Active ingredients: Epoetin beta (Erythropoietin)
NeoRecormon 500 IU
NeoRecormon 2000 UI
NeoRecormon 3000 IU
NeoRecormon 4000 IU
NeoRecormon 5000 IU
NeoRecormon 6000 IU
NeoRecormon 10000 IU
NeoRecormon 20000 IU
NeoRecormon 30000 IU
Solution for injection in pre-filled syringe
Neorecormon package inserts are available for pack sizes: - NeoRecormon 500 IU, NeoRecormon 2000 IU, NeoRecormon 3000 IU, NeoRecormon 4000 IU, NeoRecormon 5000 IU, NeoRecormon 6000 IU, NeoRecormon 10000 IU, NeoRecormon 20000 IU, NeoRecormon 30000 IU, pre-injection syringe
- NeoRecormon Multidose 50,000 IU - Lyophilisate and solvent for solution for injection
Why is Neorecormon used? What is it for?
NeoRecormon is a clear, colorless solution to be injected under the skin (subcutaneously) or into a vein (intravenously). It contains a hormone called epoetin beta, which stimulates the production of red blood cells. Epoetin beta is produced by a special genetic technique and acts exactly like the natural hormone erythropoietin.
NeoRecormon injections are used to:
- the treatment of symptomatic anemia caused by chronic renal failure (renal anemia) in patients undergoing dialysis or not yet on dialysis;
- the prevention of anemia in premature babies (weighing from 750 to 1500 g and gestational age less than 34 weeks);
- the treatment of anemia, with related symptoms, in adult cancer patients undergoing chemotherapy;
- the treatment of patients who donate their blood in anticipation of surgery. Injections of epoetin beta increase the amount of blood that can be withdrawn from the body before surgery and that can be transfused during or after surgery (this is an autologous transfusion).
Contraindications When Neorecormon should not be used
Do not use NeoRecormon:
- if you are allergic (hypersensitive) to epoetin beta or to any of the other ingredients of NeoRecormon or to benzoic acid, a metabolite of benzyl alcohol
- if you have uncontrollable blood pressure problems
- if you donate blood before surgery and:
- have had a heart attack or stroke in the month before treatment
- suffer from unstable angina pectoris - recent or increasing chest pain
- if you are at risk of blood clots forming in your veins (deep vein thrombosis) - for example if you have had a blood clot before.
If any of the above exists, or could exist, please inform your doctor immediately.
Precautions for use What you need to know before taking Neorecormon
Take special care with NeoRecormon:
- if your anemia does not improve following treatment with epoetin
- if you have low levels of certain B vitamins (folic acid or vitamin B12)
- if you have very high levels of aluminum in your blood
- if you have a high number of platelets
- if you have chronic liver disease
- if you have epilepsy
- if you have developed antibodies to erythropoietin and pure red cell aplasia (reduced or absent production of red blood cells) during previous exposure to any erythropoietic substance. In this case you should not switch to NeoRecormon treatment.
If any of the above exist, please inform your doctor.
Take special care with other products that stimulate the production of red blood cells:
NeoRecormon belongs to a group of products that stimulate the production of red blood cells as well as the human protein erythropoietin. Your doctor will always have to record the specific product you are using.
Interactions Which drugs or foods can modify the effect of Neorecormon
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
During treatment with Neorecormon
If you have chronic renal failure, and in particular if you do not respond adequately to NeoRecormon, your doctor will check the dose of NeoRecormon you receive because if you do not respond to treatment, repeatedly increasing the dose of NeoRecormon may increase the risk of problems. to the heart or blood vessels and could increase the risk of myocardial infarction, stroke and death.
If you have cancer, you should be aware that Neorecormon can act as a growth factor for blood cells and that, in some circumstances, it can have negative effects on the cancer. Depending on the specific situation, a blood transfusion may be preferable. Discuss this with your doctor.
If you suffer from nephrosclerosis and are not undergoing dialysis, your doctor will decide on the appropriateness of treatment. This is because it is not possible to exclude with absolute certainty a possible acceleration of the progression of kidney disease.
Your doctor may order blood tests on a regular basis to check:
- your potassium levels. If you have high or rising potassium levels, your doctor may consider treatment again
- the platelet count. The number of platelets may increase slightly to moderately during treatment with epoetin, which can lead to changes in blood clotting.
If you have kidney disease and are undergoing hemodialysis, your doctor may change the dose of heparin. This will prevent blockage of the dialysis system.
If you have kidney disease, are undergoing hemodialysis and are at risk of shunt thrombosis, it is possible that blood clots (thrombosis) may form in your shunt (blood vessel used to connect to the dialysis system). Your doctor might prescribe acetylsalicylic acid or change the shunt.
If you donate your own blood before surgery, your doctor will need to:
- check that he is able to donate blood, especially if he weighs less than 50 kg
- check that you have a sufficient level of red blood cells (hemoglobin levels of at least 11 g / dl)
- make sure that a single donation does not exceed 12% of your blood.
Do not misuse NeoRecormon
Misuse of NeoRecormon by healthy people can cause an increase in blood cells and consequently thicken the blood. This can lead to life-threatening complications affecting the heart or blood vessels.
Pregnancy and breastfeeding
There is limited experience with NeoRecormon in pregnant or breastfeeding women. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No effects on ability to drive or use machines have been observed.
Important information about some of the ingredients of NeoRecormon
This medicine contains phenylalanine. It can be harmful to you if you have phenylketonuria. If you have phenylketonuria, talk to your doctor about NeoRecormon treatment. NeoRecormon is almost sodium-free.
Dose, Method and Time of Administration How to use Neorecormon: Posology
NeoRecormon therapy should be started by a doctor who is experienced in your health condition. The first dose is usually given to you under medical supervision due to a possible allergic reaction.
Subsequently, NeoRecormon injections can be given by a registered nurse, doctor, or other professional. After you have seen how, you can also inject the solution yourself.
The NeoRecormon pre-filled syringe is ready to use. Each syringe is for one injection only. Do not mix NeoRecormon with other injectable or infusion solutions.
Instructions for Use
First wash your hands!
- Take a syringe out of the package,
Check the liquid in the syringe:
- it's clear?
- is it colorless?
- does it contain particles?
If the answer to a question is NO, do not inject.
Discard the syringe and start again with another one. If your answer is yes to all three questions, remove the cap from the syringe and go to step 2.
- Take a needle out of the package, attach it firmly to the syringe and remove the protective cap from the needle.
- Eliminate the air from the syringe and needle. To do this, lightly tap the top half of the syringe. This will cause any air bubbles to rise to the surface. Then hold the syringe vertically, with the needle pointing upwards, and gently push the plunger upwards. Press and hold the plunger until the amount of NeoRecormon in the syringe is as prescribed.
- Disinfect the skin at the injection site with alcohol. Form a skin fold by pinching the skin between your thumb and forefinger.
- Holding the syringe close to the needle, insert the needle into the skin crease with a quick and safe motion. Inject the NeoRecormon solution. Quickly withdraw the needle and press the injection site with a dry, sterile swab.
NeoRecormon dosage
The dose of NeoRecormon depends on the condition of your disease, the route of injection (under the skin or into a vein) and your weight.
Your doctor will work out the right dose for you. Your doctor will use the lowest effective dose to control the symptoms of anemia.
If you do not respond adequately to NeoRecormon, your doctor will check the dose you are receiving and will inform you if he changes it.
Symptomatic anemia caused by chronic renal failure
The injections are given under the skin or into a vein. If the solution is administered into a vein, it should be injected over approximately 2 minutes; for example, patients on hemodialysis will receive injection through the vascular access at the end of dialysis. Patients not on hemodialysis will usually receive injections under the skin.
NeoRecormon treatment is divided into two phases:
- Correction of anemia
The starting dose for injections under the skin is 20 IU per injection for every kg of body weight, given three times per week.
After 4 weeks, your doctor will perform tests and, if the response to treatment is not sufficient, they may increase the dose up to 40 IU / kg per injection, three times per week. If necessary, your doctor may continue to increase the dose at monthly intervals. The weekly dose can also be divided into daily doses.
The starting dose for injections into a vein is 40 IU per injection for every kg of body weight, given three times per week.
After 4 weeks, your doctor will perform tests and, if the response to treatment is not sufficient, they may increase the dose up to 80 IU / kg per injection, three times per week. If necessary, your doctor may continue to increase the dose at monthly intervals.
For both types of injection, the maximum dose should not exceed 720 IU for each kg of body weight per week.
- Maintaining sufficient levels of red blood cells
Maintenance dose: Once the red blood cells have reached an acceptable level, the dose is reduced to half that given for the correction of the anemia. The weekly dose can be given once a week, or it can be divided into three or seven doses per week.If your red blood cell level is stable on a weekly dose, it can be changed to one dose every two weeks, in which case dose increases may be necessary.
Every one or two weeks the doctor may adjust the dosage to find the individual maintenance dose.
Children will start treatment following the same criteria. In clinical trials, children usually required higher doses of NeoRecormon (the younger the child, the higher the dose).
Treatment with NeoRecormon is usually long-term. However, if necessary, it can be stopped at any time.
Anemia in premature babies
The injections are given under the skin.
The starting dose is 250 IU per injection for each kg of the baby's body weight, three times per week.
NeoRecormon treatment should start as soon as possible, preferably by the third day of the baby's life. Premature infants who are transfused prior to initiation of NeoRecormon treatment are unlikely to benefit as much as non-transfused infants.
The treatment should last 6 weeks.
Adults with symptomatic anemia undergoing chemotherapy for cancer
The injections are given under the skin.
Your doctor may start NeoRecormon treatment if your hemoglobin level is 10 g / dl or less.
After starting therapy, your doctor will keep your hemoglobin level between 10 and 12 g / dl.
The starting weekly dose is 30,000 IU. This can be given as a single weekly injection or it can be divided into 3 to 7 weekly injections. Your doctor will take blood samples regularly and may increase or decrease the dose, or stop treatment based on test results. of hemoglobin must not exceed 12 g / dl.
Therapy should continue for up to 4 weeks after the end of chemotherapy.
The maximum weekly dose should not exceed 60,000 IU.
Patients who donate their blood before surgery
The injections are given into a vein in two minutes or under the skin.
The dose of NeoRecormon depends on your condition, the levels of red blood cells and the amount of blood that will be donated before the surgery.
The dose calculated by your doctor will be given twice a week for 4 weeks. When you donate blood, you will receive NeoRecormon at the end of the donation session.
The maximum dose should not exceed
- injections into a vein: 1600 IU per kg of body weight per week
- injections under the skin: 1200 IU per kg of body weight per week.
If you forget to take NeoRecormon
If you have forgotten to inject or if you have injected too low a dose, please contact your doctor.
Do not take a double dose to make up for any forgotten doses.
If you have any further questions on the use of this medicine, consult your doctor or pharmacist.
Overdose What to do if you have taken too much Neorecormon
Do not increase the dose prescribed by your doctor. If you think you have injected more NeoRecormon than you should, contact your doctor. This is unlikely to be a serious problem. No symptoms of poisoning have been observed even at very high blood levels.
Side Effects What are the side effects of Neorecormon
Like all medicines, NeoRecormon can cause side effects, although not everybody gets them.
Side effects that can occur in any patient
- Many patients achieve low levels of iron in their blood. Almost all patients should be treated with iron supplements during NeoRecormon therapy.
- Rarely, allergies or skin reactions such as redness or swelling, itching or reactions around the injection site have occurred.
- Very rarely a severe form of allergic reaction has occurred, especially soon after the injection. It should be treated immediately. If you experience unusual wheezing or have difficulty breathing; swelling (swelling) of the tongue, face or throat, or swelling around it. at the injection site; if you feel dizzy or faint or collapse, call your doctor immediately.
- Very rarely, patients have experienced flu-like symptoms, especially at the start of treatment. These symptoms include fever, chills, headache, pain in limb, bone pain and / or general malaise. These reactions were usually mild to moderate. and they disappeared within hours or days.
Additional side effects in patients with chronic renal failure (renal anemia)
- Increased blood pressure, worsening of existing hypertension and headache are the most common side effects. Your doctor will check your blood pressure regularly, particularly at the start of therapy. Your doctor may treat your hypertension with medication or temporarily stop NeoRecormon therapy.
- Call your doctor immediately if you have a headache, especially sudden, acute and migraine-like, confusion, slurred speech, uncertain walking, seizures. These may be signs of very high blood pressure (hypertensive crisis), even if your blood pressure blood is usually normal or low and should be treated immediately.
- If you have hypotension (low blood pressure) or shunt complications, you may be at risk for shunt thrombosis (a blood clot in the blood vessel used to connect to the dialysis system).
- Very rarely, patients have had elevated blood levels of potassium or phosphate. These can be treated by the doctor.
- Specific red cell aplasia caused by neutralizing antibodies has been observed during erythropoietin therapy, including isolated cases during NeoRecormon therapy. The presence of specific red cell aplasia means that the body has stopped or reduced the production of red blood cells. This causes severe anemia, symptoms of which include unusual tiredness and lack of energy. If your body produces neutralizing antibodies, your doctor will have you stop taking NeoRecormon and will determine the best therapy to treat your anemia.
Additional side effects in adults undergoing cancer chemotherapy
- Occasionally, blood pressure increases and headaches occur. Your doctor can treat high blood pressure with medicines.
- An increase in blood clot formation was observed.
Additional side effects in patients who donate their blood before surgery
- A slight increase in blood clot formation was observed.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
- Keep NeoRecormon out of the reach and sight of children.
- Do not use NExpiry "> eoRecormon after the expiry date which is stated on the carton.
- Keep the pre-filled syringe in the outer carton in order to protect it from light.
- Store in a refrigerator (2 ° C - 8 ° C).
- The syringe can be removed from the refrigerator and left at room temperature for a single period of up to 3 days (but not above 25 ° C).
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What NeoRecormon contains
- The active ingredient is epoetin beta. One pre-filled syringe contains 500, 2000, 3000, 4000, 5000, 6000, 10,000, 20,000 or 30,000 IU (international units) of epoetin beta in 0.3 ml or 0.6 ml of water for injections.
- The other ingredients are urea, sodium chloride, polysorbate 20, monobasic sodium phosphate dihydrate, disodium phosphate dodecahydrate, calcium chloride dihydrate, glycine, L-leucine, L-isoleucine, L-threonine, L-glutamic acid and L-phenylalanine.
What NeoRecormon looks like and contents of the pack
Colorless, clear to slightly opalescent solution.
NeoRecormon is supplied as a solution for injection in 1, 4 or 6 pre-filled syringes with 1, 4 or 6 needles.
Pack of 1, 4 or 6.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NEORECORMON 10000 IU SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One pre-filled syringe with 0.6 ml of solution for injection contains 10,000 international units (IU) corresponding to 83 micrograms of epoetin beta * (recombinant human erythropoietin).
One ml of solution for injection contains 16667 IU of epoetin beta.
* Produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technique.
Excipients:
Phenylalanine (up to 0.3 mg per syringe)
Sodium (less than 1 mmol per syringe)
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
Colorless, clear to slightly opalescent solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
- treatment of symptomatic anemia associated with chronic renal failure (CRI) in adult and pediatric patients.
- prevention of anemia in premature babies with a birth weight between 750 and 1500 g and with a gestation period of less than 34 weeks.
- treatment of symptomatic anemia in adult patients with non-myeloid cancer undergoing chemotherapy.
- increase the amount of autologous blood in patients who are part of a predonation program. Its use in this indication should be weighed against the increased risk of thromboembolic events. Treatment should only be reserved for patients with moderate anemia (hemoglobin 10 - 13 g / dl [6.21 - 8.07 mmol / l], in the absence of iron deficiency) if storage procedures are not available or insufficient when major elective surgery requires a large volume of blood (4 or more units of blood for women or 5 or more units For the men).
04.2 Posology and method of administration
NeoRecormon therapy should be initiated by physicians experienced in the aforementioned indications.
As anaphylactoid reactions have been reported in isolated cases, it is recommended that the first dose be administered under medical supervision.
NeoRecormon pre-filled syringe is ready to use. Only clear or slightly opalescent solutions with virtually no visible particles can be injected.
NeoRecormon in pre-filled syringe is a sterile but unpreserved product. Under no circumstances should more than one dose be administered per syringe; the medicine is for single dose only.
Treatment of symptomatic anemia in adult and pediatric chronic renal failure patients: Symptoms and sequelae of anemia may vary according to age, sex and overall disease burden; the clinical course and condition of the individual patient is required are evaluated by the physician. NeoRecormon should be administered subcutaneously or intravenously to increase hemoglobin to a level not exceeding 12 g / dL (7.5 mmol / L). The subcutaneous route is preferable in patients not undergoing hemodialysis to avoid punctures to the peripheral veins. In case of intravenous administration, the solution should be injected over approximately 2 minutes in hemodialysis patients through the arteriovenous fistula at the end of dialysis.
In view of intra-patient variability, single hemoglobin values above and below the desired hemoglobin level may occasionally be detected in a patient. Variability in hemoglobin should be managed through dose adjustment, referring to a target hemoglobin range between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l). A prolonged hemoglobin level above 12 g / dl (7.5 mmol / l) should be avoided; directions for appropriate dosage adjustment for when hemoglobin values above 12 g / dl (7.5 mmol / l) are observed are given below.
A rise in hemoglobin of greater than 2 g / dl (1.25 mmol / l) over a four-week period should be avoided. If this occurs, appropriate dosage adjustment should be made as indicated. If the extent of the increase in hemoglobin is greater than 2 g / dl (1.25 mmol / l) in a month or if the hemoglobin level rises and approaches 12 g / dl (7.45 mmol / l ), the dose should be reduced by approximately 25%. If the hemoglobin level continues to rise, therapy should be stopped until the hemoglobin level begins to decrease, at which time therapy should be restarted at a lower dose than the About 25% of that given previously.
Patients should be monitored closely to ensure that the lowest authorized effective dose of NeoRecormon is used to adequately control the symptoms of anemia by maintaining a hemoglobin concentration of less than or equal to 12g / dL (7.45mmol / L).
Caution should be exercised in increasing NeoRecormon doses in patients with chronic renal failure. In patients with a poor hemoglobin response to NeoRecormon, alternative explanations for this poor response should be considered (see sections 4.4 and 5.1).
In the presence of hypertension or cardiovascular, cerebrovascular or peripheral vascular diseases, the weekly increase in Hb and the maximum Hb value to be reached must be determined on an individual basis, considering the clinical picture.
NeoRecormon treatment is divided into two phases:
1. Correction phase
- Subcutaneous administration:
The starting dosage is 3 x 20 IU / kg of body weight per week. If the increase in Hb was not adequate (
The weekly dosage can be divided into daily administrations.
- Intravenous administration:
The starting dosage is 3 x 40 IU / kg per week. The dosage can be increased, after 4 weeks, to 80 IU / kg - three times per week - and in further increments of 20 IU / kg, if needed, three times per week, at monthly intervals.
For both routes of administration, the maximum dose of 720 IU / kg per week should not be exceeded.
2. Maintenance phase
To maintain the Hb level within a range of 10 to 12 g / dl, the dose is initially reduced to half the previously administered dose. Thereafter, the dose is adjusted on an individual patient basis (maintenance dose) at intervals of one or two weeks.
In case of subcutaneous administration, the total weekly dose can be given as a single weekly injection or can be divided into three or seven weekly doses. Stable patients on a once weekly regimen can be switched to once every two weeks. the dose may need to be increased.
Results from clinical trials in children have shown that, on average, the younger the patients, the higher the doses of NeoRecormon needed. However, the recommended dosing schedule should be followed as the individual response cannot be predicted.
Treatment with NeoRecormon is usually long-term. However, if necessary, it can be interrupted at any time. The data for the once weekly dosing regimen are based on clinical trials lasting 24 weeks of therapy.
Prevention of anemia of the premature baby:
The solution is administered subcutaneously at a dose of 3 x 250 IU / kg body weight per week. NeoRecormon treatment should start as early as possible, preferably on the third day of life. Premature babies who have already received transfusions at the start of NeoRecormon treatment respond less to therapy than non-transfused babies. Treatment duration should be 6 weeks.
Treatment of symptomatic chemotherapy induced anemia in cancer patients:
NeoRecormon should be administered subcutaneously in anemic patients (e.g. with hemoglobin concentration ≤ 10 g / dl (6.2 mmol / l)). Symptoms and sequelae of anemia may vary with age, sex and overall disease burden; it is necessary that the clinical course and the condition of the individual patient be evaluated by the physician.
The weekly dose can be provided through a single weekly administration or through 3-7 weekly injections.
The recommended starting dose is 30,000 IU per week (approximately 450 IU / kg body weight per week, based on the patient's body weight).
In view of intra-patient variability, single hemoglobin values above and below the desired hemoglobin level may occasionally be detected in a patient. Variability in hemoglobin should be managed through dose adjustment, referring to a target hemoglobin range between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l). A prolonged hemoglobin level above 12 g / dl (7.5 mmol / l) should be avoided; directions for appropriate dosage adjustment for when hemoglobin values above 12 g / dl (7.5 mmol / l) are observed are given below.
If, after 4 weeks of therapy, the hemoglobin value has increased by at least 1 g / dl (0.62 mmol / l), the current dose should be maintained. If the hemoglobin value has not increased by at least 1 g / dl (0.62 mmol / l), doubling the weekly dose can be considered. If, after 8 weeks of therapy, the hemoglobin value has not increased by at least 1 g / dL (0.62 mmol / L), a response is unlikely to occur and treatment should be stopped.
Therapy should be continued for 4 weeks after the end of chemotherapy.
The maximum dose should not exceed 60,000 IU per week.
Once the therapeutic goal for a patient is reached, the dose must be reduced by 25 to 50% in order to maintain hemoglobin at that level.
Appropriate dose titration should be considered.
If the hemoglobin exceeds 12 g / dl (7.5 mmol / l), the dose should be reduced by approximately 25 - 50%. NeoRecormon treatment should be temporarily stopped if the hemoglobin levels exceed 13 g / dl (8 , 1 mmol / l). When the hemoglobin level drops to 12 g / dl (7.5 mmol / l) or less, therapy should be resumed at approximately 25% lower than the normal dose. previous.
If the increase in hemoglobin is greater than 2 g / dl (1.3 mmol / l) in 4 weeks, the dose should be reduced by 25 to 50%.
Patients should be monitored closely to ensure that the lowest authorized dose of NeoRecormon is used to adequately control symptoms of anemia.
Treatment to increase the amount of autologous blood:
The solution is administered intravenously over approximately 2 minutes or subcutaneously.
NeoRecormon is administered twice a week for 4 weeks. In cases where the hematocrit value is such that blood donation is possible (Ht ≥ 33%), NeoRecormon is administered at the end of the blood donation.
During the entire course of treatment, the hematocrit should not exceed 48%. The dosage must be determined by the surgical team on an individual basis for each patient according to the amount of predonated blood required and the endogenous erythrocyte reserve:
1. The required amount of predonated blood depends on the anticipated blood loss, the use of blood storage procedures, and the patient's physical condition. This amount of blood should be that expected to be sufficient to avoid homologous blood transfusions.
The amount of predonated blood required is expressed in units, where one unit in the nomogram corresponds to 180 ml of erythrocytes.
2. The ability to donate blood primarily depends on the patient's blood volume and baseline hematocrit value. Both variables determine the endogenous erythrocyte reserve which can be calculated according to the following formula:
Endogenous erythrocyte reserve = blood volume [ml] x (Ht - 33): 100
women: blood volume [ml] = 41 [ml / kg] x body weight [kg] + 1200 [ml]
men: blood volume [ml] = 44 [ml / kg] x body weight [kg] + 1600 [ml]
(body weight ≥ 45 kg)
The indication for starting treatment with NeoRecormon and for determining the single dose should be based on the amount of predonated blood required and the endogenous red cell reserve.
The single dose, thus determined, is administered twice a week for 4 weeks. The maximum dose should not exceed 1600 IU / kg body weight per week for intravenous administration or 1200 IU / kg body weight per week for subcutaneous administration.
04.3 Contraindications
Known hypersensitivity to the active substance or to any of the excipients.
Poorly controlled hypertension.
In the indication "increase in the amount of autologous blood": myocardial infarction or stroke in the month prior to treatment, unstable angina pectoris, increased risk of deep vein thrombosis such as a history of thromboembolic venous disease.
04.4 Special warnings and appropriate precautions for use
NeoRecormon should be used with caution in the presence of refractory anemia with excess transforming blasts, epilepsy, thrombocytosis, chronic liver failure. Deficiencies in folic acid and vitamin B12 must be compensated as they reduce the effectiveness of NeoRecormon.
Caution should be exercised in increasing NeoRecormon doses in patients with chronic renal failure as high cumulative doses of epoetin may be associated with an increased risk of mortality and serious cardiovascular and cerebrovascular events. In patients with poor hemoglobin response to epoetins, Alternative explanations for this poor response should be considered (see sections 4.2 and 5.1).
To ensure effective erythropoiesis, martial state must be assessed in all patients before and during treatment and supplementary iron therapy, conducted in accordance with therapy guidelines, may be required.
Severe aluminum overload following treatment of renal insufficiency may compromise the efficacy of NeoRecormon.
The indication for the treatment with NeoRecormon of patients with nephrosclerosis, not yet undergoing dialysis, must be determined individually, since a possible acceleration in the progression of renal insufficiency cannot be excluded.
Specific red cell aplasia caused by neutralizing antibodies to erythropoietin has been reported in association with erythropoietin therapy, including NeoRecormon. These antibodies have been shown to cross-react with all erythropoietic proteins and in patients with suspected or confirmed presence of neutralizing antibodies. anti-erythropoietin should not be switched to NeoRecormon treatment (see section 4.8).
A paradoxical decrease in hemoglobin and the development of severe anemia associated with a low reticulocyte count should lead to discontinuation of epoetin treatment and to perform anti-erythropoietin antibody tests.Cases have been reported in patients with hepatitis C treated with interferon and ribavirin concurrently with the use of epoetins. Epoetins are not approved for the treatment of anemia associated with hepatitis C.
In patients with chronic renal failure an increase in blood pressure or an aggravation of an existing hypertensive state may occur, especially in the case of a rapid rise in hematocrit.
These increases in blood pressure can be treated with medication. If blood pressure rises cannot be controlled with drugs, a temporary interruption of NeoRecormon therapy is recommended. In particular, regular blood pressure monitoring, including intervals between dialysis, is recommended at the start of therapy. Hypertensive crises with encephalopathy-like symptoms may occur that require immediate medical attention and intensive medical care. As a warning sign, special attention should be paid to sudden throbbing migraine episodes, such as headaches.
In patients with chronic renal failure A moderate dose-dependent increase in platelet counts within the normal range may be observed during treatment with NeoRecormon, especially following intravenous administration. This phenomenon regresses with the continuation of the therapy. It is recommended that platelet counts are checked regularly during the first 8 weeks of therapy.
Concentration of hemoglobin
In patients with chronic renal failure, the maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin level, recommended in section 4.2. An increased risk of death and serious cardiovascular or cerebrovascular events has been observed in clinical trials. which include stroke when erythropoiesis stimulating agents (ESA) have been administered, to achieve a target hemoglobin level above 12 g / dl (7.5 mmol / l). Controlled clinical trials have shown no significant benefit attributable to administration of epoetins, when the concentration of hemoglobin is increased beyond the level necessary to control the symptoms of anemia and to avoid blood transfusions.
In premature infants, a slight increase in platelet counts may occur, particularly up to the 12th-14th day of life; platelet counts should therefore be checked regularly.
Effect on tumor growth
Erythropoietins are growth factors that primarily stimulate the production of red blood cells. Erythropoietin receptors may be expressed on the surface of various tumor cells. As with all growth factors, there is a possibility that erythropoietins may stimulate the growth of tumors. In several controlled studies, epoetins have not been shown to improve overall survival or reduce the risk of tumor progression in patients with cancer-associated anemia.
In controlled clinical trials, the use of NeoRecormon and other erythropoiesis stimulating agents (ESAs) demonstrated:
- a reduction in the time to tumor progression in patients with advanced head and neck cancer undergoing radiotherapy, when treated to achieve a target hemoglobin level greater than 14 g / dl (8.7 mmol / l);
- reduced overall survival and increased deaths attributed to disease progression at 4 months, in patients with metastatic breast cancer receiving chemotherapy when treated to achieve a target hemoglobin level between 12 and 14 g / dl (7.5-8, 7 mmol / l);
- an increased risk of death in patients with active malignancy not undergoing chemotherapy or radiotherapy, when treated to achieve a target hemoglobin level of 12 g / dl (7.5 mmol / l). The use of ESAs is not indicated in this patient population.
Based on the above, in some clinical conditions blood transfusion should be the preferred treatment for the management of anemia in cancer patients. The decision to administer recombinant erythropoietins should be based on an assessment of the benefit-risk ratio with the involvement of the individual patient and must take into account the specific clinical context. Factors that must be considered in this evaluation must include the type of cancer and its stage, the degree of anemia, the life expectancy, the environment in which the patient is treated and the patient's preferences (see section 5.1).
There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, particularly in the initial phase of treatment in patients with cancer.
Platelet counts and hemoglobin counts should also be checked at regular intervals in patients with cancer.
In patients involved in a autologous blood predonation program an increase in platelet counts may occur, predominantly within the normal range. Therefore it is recommended that platelet counts be measured at least once a week in these patients. If the platelet count is greater than 150 x 109 / l or exceeds normal values, NeoRecormon treatment should be discontinued.
In patients with chronic renal failure an increase in the dose of heparin during hemodialysis is often required during treatment with NeoRecormon due to an increase in the hematocrit value. Occlusion of the dialysis system may occur if heparinization is not optimal.
In patients with chronic renal failure at risk of thrombosis of the shunt arteriovenous should be considered an early revision of the shunt and antithrombotic prophylaxis through, for example, the administration of acetylsalicylic acid.
Serum potassium and phosphate levels should be monitored regularly during NeoRecormon therapy. An increase in potassium has been reported in a limited number of uremic patients receiving NeoRecormon, although causality has not been established. If an elevated or rising potassium level is observed, consideration should be given to discontinuing NeoRecormon treatment until normal values are restored.
For the use of NeoRecormon in an autologous predonation program, the official guidelines on blood donation must be followed, in particular:
- only patients with an Ht value ≥ 33% (hemoglobin ≥ 11 g / dl [6.83 mmol / l]) can undergo donations;
- special caution should be observed in patients weighing less than 50 kg;
- the volume of a single sample should not exceed approximately 12% of the patient's estimated total blood volume.
Treatment should be reserved for patients for whom it is considered of particular importance to avoid homologous blood transfusions and the risk / benefit ratio of homologous transfusions has been evaluated.
Improper use by healthy subjects can lead to an excessive increase in the hematocrit. This may be associated with life-threatening cardiovascular complications.
NeoRecormon in pre-filled syringes contains up to 0.3 mg phenylalanine / syringe as an excipient.
Therefore this should be taken into account in patients with severe phenylketonuria.
This medicinal product contains less than 1 mmol (23 mg) sodium per syringe, ie it is essentially "sodium-free".
In order to improve the traceability of ESAs, the name of the prescribed ESA must be clearly recorded (or specified) in the patient record.
04.5 Interactions with other medicinal products and other forms of interaction
The clinical results obtained so far have not shown any interaction of NeoRecormon with other medicinal products.
Animal experiments have shown that epoetin beta does not potentiate the myelotoxic effect of cytostatic drugs such as etoposide, cisplatin, cyclophosphamide and fluorouracil.
04.6 Pregnancy and breastfeeding
For epoetin beta, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised when prescribing the medicine to pregnant women.
04.7 Effects on ability to drive and use machines
NeoRecormon does not affect the ability to drive or use machines.
04.8 Undesirable effects
Based on the results of clinical trials involving 1725 patients, approximately 8% of patients treated with NeoRecormon are expected to experience adverse reactions.
- Anemic patients with chronic renal failure
The most frequent adverse reaction during treatment with NeoRecormon is an increase in blood pressure or an aggravation of a pre-existing hypertensive state, especially in cases of a rapid rise in the hematocrit value (see section 4.4). Hypertensive crises accompanied by similar symptoms. those of encephalopathy (eg headache and confusional state, sensory-motor disturbances - such as speech and gait disturbances - up to tonic-clonic convulsions) may also arise in normotensive or hypotensive patients (see section 4.4).
Shunt thrombosis may occur in patients who have a tendency to hypotension or whose arteriovenous fistulas have complications (eg stenosis, aneurysms), see section 4.4. hematocrit (see section 4.4). In addition, transient increases in serum potassium and phosphate levels have been observed in isolated cases (see section 4.4).
Red cell aplasia caused by neutralizing antibodies to erythropoietin associated with NeoRecormon therapy has been reported in isolated cases. If red cell aplasia caused by antibodies to erythropoietin is diagnosed, NeoRecormon therapy should be discontinued and patients should not be treated with an "other erythropoietic protein (see section 4.4). The incidences in clinical trials of the undesirable effects considered. Related to NeoRecormon treatment, are listed in the table below. Within each frequency class, undesirable effects are listed in descending order of severity.
- Patients with tumors
Epoetin beta treatment-related hypertension and headache, which can be treated with drugs, are common (> 1%,
A decrease in serum iron parameters has been observed in some patients (see section 4.4).
Clinical trials have shown a higher frequency of thromboembolic events in cancer patients treated with NeoRecormon compared to patients in the placebo or untreated control groups. In patients treated with NeoRecormon this incidence is 7% compared to 4% in the control group; this is not associated with any increase in mortality from thromboembolic events compared to the control group.
The incidences in clinical studies of undesirable effects considered related to NeoRecormon treatment are shown in the table below. Within each frequency class, undesirable effects are reported in descending order of severity.
- Patients in an autologous blood predonation program
A slightly higher incidence of thromboembolic events has been reported in patients undergoing an autologous blood predonation program. However, a causal relationship with NeoRecormon therapy could not be established.
In placebo-controlled studies, transient iron deficiency is more pronounced in the NeoRecormon group than in the control (see section 4.4).
The incidences in clinical studies of undesirable effects considered related to NeoRecormon treatment are shown in the table below. Within each frequency class, undesirable effects are reported in descending order of severity.
- Premature babies
A decrease in serum ferritin values is very common (> 10%) (see section 4.4).
- All indications
Rarely (≥1 / 10,000, ≤1 / 1,000) skin reactions related to epoetin beta treatment, such as rash, pruritus, urticaria or injection site reactions have been observed. In very rare cases (≤1 / 10,000), anaphylactoid reactions related to treatment with epoetin beta have been observed. However, a higher incidence of hypersensitivity reactions was not observed in controlled clinical trials.
In very rare cases (≤1 / 10,000), particularly at the start of treatment, flu-like symptoms related to epoetin beta treatment, such as fever, chills, headache, pain in limb, malaise and / or bone pain. These reactions were mild or moderate and disappeared within a couple of hours or days.
Data from a controlled study with epoetin alfa or darbepoetin alfa reported an "incidence of stroke as common (≥ 1/100,
04.9 Overdose
NeoRecormon's therapeutic window is very broad. No symptoms of overdose were observed even at very high serum concentrations.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-anemic, ATC code: B03XA
From the point of view of the composition of amino acids and carbohydrates, epoetin beta is identical to erythropoietin isolated from the urine of anemic patients.
Erythropoietin is a glycoprotein that stimulates the formation of erythrocytes from its obligate precursors. It acts as a factor stimulating mitosis and as a hormone that stimulates differentiation.
The biological efficacy of epoetin beta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (normal and uremic rats, polycythemic mice, dogs). After administration of epoetin beta, the number of erythrocytes, the hemoglobin values and the reticulocyte count increase as well as the rate of 59Fe incorporation.
In tests in vitro (mouse splenic cell cultures), increased incorporation of 3H-thymidine in nucleated splenic erythroid cells was observed after incubation with epoetin beta. Studies performed on cell cultures of human bone marrow cells have shown that epoetin beta specifically stimulates erythropoiesis, without altering leukopoiesis. No cytotoxic activity of epoetin beta has been observed on bone marrow or human epidermal cells. After single administration of epoetin beta, no changes in behavior or locomotor activity in mice and in circulatory or respiratory function in dogs were found.
In a randomized, double-blind, placebo-controlled study of 4,038 patients with CRF not on dialysis, with type 2 diabetes and hemoglobin levels ≤ 11 g / dL, patients received either darbepoetin alfa treatment to achieve a target hemoglobin of 13 g / dL or placebo (see section 4.4). The study did not meet the primary objective of demonstrating a reduction in the risk of all cause mortality, cardiovascular morbidity or end stage renal failure (IRT). The analysis of the individual components of the composite endpoint showed the following HR (95% CI ): death 1.05, stroke 1.92, congestive heart failure (CHF) 0.89, myocardial infarction (MI) 0.96, hospitalization for myocardial ischaemia 0.84, IRT 1.02.
Pooled analyzes of post-hoc data from clinical trials with ESA conducted in patients with CRF (on dialysis, not on dialysis, with or without diabetes) were performed. There was a trend towards increasing risk estimates for all cause mortality, cardiovascular and cerebrovascular events associated with the highest cumulative doses of ESA regardless of diabetes or dialysis status (see sections 4.2 and 4.4).
Erythropoietin is a growth factor that primarily stimulates the production of red blood cells. Erythropoietin receptors can be expressed on the surface of various cancer cells. Cancer survival and progression were examined in five large controlled studies involving a total of 2,833 patients, four of which were double-blind, placebo-controlled studies, and one was an open-label study. Two of the studies enrolled patients who were on chemotherapy treatment. The target hemoglobin concentration in two studies was greater than 13 g / dl; in the other three studies it was between 12 and 14 g / dl. In the open-label study, there was no difference in overall survival between patients treated with recombinant human erythropoietin and patients in the control groups. In the four placebo-controlled studies, the hazard ratios for overall survival ranged from 1.25 to 2.47 in favor of patients in the control groups.These studies demonstrated an unexplained constant statistically significant excess mortality in patients with anemia associated with several common tumor types who were treated with recombinant human erythropoietin compared to patients in the control groups.
The overall survival outcome in these studies could not be satisfactorily explained by the differences in the incidence of thrombosis and related complications between subjects treated with recombinant human erythropoietin and subjects in the control groups.
A meta-analysis based on individual patient data, which included data from all 12 controlled clinical trials conducted with NeoRecormon in anemic cancer patients (n = 2301), showed a point estimate of the hazard ratio for survival of 1.13 in favor of subjects in the control groups (95% CI: 0.87-1.46). In patients with a baseline hemoglobin level less than or equal to 10 g / dL (n = 899), the point estimate of the hazard ratio for survival was 0.98 (95% CI: 0.68-1, 40). A higher relative risk of thromboembolic events was found in the overall population (RR: 1.62; 95% CI: 1.13-2.31).
A single patient data analysis was also performed on more than 13,900 cancer patients (undergoing chemotherapy, radiotherapy, chemo-radiotherapy or no therapy) who participated in 53 controlled clinical trials involving different epoetins. The meta-analysis of the overall survival data led to a point estimate of the hazard ratio of 1.06 in favor of the subjects in the control groups (95% CI: 1.00, 1.12; 53 studies and 13,933 patients) and for cancer patients treated with chemotherapy, the hazard ratio for overall survival was 1.04 (95% CI: 0.97, 1.11; 38 studies and 10,441 patients). Meta-analyzes also consistently indicate a significantly increased relative risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin (see section 4.4).
In very rare cases, neutralizing antibodies to erythropoietin have been found, with or without specific red cell aplasia, during therapy with rHu-Epo.
05.2 Pharmacokinetic properties
Pharmacokinetic studies performed in healthy volunteers and in uremic patients show that the half-life of intravenous epoetin beta is between 4 and 12 hours and that the volume of distribution corresponds to 1-2 times the plasma volume. Similar results were observed in studies performed on normal and uremic rats.
After subcutaneous administration of epoetin beta to uremic patients, the prolonged absorption determines a plateaued serum concentration, so that the maximum concentration is reached after about 12 - 28 hours. The terminal half-life, on average equal to 13 - 28 hours, is higher. to that obtained following intravenous administration.
The bioavailability of epoetin beta, after subcutaneous administration, is 23 - 42%, compared to that obtained after intravenous administration.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity.
A carcinogenicity study with homologous erythropoietin in mice showed no evidence of proliferative or oncogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Urea,
Sodium chloride,
Polysorbate 20,
Sodium monobasic phosphate dihydrate,
Disodium phosphate dodecahydrate,
Calcium chloride dihydrate,
Glycine,
L-Leucine,
L-Isoleucine,
L-Threonine,
L-Glutamic acid,
L-Phenylalanine,
Water for injections.
06.2 Incompatibility
In the absence of incompatibility studies, the medicinal product must not be mixed with other products.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
Keep the pre-filled syringe in the outer carton in order to protect it from light.
For outpatient use, the patient can remove the product from the refrigerator and store it at room temperature (not above 25 ° C) for a single period of 3 days maximum.
06.5 Nature of the immediate packaging and contents of the package
0.6 ml of solution in pre-filled syringe (type I glass) with a stopper and plunger block (Teflon rubber) and a 27G1 / 2 needle.
Pack of 1 or 6.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
First wash your hands!
1. Remove a syringe from the package and check that the solution is clear, colorless and practically free of visible particles. Remove the cap from the syringe.
2. Remove a needle from the package, attach it to the syringe and remove the protective cap from the needle.
3. Expel the air from the syringe and needle by holding the syringe upright and pushing the plunger slightly upwards. Press and hold the plunger until the syringe contains the prescribed amount of NeoRecormon.
4. Clean the skin with alcohol at the injection site. Lift a skin fold, pinching it with your thumb and forefinger. Hold the barrel of the syringe close to the needle and insert the needle into the crease of the skin with a quick, firm motion. Inject NeoRecormon solution. Quickly pull out the needle and hold down the injection site with sterile, dry gauze.
This medicine is for single dose only. The unused product and the waste derived from this medicinal product must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/97/031/035 - 036
034430355
034430367
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 16 July 1997
Date of last renewal: July 16, 2007
10.0 DATE OF REVISION OF THE TEXT
D.CCE July 2016
