim versus placebo (1% versus 17%, p
A small-sample (n = 83) Phase II, randomized, double-blind study conducted in patients undergoing chemotherapy for acute myeloid leukemia de novo compared pegfilgrastim (single dose of 6 mg) with filgrastim, given during induction chemotherapy. The median time to remission from severe neutropenia was 22 days in both treatment groups. The long-term outcome has not been studied (see section 4.4).
In a multicentre, randomized, open-label phase II study (n = 37) in pediatric patients with sarcoma who received 100 mcg / kg of pegfilgrastim after the first course of chemotherapy with vincristine, doxorubicin and cyclophosphamide (VAdriaC / IE ), a longer duration of severe neutropenia (neutrophils
05.2 "Pharmacokinetic properties -
The maximum serum concentration of pegfilgrastim is observed 16 to 120 hours after administration of a single subcutaneous dose; serum concentrations remain stable during the period of neutropenia following myelosuppressive chemotherapy. Elimination of pegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be eliminated mainly through neutrophil-mediated clearance, which is saturated at higher doses. According to a self-regulated mechanism of clearance, the serum concentration of pegfilgrastim rapidly declines in coincidence with the rise of neutrophils.
Due to the neutrophil-mediated clearance mechanism, hepatic or renal impairment is not expected to affect the pharmacokinetics of pegfilgrastim. In an open-label single dose study (n = 31), various stages of renal impairment, including end stage renal disease, did not affect the pharmacokinetics of pegfilgrastim.
Elderly population
The limited data available indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) are similar to that in adults.
Pediatric population
The pharmacokinetics of pegfilgrastim were studied in 37 pediatric sarcoma patients who received 100 μg / kg of pegfilgrastim after completion of VAdriaC / IE chemotherapy. The younger age group (0-5 years) had higher "mean pegfilgrastim exposure (AUC) (± standard deviation) (47.9 ± 22.5 mcg • hr / ml) than children older than 6-11 years and 12-21 years (22.0 ± 13.1 mcg • hr / ml and 29.3 ± 23.2 mcg • hr / ml, respectively) (see section 5.1).
With the exception of the younger age group (0-5 years), the mean AUC in pediatric patients appeared similar to that of adult patients with stage II-IV high-risk breast cancer who received 100 mcg / kg of pegfilgrastim after completion of doxorubicin / docetaxel (see sections 4.8 and 5.1).
05.3 Preclinical safety data -
Preclinical data from traditional repeat dose toxicity studies revealed expected pharmacological effects, including increases in white blood cell count, bone marrow myeloid hyperplasia, extramedullary haematopoiesis and splenomegaly.
No adverse effects were observed in rats born to pregnant females to which pegfilgrastim was administered subcutaneously, however in rabbits, pegfilgrastim administered subcutaneously caused embryo-fetal toxicity (loss of the embryo) at cumulative doses of 4 times the recommended dose for humans. Studies in rats have shown that transplacental passage of pegfilgrastim is possible. Studies in rats indicated that subcutaneous administration of pegfilgrastim had no effect on reproductive performance, fertility, oestrus cycle, days between mating and coitus, and intrauterine survival. The relevance of these data to humans is unknown.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Sodium acetate *
Sorbitol (E420)
Polysorbate 20
Water for injections
* Sodium acetate is obtained by titration of glacial acetic acid with sodium hydroxide.
06.2 Incompatibility "-
This medicinal product must not be mixed with other products, especially with sodium chloride solutions.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C).
Neulasta can be stored at room temperature (not above 30 ° C) once and for a maximum period of 72 hours. Neulasta left at room temperature for more than 72 hours should be discarded.
Do not freeze. Accidental exposure to freezing temperatures, once for less than 24 hours, does not affect the stability of Neulasta.
Keep the container in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package -
Pre-filled syringe (Type I glass) with rubber plunger and stainless steel needle with or without an automatic needle guard.
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex) (see section 4.4).
Each pre-filled syringe contains 0.6 ml of solution for injection. Pack size of one pre-filled syringe, packed with blister or without blister.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Before administering the Neulasta solution, the absence of visible particles should be checked. Only a clear and colorless solution should be injected.
If agitated excessively, pegfilgrastim can form aggregates and become biologically inactive.
Allow the pre-filled syringe to reach room temperature before injecting the solution.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/02/227/001 1 package syringe with blister
035716012
EU / 1/02/227/002 1 syringe pack without blister
EU / 1/02/227/004 1 pack syringe with blister with needle guard
035716036
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 22 August 2002
Date of most recent renewal: July 16, 2007
10.0 DATE OF REVISION OF THE TEXT -
May 2015
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