Active ingredients: Erythropoietin (epoetin alfa)
EPREX 2,000 IU / ml, 4,000 IU / ml, 10,000 IU / ml and 40,000 IU / ml SOLUTION FOR INJECTION in PRE-FILLED SYRINGES
Why is Eprex used? What is it for?
What is EPREX and what is it for
EPREX contains the active substance epoetin alfa, a protein that stimulates the bone marrow to produce more red blood cells, cells that carry hemoglobin (a substance capable of carrying oxygen). Epoetin alfa is a copy of human erythropoietin and acts in it. way.
- EPREX is used for the treatment of symptomatic anemia caused by kidney failure.
- in children on hemodialysis
- in adults on hemodialysis and peritoneal dialysis
- in adults with severe anemia not yet undergoing dialysis.
If you have kidney failure and your kidneys do not produce enough erythropoietin (necessary for the production of red blood cells), you may have few red blood cells in your blood. EPREX is prescribed to stimulate the bone marrow to produce more red blood cells.
- EPREX is used to treat anemia which may arise during chemotherapy for solid tumors, malignant lymphoma or multiple myeloma (bone marrow cancer), if your doctor thinks you may need a blood transfusion. EPREX may reduce the need for transfusions.
- EPREX is used to treat moderately anemic patients who are candidates to deposit their blood in anticipation of surgery, so that it can be transfused during or after surgery. Since EPREX stimulates the production of red blood cells, it is possible to withdraw blood from these. people a greater amount of blood.
- EPREX is used to treat moderately anemic adult patients who are undergoing major orthopedic surgery (eg hip or knee replacement) to reduce the need for blood transfusions.
Contraindications When Eprex should not be used
Do not use EPREX
- If you are allergic (hypersensitive) to epoetin alfa or any of the other ingredients of EPREX (listed under Contents of the pack and other information);
- If you have been diagnosed with "Pure Red Cell Aplasia (the bone marrow cannot make enough red blood cells) after previous treatment with any substance that stimulates red blood cell production (including EPREX). See section Possible side effects.
- If you have problems with uncontrolled high blood pressure
- To stimulate the production of red blood cells (so that more blood can be drawn from you) if you cannot receive transfusions of your own blood during or after surgery.
- If you are to undergo elective major orthopedic surgery (eg hip or knee replacement) and:
- has severe heart disease
- you have severe problems with your veins and arteries
- have recently had a heart attack or stroke
- cannot take blood thinning medications
EPREX may not be suitable for you. Please discuss this with your doctor. While using EPREX some people may need medicines to reduce the risk of blood clots. If you cannot take anticoagulant medicines, you should not take EPREX.
Precautions for use What you need to know before taking Eprex
Take special care with EPREX
EPREX and other red blood cell stimulating agents may increase the risk of developing blood clots in all patients. This risk may be higher if you have other risk factors for developing blood clots (for example, if you have had a blood clot in the past or are overweight, have diabetes, have heart disease, or have been immobilized for a long time due to surgery or illness). Tell your doctor about any of these things. Your doctor will help you decide if EPREX is right for you.
It is important that you speak to your doctor if any of the following apply to you.
You can still use EPREX, but you should discuss this with your doctor first.
- If you know you are in pain, or have suffered from:
- High blood pressure;
- Seizures or fits
- Liver disease;
- Anemia from other causes;
- Porphyria (a rare blood disorder).
- If you have cancer, you should be aware that substances that stimulate the production of red blood cells (such as EPREX) can act as a growth factor and theoretically influence tumor progression. A blood transfusion may be preferable depending on your individual condition. Discuss this with your doctor.
Pay particular attention to substances that stimulate the production of red blood cells:
EPREX belongs to a group of substances that stimulate the production of red blood cells like human erythropoietic factors. The doctor will always take care to record the exact name of the product he is using. If during your treatment you are given a substance belonging to the same group but different from EPREX, please contact your doctor or pharmacist before use.
Interactions Which drugs or foods may change the effect of Eprex
EPREX does not normally interfere with other medicines, but always tell your doctor if you are taking or have recently taken any other medicines, including those that do not require a prescription.
If you are taking a drug called cyclosporine (used for example after kidney transplantation), your doctor may order blood tests to check cyclosporin levels during treatment with EPREX.
Iron supplements and other anti-anemic factors can increase the efficiency of EPREX. Your doctor will decide if you should take them.
In case of hospitalization or medical examination, please inform that you are being treated with EPREX. This can affect other treatments or test results.
Warnings It is important to know that:
Pregnancy and breastfeeding
It is important to tell your doctor if any of the following conditions apply to you. You can still use EPREX but discuss this with your doctor first.
- If you are pregnant, or think you may be.
- If you are breastfeeding.
Dose, Method and Time of Administration How to use Eprex: Posology
Always use this medicine exactly as instructed by your doctor. Check with your doctor if you are unsure.
Your doctor has determined based on your blood tests that you need EPREX.
EPREX can be given by injection:
- Into a vein or tube into a vein (intravenously)
- Under the skin (subcutaneously)
Your doctor will decide how EPREX should be administered. Injections are usually given by a doctor, nurse, or health care practitioner; some people may learn to administer the drug subcutaneously on their own: see Instructions for injecting EPREX yourself.
- Eprex should not be used:
- after the expiration date indicated on the label or outer carton
- if you know or think that the medicine may have been accidentally frozen or yes
- and there was a refrigerator failure
The dose of EPREX is based on your body weight in kilograms, and will be chosen by your doctor depending on the cause of the anemia.
Your doctor will check your blood pressure regularly during treatment with EPREX.
Patients with renal insufficiency
- Your hemoglobin value will be maintained between 10 and 12 g / dl as higher hemoglobin levels can increase the risk of thrombosis and death.
- The usual starting dose of EPREX for adults or children is 50 International Units (IU) per kilogram (/ kg) of body weight, given 3 times per week.
- In patients on peritoneal dialysis, administration can be done twice a week.
- EPREX is administered intravenously (vein or tube into a vein) to adults and children. When the intravenous route (vein or tube into a vein) is not available, your doctor may decide whether to inject EPREX under the skin (subcutaneously). Including dialysis patients and patients not yet on dialysis.
- Your doctor will have regular blood tests to check if your anemia is responding, and may adjust the dose, usually no more frequently than once every 4 weeks.
- Once the anemia is corrected, your doctor will continue to check your blood tests regularly. The dose of EPREX and the frequency of administration may be further adjusted to maintain the response to treatment.
- If you are being treated with EPREX at longer dose intervals (greater than once a week), you may not be able to maintain your hemoglobin levels adequately and you may need to increase your EPREX dose or its frequency of administration.
- To make the treatment more effective, iron supplements may be useful before and during treatment with EPREX.
- If you are on hemodialysis when you start treatment with EPREX, your dialysis regimen may need to be adjusted. The doctor will decide.
Adult patients on chemotherapy
- Your doctor may start treatment with EPREX if your hemoglobin level is 10 g / dl or less.
- Your hemoglobin value will be maintained between 10 and 12 g / dl as higher hemoglobin levels can increase the risk of thrombosis and death.
- The starting dose is 150 IU per kilogram of body weight 3 times per week, or 450 IU per kilogram of body weight once per week.
- EPREX is administered by subcutaneous injection.
- Your doctor will have regular blood tests and may adjust the dose, depending on your response to treatment with EPREX.
- To make the treatment more effective, an Iron supplement may be useful to you before and during the treatment with EPREX.
- EPREX treatment is usually continued for 1 month after the end of chemotherapy.
Adult patients who deposit their own blood
- The usual dose is 600 IU per kilogram of body weight 2 times per week.
- EPREX is administered into a vein immediately after depositing blood for 3 weeks prior to surgery.
- To make the treatment more effective, an Iron supplement may be useful to you before and during the treatment with EPREX.
Adult patients who are candidates for major orthopedic surgery
- The recommended dose is 600 IU per kilogram of body weight once a week.
- EPREX is administered by subcutaneous injection every week for 3 weeks prior to surgery, and on the day of surgery.
- If it is necessary to reduce the time before surgery, you will be given the daily dose of 300 IU / kg in the 10 days preceding the surgery, on the day of the surgery and in the 4 days following the surgery.
- If the blood tests before the operation reveal too high hemoglobin values, the treatment will be stopped.
- To make the treatment more effective, iron supplements may be useful before and during treatment with EPREX.
Instructions for injecting EPREX yourself
- At the start of treatment, EPREX is usually given by a doctor or nurse. Thereafter, your doctor may suggest that you (or your caregiver) learn how to inject (subcutaneously).
- Do not try to inject yourself if your doctor or nurse has not told you how.
- Always follow the instructions given to you by your doctor or nurse.
- Only use EPREX if it has been stored correctly - see section, How to store EPREX
- Before use, remove the Eprex syringe from the refrigerator and allow it to reach room temperature. It usually takes 15-30 minutes.
Withdraw a single dose of EPREX from each pre-filled syringe. When EPREX is administered under the skin (subcutaneously), the volume normally does not exceed 1 milliliter (1 ml) for any single injection.
EPREX must be administered alone and not mixed with other injection fluids.
Do not shake the EPREX pre-filled syringes. Prolonged vigorous shaking can damage the product. Do not use the product if it has been shaken vigorously.
How to inject yourself using the pre-filled syringes
The pre-filled syringes are equipped with a needle safety device, PROTECS ™, to prevent the risk of needle sticking after use. This is indicated on the packaging.
- Remove the pre-filled syringe from the refrigerator before use. The liquid must reach room temperature. Do not remove the protective cap from the needle while waiting for it to reach room temperature.
- Check the pre-filled syringe to make sure it is the right dose, that it has not expired, that it is not damaged and that the liquid is clear and not frozen.
- Choose the injection site. The most suitable places for injection are the upper thigh and abdomen, except the area around the navel. Change the injection site each time.
- To wash hands. Use an antiseptic wipe to disinfect the injection site.
- Hold the pre-filled syringe by the syringe barrel with the covered needle pointing up.
- Do not hold by the plunger head, the plunger, the needle guard wing or the needle guard cap.
- Do not pull back the plunger under any circumstances
- Do not remove the needle cap of the pre-filled syringe until you are ready to administer EPREX
- Remove the protective cap from the syringe needle by holding it by the body and pulling the cap without twisting it. Do not push the plunger, touch the needle or shake the syringe. - Do not touch the safety device activation clips to prevent premature needle cover with the needle protection flap
- Lift the skin between the thumb and forefinger without squeezing it too much.
- Push the needle all the way in. Your doctor or nurse will have shown you how.
- Push the plunger with your thumb until the full amount of liquid corresponding to the correct dose is injected. Push slowly and evenly, keeping the skin elevated. The PROTECS ™ needle safety device will not activate until the injection is delivered. dose in full. You may hear a "click" when the PROTECS ™ needle safety device is activated.
- When the plunger has reached the end of its stroke, pull out the needle and release the skin.
- Slowly remove your thumb from the plunger to allow the needle to be completely covered by the safety device.
- At the end of the injection, there may be a small amount of blood at the injection site. This is normal. You can disinfect the injection site by pressing the antiseptic pad for a few seconds.
- Discard used syringes in a safe container - see section, How to store Eprex
Overdose What to do if you have taken too much Eprex
If you use more EPREX than you should
Tell your doctor or nurse straight away if you think you have used too much EPREX. Side effects from overdose are unlikely.
If you forget to inject EPREX
Carry out the next injection as soon as you remember. If the next injection falls within a day, skip the missed dose and proceed with the usual schedule. Don't double the injections.
If you are a patient with hepatitis C and receive interferon and ribavirin
You should see your doctor because the combination of epoetin alfa with interferon and ribavirin has led, in rare cases, to loss of effect and the development of a severe form of anemia called pure red cell aplasia (PRCA). EPREX does not is approved for the treatment of anemia associated with hepatitis C.
If you have any further questions on the use of this product, ask your doctor, nurse or pharmacist.
Side Effects What are the side effects of Eprex
Like all medicines, EPREX can cause side effects, although not everybody gets them. Tell your doctor or nurse straight away if any of the effects listed below appear.
Very common side effects
They occur in more than 1 in 10 patients using EPREX
- Diarrhea
- Feeling sick in the stomach
- He retched
- Fever
- Respiratory tract congestion, such as stuffy nose and sore throat, has been reported in patients with kidney disease not yet undergoing dialysis.
Common side effects
These affect up to 1 in 10 patients using EPREX
- Raising of blood pressure values. Headache (especially if sudden, acute and migraine-like), or confusion, or seizures. These may be signs of a sudden increase in blood pressure, which requires immediate treatment. The increase in blood pressure may require treatment. with medications (or a dose adjustment of medications you are already taking for high blood pressure).
- Blood clots (including deep vein thrombosis and embolism) which may require urgent treatment. Symptoms may be chest pain, wheezing, painful swelling of the lower limbs and redness, usually in the legs.
- cough.
- Skin irritation which may be caused by an allergic reaction.
- Bone or muscle pain.
- Flu-like syndrome, such as headache, aches and pains in the joints, feeling of weakness, chills, tiredness and dizziness. These reactions are more common at the start of treatment. If you experience these symptoms while injecting into a vein, slower administration can help avoid them in the future.
- Redness, burning and pain at the injection site.
- Swelling in the ankles, feet or fingers.
Uncommon side effects
These affect up to 1 in 100 patients using EPREX
- High levels of potassium in the blood which can cause an abnormal heart rhythm (this is a very common side effect in dialysis patients).
- Convulsions
- Congestion of the nose or airways
Very rare side effects
These affect up to 1 in 10,000 patients using EPREX
- Symptoms of Pure Red Cell Aplasia (PRCA). PRCA means inability to make enough red blood cells in the bone marrow. PRCA can cause sudden and severe anemia, the symptoms of which are:
- unusual tiredness,
- sense of dizziness,
- breathlessness.
PRCA has been found very rarely especially in patients with kidney disease after months or years of treatment with EPREX and other substances that stimulate red blood cell production.An increase in the level of small blood cells (called platelets), normally involved in clot formation, called platelets, may occur, especially at the start of treatment. Your doctor will check this.
If you are on hemodialysis:
- Blood clots (thrombosis) can form in the dialysis shunt. This can happen more easily if you have low blood pressure (hypotension) or if you have problems with your fistula.
- Blood clots can also form in the hemodialysis system. Your doctor may decide to increase the dose of heparin during dialysis.
Tell your doctor or nurse straight away if you become aware of any of these effects, or if you notice any other effects while taking EPREX.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Expiry and Retention
Keep out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and label after the letters EXP. The expiry date is the last day of the month indicated.
EPREX must be stored in the refrigerator (2 ° C - 8 ° C).
EPREX can be removed from the refrigerator and stored at room temperature (not above 25 ° C) for up to 3 days. Once the pre-filled syringe has been removed from the refrigerator and has reached room temperature (not above 25 ° C) it must be used within 3 days, or discarded.
It must not be frozen or shaken
Store in the original packaging to protect them from light.
Do not use this medicine if the seal is broken or if the solution is colored or suspended particles are observed. If these conditions are observed, discard the medicine
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.
Contents of the pack and other information
What Eprex contains
The active ingredient is: Epoetin alfa (for the quantity refer to the table below).
The other ingredients are: Polysorbate 80, sodium chloride, monobasic sodium phosphate dihydrate, dibasic sodium phosphate dihydrate, glycine and water for injections. This medicine contains less than 1mmol sodium (23mg) per dose, so it is essentially sodium-free.
What EPREX looks like and contents of the pack
EPREX is a solution for injection in pre-filled syringes. The pre-filled syringes are equipped with a PROTECS ™ needle safety device (see table below). EPREX is a clear and colorless solution.
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
EPREX 10000 IU / ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Epoetin alfa 10,000 IU / ml (84.0 μg per ml) produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells.
One 0.3 ml pre-filled syringe contains 3,000 IU (25.2 mcg) of epoetin alfa
One 0.4 ml pre-filled syringe contains 4,000 IU (33.6 mcg) of epoetin alfa
One 0.5 ml pre-filled syringe contains 5,000 IU (42.0 mcg) of epoetin alfa
One 0.6 ml pre-filled syringe contains 6,000 IU (50.4 micrograms) of epoetin alfa
One 0.8 ml pre-filled syringe contains 8,000 IU (67.2 mcg) of epoetin alfa
One 1.0 ml pre-filled syringe contains 10,000 IU (84.0 mcg) of epoetin alfa
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, ie it is essentially "sodium-free".
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Solution for injection in pre-filled syringes
Clear, colorless solution
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
EPREX is indicated for the treatment of symptomatic anemia associated with chronic renal failure (CRI):
• in adult and pediatric patients aged 1 - 18 years on hemodialysis and in adult patients on peritoneal dialysis.
• in adult patients with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients.
EPREX is indicated in adult patients receiving chemotherapy for solid tumors, malignant lymphoma or multiple myeloma and at risk of transfusion as indicated by the patient's general status (cardiovascular situation, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of the need transfusion.
EPREX is indicated in adult patients who are part of a predonation program to increase the amount of autologous blood. Treatment is indicated only in patients with moderate anemia (hemoglobin concentration in the range of Hb 10-13 g / dl [6 , 2 - 8.1 mmol / l], no iron deficiency) if blood storage procedures are not available or are insufficient in case of major elective surgery requiring a large amount of blood (4 or more units per women or 5 or more units for men).
EPREX is indicated in adult patients who do not have iron deficiency prior to major elective orthopedic surgery, believed to be at high risk of transfusion complications, to reduce exposure to allogeneic blood transfusions. Use should be limited. to patients with moderate anemia (hemoglobin concentration in the range of Hb10-13 g / dl), for whom an autologous blood predonation program is not available, and for whom moderate blood loss is expected ( from 900 to 1800 ml).
04.2 Posology and method of administration
Dosage
Before starting treatment with epoetin alfa and when deciding to increase the dose, all other causes of anemia (iron, folate or vitamin B12 deficiency, aluminum intoxication, infections or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin). In order to ensure an optimal response to epoetin alfa, adequate iron stores must be ensured and iron supplementation administered if necessary (see section 4.4).
Treatment of symptomatic anemia in adult patients with chronic renal failure (CRI)
Symptoms and sequelae of anemia may vary according to sex, age and ongoing comorbidities; the physician's evaluation of the clinical condition of the individual patient is necessary.
The desired hemoglobin concentration is between 10 g / dl and 12 g / dl (6.2 to 7.5 mmol / l). EPREX should be administered in such a way as to achieve a hemoglobin concentration not exceeding 12 g / dl (7.5 mmol / l). A rise in hemoglobin greater than 2 g / dl (1.25 mmol / l) over a four-week period should be avoided. If this occurs, an appropriate dose adjustment should be made.
Due to intra-patient variability, hemoglobin values above and below the desired hemoglobin concentration may occasionally be observed in a patient. This variability must be managed through dose adjustments, respecting the hemoglobin concentration range between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l).
A hemoglobin level consistently above 12 g / dl (7.5 mmol) should be avoided. If the hemoglobin increases more than 2 g / dL (1.25 mmol / L) per month or if the hemoglobin level consistently exceeds 12 g / dL (7.5 mmol), reduce the EPREX dose by 25%. If the hemoglobin exceeds 13 g / dl (8.1 mmol / l), suspend the therapy until it returns to 12 g / dl (7.5 mmol / l) and then continue EPREX at doses 25% lower than the previous ones.
Patients should be closely monitored to ensure that the lowest authorized effective dose of EPREX is used to ensure adequate control of anemia and related symptoms by maintaining a hemoglobin concentration below or equal to 12 g / dl (7, 5 mmol / l).
Caution should be exercised in increasing the ESA dose in patients with chronic renal failure. For patients with poor hemoglobin response to ESAs, an alternative cause of the poor response should be sought (see sections 4.4 and 5.1).
EPREX treatment is divided into two phases - correction phase and maintenance phase.
Adult patients on hemodialysis
In hemodialysis patients where venous access is readily available, use of the intravenous route of administration is preferable.
Correction phase :
The starting dose is 50 IU / kg of weight 3 times a week.
If necessary, increase or decrease the dose by 25 IU / kg (3 times per week) until the desired hemoglobin concentration in the range of 10g / dl to 12g / dl (6.2 to 7.5 mmol / l) (this must be done gradually at intervals of at least four weeks).
- Maintenance phase :
The recommended total weekly dose is between 75 IU / kg and 300 IU / kg.
Appropriate dose adjustment should be made to maintain hemoglobin values within the desired hemoglobin concentration between 10 g / dl and 12 g / dl (6.2 to 7.5 mmol / l).
Patients with a very low initial hemoglobin level (8 g / dl or> 5 mmol / l).
Adult patients with renal insufficiency not yet undergoing dialysis
In patients in whom venous access is not readily available, EPREX can be administered subcutaneously.
Correction phase
The starting dose is 50 IU / kg of weight, 3 times per week followed, if necessary, by a dose increase of 25 IU / kg (3 times per week) until the desired hemoglobin concentration is reached (this should be done gradually. at intervals of at least four weeks).
Maintenance phase
During the maintenance phase, EPREX can be administered either 3 times per week and, in the case of subcutaneous administration, once a week or once every two weeks.
The dose and dosing intervals must be adjusted correctly to maintain hemoglobin values at the desired level: Hb between 10 and 12 g / dl (6.2-7.5 mmol / l). Extending the dosing interval may require a dose increase.
The maximum dose should not exceed 150 IU / kg 3 times per week, 240 IU / kg (up to a maximum of 20,000 IU) once a week or 480 IU / kg (up to a maximum of 40,000 IU) once every 2 weeks.
Adult patients on peritoneal dialysis
In patients in whom venous access is not readily available, EPREX can be administered subcutaneously.
Correction phase
The starting dose is 50 IU / kg, twice a week.
Maintenance phase
The recommended maintenance dose is between 25 IU / kg and 50 IU / kg, twice a week, divided into 2 equal administrations.
Appropriate dose adjustment should be made to maintain hemoglobin values at the desired level: hemoglobin between 10 g / dl and 12 g / dl (6.2-7.5 mmol / l).
Treatment of adult patients with chemotherapy-induced anemia
The symptoms and sequelae of anemia can vary according to age, sex, and the general situation of the disease; the physician's evaluation of the clinical condition of the individual patient is necessary.
EPREX should be administered to anemic patients eg. hemoglobin concentration ≤10 g / dl (6.2 mmol / l).
The starting dose is 150 IU / kg, administered subcutaneously, 3 times per week.
Alternatively, EPREX can be administered subcutaneously at the starting dose of 450 IU / kg once weekly.
Appropriate dose adjustment should be made to maintain hemoglobin values at the desired level: hemoglobin between 10 g / dl and 12 g / dl (6.2-7.5 mmol / l).
Due to intra-patient variability, hemoglobin values above and below the desired hemoglobin concentration may occasionally be observed in a patient. This variability must be managed through dose adjustments, respecting the desired hemoglobin concentration range between 10 g / dl (6.2 mmol / l) and 12 g / dl (7.5 mmol / l).
A hemoglobin concentration consistently above 12 g / dl (7.5 mmol) should be avoided. Instructions for proper dose adjustment should hemoglobin reach concentrations above 12 g / dl (7.5 mmol) are provided below.
If, after 4 weeks of treatment, the hemoglobin concentration has increased by at least 1 g / dl (0.62 mmol / l), or the reticulocyte count has increased by ≥ 40,000 cells / mcl from baseline, the dose should remain at 150 IU / kg 3 times per week or 450 IU / kg once per week.
If the increase in hemoglobin concentration is
If the increase in hemoglobin concentration was
Dose adjustment to maintain hemoglobin concentrations between 10 g / dl - 12 g / dl
If the hemoglobin concentration increases more than 2 g / dl (1.25 mmol / l) per month, or if the hemoglobin exceeds 12 g / dl (7.5 mmol / l), reduce the dose of EPREX, of about 25 -50%.
If the hemoglobin concentration exceeds 13 g / dl (8.1 mmol / l), discontinue therapy until the concentration drops below 12 g / dl (7.5 mmol / l) and then resume therapy with EPREX at a dose 25% lower than the previous dose.
The recommended dosage is described in the following diagram:
Patients should be monitored closely to ensure that the lowest approved dose of erythropoiesis stimulating agents (ESA) is used to provide adequate control of the symptoms of anemia.
EPREX therapy should be continued for one month after the end of chemotherapy.
Treatment of adult patients who are candidates for surgery that are part of an autologous blood predonation program
Mildly anemic patients (hematocrit between 33-39%) requiring pre-deposition of 4 or more units of blood should be treated with 600 IU / kg of EPREX intravenously, twice a week, during the 3 weeks prior to surgery.
EPREX should be administered after the completion of the blood donation procedure.
Treatment of adult patients candidates for major elective orthopedic surgery
The recommended dose is 600 IU / kg of EPREX administered subcutaneously, once a week during the three weeks prior to surgery (-21 days, -14 days and -7 days) and on the day of surgery.
If there is a medical need to reduce the waiting time before surgery to less than three weeks, the dose of 300 IU / kg of EPREX should be administered subcutaneously daily for 10 consecutive days. before the surgery, on the day of the surgery and in the 4 days immediately following it.
If hemoglobin reaches 15 g / dl or more during the preoperative period, the administration of EPREX should be discontinued and no further doses should be administered.
Pediatric population
Treatment of symptomatic anemia in patients with chronic renal failure on hemodialysis
Symptoms and sequelae of anemia may vary according to age, sex and ongoing comorbidities; the physician's evaluation of the clinical condition of the individual patient is necessary.
In pediatric patients, the desired hemoglobin concentration is between 9.5 g / dl and 11 g / dl (5.9 to 6.8 mmol / l). EPREX should be administered in such a way as to achieve a hemoglobin concentration not exceeding 11 g / dl (6.8 mmol / l). A rise in hemoglobin greater than 2 g / dl (1.25 mmol / l) over a four-week period should be avoided. If this occurs, an appropriate dose adjustment should be made.
Patients should be closely monitored to ensure that the lowest authorized dose of EPREX is used to ensure adequate control of anemia and related symptoms.
EPREX treatment is divided into two phases: correction phase and maintenance phase.
In pediatric patients on hemodialysis where intravenous access is already available, intravenous administration is preferable.
Correction phase:
The starting dose is 50 IU / kg of weight intravenously, 3 times per week.
If necessary, increase or decrease the dose by 25 IU / kg (3 times per week) until the desired hemoglobin concentration in the range of 9.5 g / dl to 11g / dl (5.9 to 6, 8 mmol / l) (this should happen gradually at intervals of at least four weeks).
Maintenance phase :
Appropriate dose adjustment should be made to maintain hemoglobin values within the desired hemoglobin concentration between 9.5 g / dl and 11 g / dl (5.9 to 6.8 mmol / l).
Generally, children weighing less than 30 kg require higher maintenance doses than children weighing more than 30 kg and adults.
Pediatric patients with a very low initial hemoglobin level (6.8 g / dL or> 4.25 mmol / L).
Treatment of pediatric patients with chemotherapy-induced anemia.
The safety and efficacy of EPREX in pediatric patients receiving chemotherapy have not been established.
Treatment of pediatric surgical patients participating in an autologous predonation program
The safety and efficacy of EPREX in pediatric patients have not been established.
No data are available.
Treatment of pediatric patients awaiting major elective orthopedic surgery
The safety and efficacy of EPREX in pediatric patients have not been established.
No data are available.
Method of administration
Be careful before handling or administering the medicine.
Before use, leave the EPREX syringe to rest until it reaches room temperature. This usually takes between 15 and 30 minutes.
Treatment of symptomatic anemia in adult patients with chronic renal failure
In chronic renal failure patients where intravenous access is normally available (hemodialysis patients) intravenous administration of EPREX is preferable.
Where intravenous access is not readily available (patients not yet undergoing dialysis and patients on peritoneal dialysis) EPREX can be administered subcutaneously.
Treatment of adult patients with chemotherapy-induced anemia.
EPREX must be administered subcutaneously.
Treatment of adult surgical patients participating in an autologous predonation program
EPREX must be administered intravenously.
Treatment of adult patients scheduled for major elective orthopedic surgery
EPREX must be administered subcutaneously.
Treatment of symptomatic anemia in pediatric patients with chronic renal failure on hemodialysis
In pediatric chronic renal failure patients where intravenous access is already available (hemodialysis patients), intravenous administration of EPREX is preferable.
Intravenous administration
Administration should take at least 1-5 minutes depending on the total dose.
In hemodialysis patients, the bolus injection can be given, during dialysis, through an adequate venous access in the dialysis line. Alternatively, the injection can be given at the end of dialysis, through the access to the fistula, followed by administration of 10 ml of physiological solution to rinse the access routes and ensure a satisfactory introduction of the product into the bloodstream.
In patients who have experienced flu-like reactions, slower administration is preferable (see section 4.8).
Do not administer EPREX by intravenous infusion or in solution with other drugs.
Subcutaneous administration
The maximum volume of 1 ml at each injection site should generally not be exceeded. For larger volumes, more than one injection site should be chosen.
Injections should be done in the limbs or anterior abdominal wall.
In case the physician believes that the patient or caregiver is able to administer EPREX subcutaneously safely and appropriately, instructions for proper dose and administration should be provided.
As with other injectable products, check that there are no particles in the solution or color variations.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Patients who develop Pure Red Cell Aplasia (PRCA) following treatment with any erythropoietin, should not be treated with EPREX or other erythropoietins (see section 4.4 PRCA).
Uncontrolled hypertension.
All contraindications associated with the autologous blood pre-deposition program should be kept in mind in patients treated with EPREX.
The use of EPREX is contraindicated in the presence of severe vascular disorders at the coronary, peripheral arterial, carotid or cerebral level in patients who are candidates for major elective orthopedic surgery and are not part of an autologous predonation program. The use is also contraindicated. in patients with recent episodes of myocardial infarction or other cerebro-vascular complications.
Patients who are candidates for surgery who for any reason cannot receive adequate antithrombotic prophylaxis.
04.4 Special warnings and appropriate precautions for use
General
In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or difficult to control hypertension. Antihypertensive treatment may need to be initiated or intensified. If blood pressure cannot be controlled, treatment with epoetin alfa should be stopped.
Hypertensive crises with encephalopathy and seizures, requiring immediate medical attention and intensive medical care, have occurred during treatment with epoetin alfa even in patients with previous normal or low blood pressure. Particular attention should be paid to migraine-like twinges as a possible warning sign (see section 4.8).
Epoetin alfa should be used with caution in patients with epilepsy, history of seizures or medical conditions associated with predisposition to seizure activity such as central nervous system infections and brain metastases.
Epoetin alfa should be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa has not been established in patients with hepatic dysfunction.
An increased incidence of vascular thrombotic events (VTEs) has been observed in patients who have received ESAs (see section 4.8). These include venous and arterial thrombosis and embolism (including some with fatal outcome) such as deep vein thrombosis, pulmonary embolism, retinal thrombosis and myocardial infarction In addition, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischemic attacks) have been reported.
The risk of these VTEs should be carefully weighed against the benefit of treatment with epoetin alfa particularly in patients with pre-existing risk factors for VTE, including obesity and previous history of VTE (eg deep vein thrombosis, pulmonary embolism and cerebrovascular accidents)
Hemoglobin levels should be closely monitored in all patients due to a potential increased risk of thromboembolic events and fatal outcomes when patients are treated at hemoglobin levels above the indicated concentration.
A moderate dose-dependent increase in platelet counts may occur during treatment with epoetin alfa, although within the normal range. This phenomenon regresses during the course of therapy. In addition, thrombocythaemia above the normal range has been reported. Regular monitoring of platelets during the first 8 weeks of therapy is recommended.
All possible causes of anemia (iron deficiency, folate or vitamin B12 deficiency, aluminum poisoning, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be evaluated and treated before starting treatment. with epoetin alfa and when a decision is made to increase the dose. In most cases, serum ferritin values decrease at the same time as the hematocrit values increase. In order to ensure an optimal response to epoetin alfa, adequate iron stores should be ensured and, if necessary, iron supplements should be given ( see section 4.2):
• For patients with chronic renal failure, iron supplementation is recommended if ferritin levels are below 100 ng / ml (elemental iron for adults 200 to 300 mg / day orally and for children from 100 to 200 mg / day orally).
• For cancer patients, iron supplementation is recommended if transferrin saturation values are less than 20% (elemental iron 200 to 300 mg / day orally).
• For patients in an autologous predonation program, iron supplementation (elemental iron 200 mg / day orally) should be administered a few weeks before the start of autologous predonation in order to achieve high iron stores. before initiating therapy with epoetin alfa and during the course of therapy with epoetin alfa.
• For patients scheduled for major elective orthopedic surgery, iron supplementation (elemental iron 200 mg / day orally) should be administered during epoetin alfa therapy. "iron supplementation before starting epoetin alfa therapy in order to achieve an adequate iron reserve.
Onset or exacerbation of porphyria has been observed very rarely in patients treated with epoetin alfa.
Epoetin alfa should be used with caution in patients with porphyria.
In order to ensure the traceability of Erythropoiesis Stimulating Agents (ESA), the commercial name of the ESA administered must always be registered or indicated in the patient's medical record.
Changing therapy from one ESA to another should only be done under appropriate supervision.
Pure Red Cell Aplasia (PRCA)
Antibody-mediated Pure Red Cell Aplasia (PRCA) has been reported after months to years, mainly in chronic renal failure patients treated with subcutaneously administered epoetin.
Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin when given in combination with ESA. Epoetin alfa is not approved for the treatment of anemia associated with hepatitis C.
In patients who exhibit a sudden loss of efficacy, defined as a decrease in hemoglobin values (1 to 2 g / dl per month) with an increased need for transfusions, a reticulocyte count should be performed and known causes evaluated. which prevent the response (such as iron, folate and Vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin).
A disproportionate decrease in hemoglobin values and the development of severe anemia associated with a low reticulocyte count should lead to discontinuation of epoetin alfa treatment and to perform a test for the presence of anti-erythropoietin antibodies.
A bone marrow examination for a diagnosis of PRCA should also be considered.
No treatment with other ESAs should be initiated due to the risk of cross-reaction.
Treatment of symptomatic anemia in adult and pediatric chronic renal failure (CRI) patients:
Chronic renal failure patients receiving epoetin alfa should have their hemoglobin levels measured regularly until a stable level is reached and then measured periodically thereafter.
In patients with chronic renal failure to reduce the risk of blood pressure increases, hemoglobin should increase by approximately 1 g / dl / month (0.62 mmol / l) and should not exceed 2 g / dl / month (1.25 mmol /L).
In patients with chronic renal insufficiency the maintenance hemoglobin concentration should not exceed the maximum value of the hemoglobin concentration range as reported in section 4.2. An increased risk of mortality and serious cardiovascular events has been observed in clinical trials when Erythropoiesis stimulating agents (ESAs) were administered to achieve a hemoglobin concentration level above 12 g / dl (7.5 mmol / ml).
Controlled clinical studies have shown no significant benefit attributable to the administration of epoetins when the hemoglobin concentration exceeds the level necessary to control the symptoms of anemia and to avoid blood transfusions.
Caution should be exercised in increasing the dose of EPREX in patients with chronic renal failure as high cumulative doses of epoetin may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. For patients with poor hemoglobin response. to epoetins, an alternative cause for this poor response should be sought (see sections 4.2 and 5.1).
Chronic renal failure patients treated with subcutaneous epoetin alfa should be monitored regularly for loss of efficacy, meaning absence or decreased response to epoetin alfa in patients who had previously responded to treatment. This phenomenon is characterized by a persistent decrease in hemoglobin values compared to an increase in the dose of epoetin alfa (see section 4.8).
Some patients treated with epoetin alfa at longer dosing intervals (greater than once weekly) may not maintain adequate hemoglobin levels (see section 5.1) and may require a dose increase. Hemoglobin levels should be monitored regularly.
Thrombosis of vascular accesses has occurred in patients on hemodialysis, especially in patients with a tendency to hypotension and with complications of arteriovenous fistulas (eg stenosis, aneurysms, etc.). In these patients, preventive control of vascular access is recommended and a thrombosis prophylaxis with administration of e.g. acetylsalicylic acid.
Hyperkalaemia has been observed in isolated cases, although causality has not been established. Serum electrolytes should be monitored in patients with chronic renal failure. If elevated (or rising) serum potassium levels are observed, in addition to appropriate treatment of hyperkalaemia, consideration should be given to discontinuing epoetin alfa administration until serum potassium levels have been corrected.
Frequently during hemodialysis an increase in the heparin dose is required due to the increase in the hematocrit value. If the adjustment of heparin doses is not optimal, occlusion of the dialyzer can occur. Based on the data available so far, the correction of anemia with epoetin alfa in adult patients with chronic renal failure not yet undergoing dialysis does not accelerate the progression of renal failure.
Treatment of patients with chemotherapy-induced anemia
Cancer patients receiving epoetin alfa should have their hemoglobin levels measured regularly until a stable level is reached and then measured periodically thereafter.
Erythropoietins are growth factors that essentially stimulate the production of red blood cells. Erythropoietin receptors can be expressed on the surface of a variety of cancer cells. As with all growth factors, there is theoretical concern that erythropoietins may stimulate tumor growth.
In some controlled clinical trials, erythropoietins have not been shown to improve overall survival or reduce the risk of tumor progression in patients with tumor-associated anemia.
In controlled clinical trials the use of epoetin alfa and other erythropoiesis stimulating agents (ESAs) has shown:
• reduced locoregional control in patients with advanced head and neck cancer receiving radiotherapy when administered to achieve hemoglobin levels above 14 g / dl (8.7 mmol / l);
• reduced overall survival and increased mortality attributable to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to achieve hemoglobin levels between 12-14 g / dl (7.5-8.7 mmol /L);
• increased risk of mortality when administered to achieve hemoglobin levels of 12 g / dl (7.5 mmol / l); in patients with active neoplasia not undergoing chemo and / or radiotherapy treatment. Treatment with erythropoiesis stimulating agents (ESAs) is not indicated in this patient population.
In light of the above, in some clinical situations, for the treatment of anemia in cancer patients, blood transfusion should be preferred. The decision to administer recombinant erythropoietin should be based on a benefit-risk assessment with individual involvement. of the patient, who must consider his or her particular clinical context. Factors that must be considered during this evaluation must include the type of tumor and its progress; the degree of anemia; life expectancy; the environment in which the patient is treated; patient preferences (see section 5.1).
In cancer patients receiving chemotherapy, the 2-3 week interval between administration and the appearance of ESA-induced red blood cells should be carefully considered when assessing the appropriateness of epoetin alfa therapy (patients at risk of transfusion).
Adult patients who are candidates for surgical interventions that are part of autologous blood predonation programs
All warnings and special precautions associated with the autologous blood predonation program, especially routine volume replacement, must be observed.
Patients candidates for major elective orthopedic surgery
Good blood management practices should always be followed preoperatively.
Patients who are candidates for elective major orthopedic surgery should receive "adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in patients undergoing surgery, especially in those with underlying cardiovascular disorders. In addition, special precautions should be taken in patients. with predisposition to the development of Deep Vein Thrombosis (DVT). In addition, in patients with a "baseline hemoglobin> 13 g / dl, the possibility that epoetin alfa treatment may be associated with an increased risk of post-thrombotic / vascular events. operators cannot be excluded. Therefore, epoetin alfa should not be used in patients with baseline hemoglobin> 13 g / dl.
04.5 Interactions with other medicinal products and other forms of interaction
There is no evidence that treatment with epoetin alfa alters the metabolism of other drugs. Medicines that decrease erythropoiesis may decrease the response to epoetin alfa.
Since cyclosporine binds to red blood cells, there may be an "interaction with this drug.
In case of concomitant administration, the blood levels of ciclosporin should be monitored and the dose adjusted according to the increase in hematocrit.
There are no in vitro interactions between G-CSF, GM-CSF and epoetin alfa regarding haematological differentiation or proliferation in vitro of tumor biopsy specimens.
In adult female patients with metastatic breast cancer, the subcutaneous co-administration of 40,000 IU / ml of epoetin alfa with trastuzumab 6 mg / kg had no effect on the pharmacokinetics of trastuzumab.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Consequently, epoetin alfa should only be used in pregnancy if the expected benefit outweighs the potential risk to the fetus. The use of epoetin alfa is not recommended in pregnant women who are candidates for surgery participating in an autologous blood predonation program.
Feeding time
It is not known whether exogenous epoetin alfa is secreted in human breast milk. Epoetin alfa should be used with caution in breastfeeding women. The decision to continue / discontinue breastfeeding or to continue / discontinue epoetin alfa therapy must be made in consideration the benefit of breastfeeding for the infant and the benefit of epoetin alfa therapy for the woman.
The use of epoetin alfa is not recommended in nursing women who are candidates for surgery participating in an autologous blood predonation program.
Fertility
There are no studies evaluating the potential effect of epoetin alfa on male or female fertility.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive or use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure, or aggravation of pre-existing hypertension.
It is recommended to monitor the blood pressure trend particularly at the start of therapy (see section 4.4).
The most frequent adverse drug reactions that occurred in clinical trials with epoetin alfa are diarrhea, nausea, vomiting, pyrexia and headache. Flu-like symptoms may occur predominantly at the beginning of therapy.
Respiratory tract congestion, including events of upper respiratory tract congestion, nasal congestion and rhino-pharyngitis, has been reported in dose range extension clinical trials in adult patients with renal insufficiency not yet undergoing dialysis.
An increased incidence of vascular thrombotic events (TVE) has been observed in patients who received ESA (see section 4.4).
Table of adverse reactions
Of a total of 3,262 patients in 23 randomized, double-blind, placebo- or standard-of-care controlled clinical trials, the overall safety profile of EPREX was evaluated in 1,992 anemic patients. In 4 chronic renal failure studies, 228 ICR patients treated with epoetin alfa were included (2 studies in pre-dialysis [N = 131 ICR exposed patients] and 2 on dialysis [N = 97 ICR exposed patients]); 1,404 cancer patients exposed in 16 studies on anemia caused by chemotherapy; 147 patients exposed in 2 studies for pre-donation of autologous blood and 213 patients exposed in 1 study in the perioperative period. Adverse drug reactions reported for ≥1% of patients treated with epoetin alfa in these clinical trials are shown in the table below.
The following definitions apply for the different frequencies: very common (≥ 1/10), common (≥ 1/100 to
Description of selected adverse reactions
Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions and angioedema have been reported.
Hypertensive crises with encephalopathy and seizures, which required immediate medical attention and intensive medical care, have occurred during treatment with epoetin alfa even in patients with previous normal or low blood pressure. Particular attention should be paid to migraine-like twinges as a possible warning sign (see section 4.4).
Antibody-mediated Pure Red Cell Aplasia has been reported very rarely in
Pediatric population with chronic renal failure on hemodialysis
The exposure of pediatric chronic renal failure patients on hemodialysis in clinical trials and post marketing experience is limited. No specific adverse events from the pediatric population not mentioned in the above table or any adverse reactions typical of the underlying disease were reported in this population.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
The therapeutic margin of epoetin alfa is very broad. Overdose with epoetin alfa can produce effects that are extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high hemoglobin levels are found.
Additional supportive care should be provided as required by the patient's condition.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-anemic, ATC code: B03XA01.
Mechanism of action
Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the key regulator of red blood cell (RBC) production. "EPO is involved in all phases of erythroid development and has its main effect at the level of erythroid precursors. After" EPO binds to its receptor on the cell surface, it activates signal transduction pathways that interfere with " apoptosis and stimulates erythroid cell proliferation. Recombinant human erythropoietin (epoetin alfa), expressed in Chinese hamster ovary cells, has a sequence of 165 amino acids identical to that of human urinary EPO; the 2 are indistinguishable on the basis of functional assays The apparent molecular weight of erythropoietin is between 32,000 and 40,000 daltons.
Erythropoietin is a growth factor that primarily stimulates the production of erythrocytes. Erythropoietin receptors can be expressed on the surface of a variety of cancer cells.
Pharmacodynamic effects
Healthy volunteers
After single doses of epoetin alfa (20,000 to 160,000 IU subcutaneously), a dose-dependent response was observed for the investigated pharmacodynamic markers including: reticulocytes, red blood cells and hemoglobin. A defined concentration-temporal profile was observed with peak and return to baseline for changes in the percentage of reticulocytes. A less defined profile was observed for erythrocytes and hemoglobin. In general, all pharmacodynamic markers increased linearly with doses reaching maximal response at maximal dose levels.
Additional pharmacodynamic studies investigated 40,000 IU once per week compared to 150 IU / kg 3 times per week. Despite the differences in concentration-time profiles, the pharmacodynamic response (as measured by percentage changes in reticulocytes, hemoglobin, and total red blood cells) was similar for these regimens. Additional studies compared the 40,000 IU regimen of epoetin alfa once weekly with biweekly doses ranging from 80,000 to 120,000 IU subcutaneously. Overall, based on the results of these pharmacodynamic studies in healthy subjects, the 40,000 IU once weekly dosing regimen appears to be more effective in red blood cell production than the biweekly regimens despite a similarity in reticulocyte production. in the once-a-week and bi-weekly regimes.
Chronic renal failure
Epoetin alfa has been shown to stimulate erythropoiesis in anemic patients with chronic renal failure, including dialysis and pre-dialysis patients. The first evidence of a response to epoetin alfa is an increase in reticulocyte counts within 10 days, followed by increases in red blood cell, hemoglobin and hematocrit counts, usually within 2-6 weeks. The hemoglobin response varies between patients and can be affected by iron deposits and the presence of concomitant medical problems.
Chemotherapy induced anemia
Epoetin alfa administered 3 times per week or once per week has been shown to increase hemoglobin and decrease the need for transfusions after the first month of therapy in anemic cancer patients receiving chemotherapy.
In a study comparing dosing regimens of 150 IU / kg 3 times a week and 40,000 IU once a week in healthy subjects and in anemic cancer subjects, the temporal profiles of percentage changes in reticulocytes, hemoglobin and total red blood cells they were similar between the two dosing regimens in healthy and anemic cancer subjects. The AUCs of the respective pharmacodynamic parameters were similar between the 150 IU / kg 3 times per week and 40,000 IU once weekly dosing regimens in both healthy and anemic cancer subjects.
Adult surgical patients in an autologous predonation program
Epoetin alfa has been shown to stimulate red blood cell production in order to increase autologous blood collection and to limit the drop in hemoglobin in adult patients scheduled for major elective surgery for whom full perioperative pre-storage is not expected. their blood needs. The greatest effects were seen in patients with low hemoglobin levels (≤ 13 g / dl).
Treatment of adult patients scheduled for major elective orthopedic surgery
In patients scheduled for major elective orthopedic surgery with pretreatment of hemoglobin> 10 to ≤ 13 g / dL, epoetin alfa has been shown to reduce the risk of receiving allogeneic transfusions and accelerate erythroid recovery (increased hemoglobin levels, hematocrit and reticulocyte count).
Clinical efficacy and safety
Chronic renal failure
Epoetin alfa has been evaluated in clinical studies in anemic adult patients with CRF, including hemodialysis and pre-dialysis patients, to treat anemia and maintain hematocrit within a concentration range of 30 to 36%.
In clinical trials at starting doses of 50-150 IU / kg three times per week, approximately 95% of all patients responded with a clinically significant increase in hematocrit. After approximately two months of therapy, nearly all patients were transfused. -Independent. Once the hematocrit target was reached, the maintenance dose was customized for each patient.
In the three major clinical trials in adult dialysis patients, the mean maintenance dose needed to maintain hematocrit between 30 and 36% was approximately 75 IU / kg 3 times per week.
In a double-blind, multicenter, placebo-controlled study of the quality of life of CRF patients on hemodialysis, a clinically and statistically significant improvement was demonstrated in patients treated with epoetin alfa compared to the placebo group, measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients in the epoetin alfa group were enrolled in an open-label extension study, which demonstrated that improvements in their quality of life were maintained for an additional 12 months.
Adult patients with renal insufficiency not yet on dialysis
In clinical studies in CRF patients not on dialysis treated with epoetin alfa, the mean duration of therapy was nearly five months. These patients responded to epoetin alfa therapy in a similar manner to that seen in dialysis patients.CRF patients not on dialysis demonstrated dose dependency and steady increase in hematocrit when epoetin alfa was administered both intravenously and subcutaneously. Similar hematocrit growth rates were noted when epoetin alfa was administered for both. In addition, doses of epoetin alfa 75 to 150 IU / kg per week have been shown to maintain hematocrit at 36 to 38% for up to six months.
In 2 extended dosing interval studies of EPREX (3 times per week, once per week, once every two weeks and once every four weeks), some patients with longer dosing intervals did not maintain adequate hemoglobin levels and met the established withdrawal criteria (0% once weekly, 3.7% once every 2 weeks, and 3.3% in the once-every-4-week groups).
A prospective randomized study (CHOIR) evaluated 1432 anemic patients with chronic renal failure not undergoing dialysis. Patients were assigned treatment with epoetin alfa aiming for a maintenance hemoglobin level of 13.5 g / dl (above the recommended hemoglobin level) or 11.3 g / dl. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure), occurred among 125 (18%) of 715 patients in the higher hemoglobin group compared with 97 (14%) among 717 patients in the lower hemoglobin group (percentage of risk [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).
Cumulative retrospective analyzes of clinical studies of ESAs were performed in patients with chronic renal failure (in dialysis and non-dialysis patients, diabetic and non-diabetic patients). A trend towards increased estimated risk for all cause mortality, cardiovascular and cerebrovascular events associated with higher cumulative doses of ESA was observed regardless of the patient's diabetic or dialysis status (see section 4.2 and section 4.4).
Treatment of patients with chemotherapy induced anemia
Epoetin alfa has been evaluated in clinical trials in adult anemic cancer patients with lymphoid and solid tumors and in patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these studies, epoetin alfa administered 3 times per week and once per week was shown to increase hemoglobin and decrease the need for transfusions after the first month of therapy in anemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received epoetin alfa and maintenance of the effect was observed.
Available data suggest that patients with haematological malignancies and solid tumors respond equivalently to epoetin alfa therapy and that patients with or without tumor infiltration of the bone marrow respond equivalently to epoetin alfa therapy. The comparable intensity of chemotherapy in the epoetin alfa and placebo groups in the chemotherapy studies was demonstrated by a similar area under the neutrophil time curve in patients treated with epoetin alfa and placebo, as well as by a similar proportion of patients in the treated groups. with epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1,000 and 500 cells / mcL
In a prospective, double-blind, randomized, placebo-controlled study of 375 anemic patients with non-myeloid tumors receiving non-platinum-based chemotherapy, a significant reduction in anemia-related symptoms (such as asthenia, fatigue and decreased blood pressure) was found. activity), measured with the following evaluation scales: Functional Assessment of Cancer Therapy-Anemia (FACT-An) general scale; FACT-An fatigue scale and Cancer Linear Analogue Scale (CLAS).
Two other randomized and placebo-controlled trials conducted on a smaller number of patients did not demonstrate any improvement in Quality of Life parameters according to the EORTC-QLQ-C30 and CLAS scales.
Survival and tumor progression were examined in five large controlled studies involving a total of 2,833 patients, including four double-blind placebo-controlled and one open label. The studies enrolled patients on both chemotherapy treatment (two studies) and patients in whom the use of ESAs was not indicated: anemic cancer patients not receiving chemotherapy and patients with head and neck cancer receiving radiotherapy. The desired concentration level of radiotherapy. hemoglobin in two studies was> 13 g / dl; in the remaining three studies it was 12 to 14 g / dl. In the open-label study there was no difference in survival between patients treated with recombinant human erythropoietin and controls. In the four controlled studies the"hazard ratio for overall survival it ranged from 1.25 to 2.47 in favor of controls. These studies demonstrated an unexplained statistically significant increase in the mortality of anemic cancer patients treated with recombinant human erythropoietin compared to controls. The overall survival outcome of patients treated with recombinant human erythropoietin versus control could not be satisfactorily explained by the difference in the incidence of thrombosis and related complications.
A patient-level analysis was also performed on over 13,900 cancer patients (chemo-, radio-, radiochemio- or not on therapy), who participated in 53 controlled clinical trials on different epoetins. The meta-analysis of overall survival data indicated a punctual hazard ratio estimate of 1.06 in favor of controls (95% CI: 1.00, 1.12; 53 studies and 13933 patients), while, for cancer patients receiving chemotherapy, overall survival , in terms of hazard ratio, it was 1.04 (95% CI: 0.97, 1.11; 38 studies and 10441 patients). Furthermore, meta-analyzes consistently indicate a significant increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietins (see section 4.4).
Autologous predonation program
The effect of epoetin alfa in facilitating autologous blood donation in patients with low hematocrit (≤ 39% and without evident anemia due to iron deficiency) scheduled for major orthopedic surgery was evaluated in a double placebo controlled study. blinded in 204 patients, and a single-blinded placebo-controlled study in 55 patients.
In the double-blind study, patients were treated with epoetin alfa 600 IU / kg or placebo intravenously once daily every 3 or 4 days for 3 weeks (total 6 doses). On average, patients treated with epoetin alfa were able to pre-deposit significant more units of blood (4.5 units) than patients treated with placebo (3.0 units).
In the single-blind study, patients were treated with epoetin alfa 300 IU / kg or 600 IU / kg or placebo intravenously once daily every 3 or 4 days for 3 weeks (total 6 doses). Patients treated with epoetin alfa were also able to pre-deposit significant additional units of blood (epoetin alfa 300 IU / kg = 4.4 units; epoetin alfa 600 IU / kg = 4.7 units) compared to patients treated with placebo ( 2.9 units).
Epoetin alfa therapy reduced the risk of allogeneic blood exposure by 50% compared to patients not treated with epoetin alfa.
Major elective orthopedic surgery
The effect of epoetin alfa (300 IU / kg or 100 IU / kg) on exposure to allogeneic blood transfusions was evaluated in a double-blind, placebo-controlled clinical study in iron-deficient adult patients awaiting surgery. elective hip orthopedic surgery or knee surgery. Epoetin alfa was administered subcutaneously for 10 days prior to surgery, on the day of surgery, and for four days after surgery. Patients were classified according to their baseline hemoglobin (≤ 10 g / dL,> 10 to ≤ 13 g / dL, and> 13 g / dL).
Epoetin alfa 300 IU / kg significantly reduced the risk of allogeneic transfusions in patients with pretreatment hemoglobin from> 10 to ≤ 13g / dL. 16% of patients treated with epoetin alfa 300 IU / kg, 23% with epoetin alfa 100 IU / kg and 45% with placebo required transfusion.
An open-label parallel group study in iron-deficient adult subjects with pretreatment hemoglobin ≥ 10 to ≤ 13 g / dL who were awaiting orthopedic hip or knee surgery compared treatment with epoetin alfa 300 IU / kg subcutaneously daily for 10 days before surgery, on the day of surgery and for four days after surgery, with treatment with epoetin alfa 600 IU / kg subcutaneously once per week for 3 weeks prior to surgery and on the day of surgery.
From pretreatment to pre-surgery, the mean increase in hemoglobin in the weekly 600 IU / kg (1.44 g / dl) group was double that observed in the 300 IU / kg daily group (0, 73 g / dl). Mean hemoglobin levels were similar in the two treatment groups throughout the post-surgical period.
The erythropoietic response observed in both treatment groups led to similar transfusion rates (16% in the 600 IU / kg / week group and 20% in the 300 IU / kg / day group)
Pediatric population
Chronic renal failure
Epoetin alfa was evaluated in an open-label, non-randomized, open dose range, 52-week clinical study in pediatric CRF patients undergoing hemodialysis. The mean age of the patients enrolled in the study was 11.6 years (range 0.5 to - 20.1 years).
Epoetin alfa was administered at 75 IU / kg / week intravenously in 2 or 3 divided doses post-dialysis, titrated from 75 IU / kg / week at 4-week intervals (up to a maximum of 300 IU / kg / week. ), to achieve a 1 g / dl / month increase in hemoglobin. The desired hemoglobin level was 9.6 to 11.2 g / dl. Eighty-one percent of patients reached the target hemoglobin level. Median time to destination was 11 weeks, median dose to destination was 150 IU / kg / week. Of the patients who achieved the goal, 90% did so on a 3 times per week dosing regimen.
After 52 weeks, 57% of patients remained in the study receiving an average dose of 200 IU / kg / week.
05.2 Pharmacokinetic properties
Absorption
After subcutaneous administration, serum levels of epoetin alfa peak between 12 and 18 hours after administration. There was no accumulation after administration of multiple weekly doses of 600 IU / kg administered subcutaneously.
The absolute bioavailability of subcutaneously injected epoetin alfa is approximately 20% in healthy subjects.
Distribution
The mean volume of distribution is 49.3 ml / kg after intravenous administration of 50 and 100 IU / kg in healthy subjects. After intravenous administration of epoetin alfa in subjects with chronic renal failure, the volume of distribution ranged from 57-107 ml / kg after single administration (12 IU / kg) to 42-64 ml / kg after multiple dose administration (48-192 IU / kg) respectively. Consequently, the volume of distribution is slightly greater than the plasma volume.
Elimination
The half-life of epoetin alfa after intravenous administration of multiple doses is approximately 4 hours in healthy subjects. The half-life after subcutaneous administration is estimated at approximately 24 hours in healthy subjects.
The mean CL / F value for the 150 IU / kg 3 times per week and 40,000 IU once weekly regimens in healthy subjects were 31.2 and 12.6 ml / h / kg, respectively. The mean CL / F value for the 150 IU / kg 3 times per week and 40,000 IU once weekly regimens in anemic cancer subjects was 45.8 and 11.3 ml / h / kg, respectively. In the majority of anemic cancer subjects receiving cyclic chemotherapy, CL / F was lower after subcutaneous doses of 40,000 IU once weekly and 150 IU / kg 3 times per week, compared to the values for healthy subjects.
Linearity / non-linearity
In healthy subjects, a dose proportional increase in serum concentrations of epoetin alfa was observed after intravenous administration of 150 and 300 IU / kg, 3 times per week. Single subcutaneous doses of 300-2400 IU / kg of epoetin alfa resulted in a linear relationship between mean C and dose and between mean AUC and dose. An inverse relationship was observed between the clearanceapparent and dose in healthy subjects.
In studies exploring the extension of the interval between doses (40,000 IU once weekly and 80,000, 100,000, and 120,000 IU biweekly), a linear but non-dose proportional relationship was observed between mean Cmax and dose el " Mean AUC and dose at steady state.
Pharmacokinetic / pharmacodynamic relationship
Epoetin alfa exhibits a dose-related effect on haematological parameters which is independent of the route of administration.
Pediatric population
A half-life of approximately 6.2-8.7 hours after multiple intravenous administration of epoetin alfa has been reported in pediatric patients with chronic renal failure. The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that in adults.
Kidney failure
In patients with chronic renal failure the half-life of epoetin alfa, administered intravenously, is slightly longer, approximately 5 hours, compared to healthy subjects.
05.3 Preclinical safety data
In repeated dose toxicology studies in dogs and rats, but not in monkeys, epoetin alfa therapy was associated with a subclinical condition of bone marrow fibrosis. Bone marrow fibrosis is a known complication of chronic renal failure in humans and may be related to secondary hyperparathyroidism or be caused by unknown factors. In a study in hemodialysis patients treated with epoetin alfa for 3 years, the incidence of bone marrow fibrosis was not higher than in the group of control dialysis patients not treated with epoetin alfa.
Epoetin alfa does not induce gene mutations in bacteria (Ames test), chromosomal aberration in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.
Long-term carcinogenicity studies have not been conducted. Conflicting results in the literature based on the data in vitro from human tumor samples, suggest that erythropoietins may play a role in tumor proliferation. This is of uncertain significance in clinical practice.
In cell cultures of human bone marrow cells, epoetin alfa specifically stimulates erythropoiesis and does not involve leukopoiesis. No cytotoxic activity of epoetin alfa has been observed on bone marrow cells.
In animal studies, epoetin alfa has been shown to decrease fetal body weight, delay ossification and increase fetal mortality when administered at weekly doses approximately 20 times the recommended weekly dose in humans. These changes are considered secondary to the decrease in maternal body weight and the significance for humans is unknown at therapeutic doses.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Polysorbate 80
Glycine
Water for injections.
Sodium monobasic phosphate dihydrate
Dibasic sodium phosphate dihydrate
Sodium chloride
06.2 Incompatibility
In the absence of compatibility studies, the medicinal product must not be mixed with other products.
06.3 Period of validity
18 months.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C). This temperature range must be guaranteed until the time of administration to the patient.
Store in the original container to protect the product from light.
Do not freeze or shake.
For outpatient use, the medicine can be taken out of the refrigerator, without being replaced, for a maximum period of 3 days at a temperature not exceeding 25 ° C. If the medicine has not been used at the end of this period, it must be disposed of.
06.5 Nature of the immediate packaging and contents of the package
0.3 ml (3,000 IU) solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate ) attached to the syringe - pack of 1.
0.4 ml (4,000 IU) in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate) attached to the syringe - pack of 1.
0.5 ml (5,000 IU) solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate ) attached to the syringe - pack of 1.
0.6 ml (6,000 IU) solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate ) attached to the syringe - pack of 1.
0.8 ml (7,000 IU) solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate ) attached to the syringe - pack of 1.
1.0 ml (10,000 IU) solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-coated rubber) and needle with housing (rubber with polypropylene coating) and PROTECS needle safety device (polycarbonate ) attached to the syringe - pack of 1.
06.6 Instructions for use and handling
The product must not be used and must be thrown away:
• If the seal is broken;
• If the solution is colored or in the presence of particles;
• If freezing has occurred or is suspected;
• If there is a refrigerator failure.
Disposable product. Do not administer more than one dose per syringe after removing the unwanted amount of solution from the syringe. See section 3. How to use EPREX (injection instructions) of the package leaflet.
The pre-filled syringes are equipped with a PROTECS needle safety device to prevent the risk of needle stick. The package leaflet contains all the information for the use and handling of the pre-filled syringes with the safety device. PROTECS needle.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Janssen-Cilag SpA, via M.Buonarroti, 23 - 20093 Cologno Monzese (MI)
08.0 MARKETING AUTHORIZATION NUMBER
027015167 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 3,000 IU / 0.3ML
027015179 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 4,000 IU / 0.4ML
027015231 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 5,000 IU / 0.5ML
027015243 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 6,000 IU / 0.6ML
027015268 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 8,000 IU / 0.8ML
027015181 - "10,000 IU / ML solution for injection in pre-filled syringe" 1 syringe of 10,000 IU / 1ML
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
May 1989
AIC renewal: 4 August 2008
10.0 DATE OF REVISION OF THE TEXT
08/2015
