Active ingredients: Epoetin zeta
Retacrit 1 000 IU / 0.3 ml solution for injection in a pre-filled syringe
Retacrit 2 000 IU / 0.6 ml solution for injection in pre-filled syringe
Retacrit 3,000 IU / 0.9 ml solution for injection in pre-filled syringe
Retacrit 4 000 IU / 0.4 ml solution for injection in pre-filled syringe
Retacrit 5 000 IU / 0.5 ml solution for injection in pre-filled syringe
Retacrit 6 000 IU / 0.6 ml solution for injection in a pre-filled syringe
Retacrit 8 000 IU / 0.8 ml solution for injection in pre-filled syringe
Retacrit 10 000 IU / 1 ml solution for injection in pre-filled syringe
Retacrit 20 000 IU / 0.5 ml solution for injection in pre-filled syringe
Retacrit 30 000 IU / 0.75 ml solution for injection in a pre-filled syringe
Retacrit 40 000 IU / 1 ml solution for injection in pre-filled syringe
Indications Why is Retacrit used? What is it for?
Retacrit contains a protein called epoetin zeta which stimulates the bone marrow to produce more red blood cells in the blood that carry hemoglobin (a substance that binds oxygen). Epoetin zeta is a copy of the human protein erythropoietin and works in the same way.
Retacrit is used:
- in adult, pediatric and adolescent patients undergoing hemodialysis, for the treatment of symptomatic anemia (reduced number of red blood cells) associated with chronic renal failure (kidney disease);
- in adult patients undergoing peritoneal dialysis, for the treatment of symptomatic anemia associated with chronic renal failure (kidney disease);
- in adult patients with renal insufficiency not yet undergoing dialysis, for the treatment of severe anemia associated with renal disease accompanied by clinical symptoms;
- in adult patients receiving chemotherapy for solid tumors, malignant lymphoma (cancer of the lymphatic system) or multiple myeloma (cancer of the bone marrow) to treat anemia and reduce the need for blood transfusions, if the doctor determines the existence of a high risk of needing transfusions; - in patients with moderate anemia who are candidates for surgery to donate blood before surgery, so that they can receive their own blood during or after surgery (autologous predonation);
- in moderately anemic adult patients scheduled for major orthopedic (bone) surgery (eg hip or knee replacement therapy) to reduce the need for blood transfusions.
Contraindications When Retacrit should not be used
Do not use Retacrit:
- if you are allergic to erythropoietins or any of the other ingredients of this medicine (listed in section 6)
- if you have developed a disease called 'Pure Red Cell Aplasia' (PRCA) following treatment with any type of erythropoietin
- if you have high blood pressure that cannot be adequately controlled with specific medicines that lower blood pressure
- if you cannot take medicines to thin your blood
- 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)
- are at risk of blood clots forming in the veins (deep vein thrombosis); for example, if you have previously suffered from thrombosis.
- If you are about to have major orthopedic surgery such as hip or knee replacement, and:
- have severe heart or blood circulation problems in veins or arteries
- have recently had a heart attack or stroke.
Precautions for use What you need to know before taking Retacrit
Before using Retacrit tell your doctor if you know you have suffered or are suffering from any of the following diseases:
- Seizures
- liver disease
- tumors
- anemia due to other causes
- heart disease (such as angina pectoris)
- blood circulation disorders that cause tingling sensations in your extremities, cold hands or feet, or muscle cramps in your legs
- thrombosis or coagulation diseases
- kidney disease.
Interactions Which drugs or foods may change the effect of Retacrit
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.
In particular, if you are taking a medicine that contains the active substance ciclosporin, to inhibit the immune system after a kidney transplant, your doctor may order specific tests to measure the concentration of cyclosporine in the blood during Retacrit therapy.
Taking iron supplements and other blood stimulants may increase the effectiveness of Retacrit. Your doctor will decide whether or not you should continue to take these substances.
Warnings It is important to know that:
During treatment with Retacrit
Your doctor will check that your hemoglobin does not exceed a certain level, as high concentrations of hemoglobin could pose a risk to the health of the heart or blood vessels and could increase the risk of myocardial infarction, stroke and death.
Doctors should try to keep hemoglobin levels between 10 and 12 g / dl. Hemoglobin levels should not exceed 12 g / dl.
Your doctor will check your blood pressure regularly while you are using Retacrit. If you experience headaches, especially sudden, throbbing migraines, or if you begin to feel confused or have convulsions, tell your doctor or nurse immediately.
These symptoms could in fact be the warning signs of a sudden increase in blood pressure, a situation that would require emergency therapeutic intervention.
During treatment with this medicine, there may be an increase in the level of platelets (cells that contribute to blood clotting). This phenomenon should improve over the course of treatment. We recommend that you check your platelet count regularly during the first 8 weeks of therapy.
If you have a medical examination in a hospital or a private clinic, or have blood tests, remember to inform your doctor about the Retacrit treatment you are following, as this medicine can alter your condition and test results.
Pay particular attention to other products that stimulate the production of red blood cells:
Retacrit is one of a group of products that stimulates the production of red blood cells as does the human protein erythropoietin. The healthcare professional will always record the exact name of the product they are using.
Patients with kidney disease
Rare cases of Pure Red Cell Aplasia (PRCA) have been reported after months or years of treatment with other erythropoietin-containing medicines; this possibility cannot be excluded with Retacrit.
Specific red cell aplasia involves the inability of the bone marrow to produce enough red blood cells. In this case, a severe state of anemia can occur, the symptoms of which are: unusual tiredness, dizziness or shortness of breath. Red cell aplasia can be caused by the production of antibodies directed against the injected erythropoietin and, subsequently, against the erythropoietin produced by the same organism.
Discuss this information with your doctor. If this aplasia, however rare disease, should occur, therapy with Retacrit will be suspended and the doctor will decide what to do to treat the anemia in the most effective way. You should know that, if this complication, however rare, should occur, you you will have to stop taking Retacrit and have regular, and possibly life-long, blood transfusions for the treatment of anemia. Tell your doctor immediately if you suddenly feel very tired or feel short of breath. Your doctor will determine how effective Retacrit is for you and stop treatment if necessary.
Patients with chronic renal failure being treated with erythropoietin must undergo tests at regular intervals to measure the level of hemoglobin (that part of the red blood cells that carries oxygen) until a constant level is reached, and thereafter at intervals. periodic, to minimize the risk of an increase in blood pressure.
If you have chronic renal failure, and in particular if you do not respond adequately to Retacrit, your doctor will check the dose of Retacrit you receive because, if you do not respond to treatment, repeatedly increasing the dose of Retacrit may increase the risk of problems. to the heart or blood vessels and could increase the risk of myocardial infarction, stroke and death.
An increase in blood potassium levels has been observed in isolated cases. In patients with chronic renal failure, correction of the anemia may lead to an increase in appetite and absorption of potassium and protein. If you are undergoing dialysis treatment at the time of starting Retacrit therapy, you may need to adjust dialysis parameters to keep urea, creatinine and potassium levels within the desired range and your doctor will decide.
In patients with chronic renal failure, serum electrolytes (substances found in the blood) should be monitored. If serum potassium values are high (or increasing) then consideration should be given to discontinuing Retacrit administration until these values are corrected.
During therapy with Retacrit it is often necessary during hemodialysis to increase the dose of heparin, a particular blood-thinning substance, in order to minimize the risk of clots. If this dose of heparin is not optimal, it is possible that an occlusion occurs in the dialyzer.
Cancer patients
Cancer patients are more likely to get thrombosis if they are taking erythropoietin-like drugs such as Retacrit (see section 4). You should therefore speak to your doctor about the benefits of Retacrit, particularly if you are obese or have previously suffered from thrombosis problems. or blood clotting diseases.
Cancer patients being treated with erythropoietin must undergo laboratory tests at regular intervals to measure the level of hemoglobin (that part of the red blood cells that carries oxygen) until a constant level is reached, and thereafter with deadlines. periodic.
If you have cancer, you should be aware that Retacrit 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.
Pregnancy and breastfeeding
If you are pregnant or breastfeeding or think you are pregnant, or planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
If you are pregnant or breastfeeding, Retacrit should only be used if the potential benefits outweigh the potential risks to the baby.
Ask your doctor for advice before taking any medicine.
Driving and using machines
Retacrit has no or very little influence on the ability to drive or use machines.
Retacrit contains phenylalanine
This medicine contains phenylalanine, a substance that can be dangerous for people with phenylketonuria (an enzyme deficiency of genetic origin that causes an increase in the elimination of a chemical substance (phenylketone) in the urine and can cause disorders of the nervous system).
Retacrit contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per dose, meaning it is considered 'sodium-free'.
Dosage and method of use How to use Retacrit: Dosage
Retacrit therapy is usually started under medical supervision. Retacrit injections can be given by a doctor, registered nurse, or other health care professionals.
If Retacrit is injected under the skin (subcutaneously), after you have seen how, you can also inject the solution yourself. Always use this medicine exactly as your doctor has told you. If you are unsure, talk to your doctor.
Dose information
Dosage is based on body weight in kilograms. Your doctor will order tests, for example blood tests, to determine if you need to take Retacrit and will assess the exact dose of Retacrit, how long you will need to undergo the treatment and how the medicine will be given. These decisions will depend on the cause of the anemia. Your doctor will use the lowest effective dose to control the symptoms of the anemia. If you do not respond adequately to Retacrit, your doctor will check the dose you are receiving and will inform you if he changes it.
You may be given iron supplements both before and during treatment with Retacrit, for greater effectiveness of the therapy.
Use in patients with kidney disease
Retacrit must be administered either under the skin (subcutaneously) or by injection either into a vein or through a catheter placed into a vein.
Use of Retacrit in adult patients receiving hemodialysis
The doctor will keep the hemoglobin concentration between 10 and 12 g / dl (6.2 - 7.5 mmol / l).
Retacrit can be administered during the dialysis session or at the end of the session.
The recommended starting dosage is 50 IU / kg (International Units per kilogram), given 3 times per week. If the solution is administered into a vein, it should be injected over 1 to 5 minutes.
Depending on how your anemia responds to treatment, this dosage may be adjusted approximately every 4 weeks until the situation is under control. Your doctor will prescribe blood tests to be performed periodically to ensure that the medicine is continue to have the desired effect. Once the situation is under control, you will continue to take Retacrit at regular doses 2 or 3 times per week. These dosages may not be as high as those initially received.
Use of Retacrit in children and adolescents
(≤18 years) being treated with hemodialysis In children, the doctor will keep the hemoglobin concentration between 9.5 and 11 g / dl.
Retacrit should be administered to the patient at the end of the dialysis session.
Pediatric and adolescent dosing is based on body weight in kilograms. The recommended starting dosage is 50 IU / kg, given 3 times per week by injection into a vein (over a duration of 1-5 minutes).
Depending on how the anemia responds to treatment, this dosage can be adjusted approximately every 4 weeks until the situation is under control. Your doctor will order blood tests to be performed periodically to make sure this happens.
Use of Retacrit in adult patients undergoing peritoneal dialysis
The doctor will keep the hemoglobin concentration between 10 and 12 g / dl.
The recommended starting dosage is 50 IU / kg, to be administered twice a week.
Depending on how the anemia responds to treatment, this dosage can be adjusted approximately every 4 weeks until the situation is under control.
Your doctor will order blood tests for you to do periodically to make sure the medicine continues to have the desired effect.
Use of Retacrit in adult patients with kidney disease but not undergoing dialysis
The recommended starting dosage is 50 IU / kg, given 3 times per week.
This starting dosage can be adjusted by your doctor until the situation is under control. Once the situation is under control, you will continue to take Retacrit at regular doses (3 times a week, or if given under the skin (subcutaneously) it can also be given once a week or every 2 weeks). The maximum dose should not exceed 150 IU / kg 3 times a 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 a week. every 2 weeks.
Your doctor will order blood tests for you to do periodically to make sure the medicine continues to have the desired effect.
If you are being treated at longer dose intervals (greater than once a week), you may not be able to maintain your Hb levels adequately and you may need to increase your dose of Retacrit or its frequency of administration.
Use of Retacrit in adult patients receiving chemotherapy
Your doctor may start Retacrit if your hemoglobin level is 10 g / dl or less.
After the start of therapy, the doctor will keep the hemoglobin concentration between 10 and 12 g / dl.
The recommended starting dosage is 150 IU / kg, to be administered 3 times per week by subcutaneous injection. Alternatively, your doctor may recommend a starting dose of 450 IU / kg once a week. Your doctor may adjust your starting dose based on your anemia response to treatment; you will continue to take Retacrit for 1 month after the end of chemotherapy.
Use in adult patients participating in an autologous predonation program
The recommended starting dosage is 600 IU / kg, given twice weekly by injection into a vein. Retacrit will be given to you in the 3 weeks before surgery. You will also take iron supplements before and during treatment with Retacrit to increase the effectiveness of this medicine.
Use in adult patients scheduled for major orthopedic (bone) surgery
A dose of 600 IU / kg is given by injection under the skin once a week for 3 weeks prior to surgery and on the day of surgery. In cases where it is necessary to reduce the time before the intervention, a dose of 300 IU / kg is administered in the ten days preceding the intervention, the day of the intervention and in the 4 following days.If blood tests before surgery show hemoglobin levels too high, treatment will be stopped.
It is also important that the iron levels in the blood are normal for the duration of treatment with Retacrit. If necessary, you will receive iron by mouth daily, preferably already before starting treatment with Retacrit.
Information on administration
The Retacrit pre-filled syringe is ready for use. Each syringe is for single injection only. Retacrit solution for injection should not be shaken or mixed with other solutions.
If Retacrit is injected under the skin the amount injected into a single site should not exceed 1 ml. The upper thigh and abdomen away from the navel are good injection sites. Change the injection site every day.
When using Retacrit, always follow these instructions:
- Take the sealed blister that contains the syringe and allow it to reach room temperature before using it. For this it will take 15 to 30 minutes.
- Remove the syringe from the blister and check that the solution is clear, colorless and practically free of visible particles.
- Remove the needle cover and let the air out of the needle and syringe by holding the syringe upright and gently pushing the plunger up.
- Inject the solution according to the instructions your doctor has given you. If something is not clear to you, ask your doctor or pharmacist.
Do not use Retacrit if:
- the blister is open or otherwise damaged;
- the solution is not colorless or contains visible particles in suspension;
- c "liquid has leaked from the pre-filled syringe or condensation is visible inside the blister which is still sealed;
- you know that the medicine has been accidentally frozen or you think this may have happened.
Switching from intravenous to subcutaneous administration
Once the situation is under control, you will continue to take Retacrit at regular dosages. Your doctor may decide that Retacrit should be given by injection under the skin (subcutaneously) rather than into a vein (intravenously).
When switching from one method of administration to the other, the dosage does not need to be changed. Your doctor may then order blood tests to check whether or not a dose adjustment is needed.
Give yourself an injection of Retacrit under the skin
At the start of treatment, Retacrit is usually given by a doctor or nurse. Thereafter, your doctor may suggest that you or your caregiver learn how to inject under the skin (subcutaneous).
- Do not try to inject yourself if your doctor or nurse has not told you how.
- Always use Retacrit as instructed by your doctor or nurse.
- Only use the medicine if it has been stored correctly (see section 5).
- Before use, remove the syringe from the refrigerator and allow it to reach room temperature. It usually takes 15-30 minutes.
Use a single dose of Retacrit from each syringe.
When the medicine is administered under the skin (subcutaneously), the volume is normally no more than 1 ml for any single injection.
Retacrit must be administered alone and not mixed with other injection fluids.
Do not shake the pre-filled syringes. Prolonged and vigorous shaking can damage the medicine. Do not use the medicine if it has been shaken vigorously.
How to inject yourself using the pre-filled syringes
- Remove the syringe from the refrigerator. The liquid must reach room temperature. Do not remove the syringe needle cover as it reaches room temperature.
- Check the syringe to make sure that 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.
- Wash your hands. Use an antiseptic wipe to disinfect the injection site.
- Hold the syringe by your body with the covered needle pointing up.
- Do not hold the syringe by the plunger head, plunger or needle cover.
- Never pull the plunger towards you.
- Do not remove the needle cover of the pre-filled syringe until you are ready to inject Retacrit.
- Remove the cover from the syringe by holding the barrel and pulling the cover gently without twisting it. Do not push the plunger, touch the needle, or shake the syringe.
- Take a skin fold between the thumb and forefinger without squeezing it too much.
- Push the needle in all the way. Your doctor or nurse will have shown you how.
- Push the plunger with your thumb all the way in to inject the full amount of liquid. Push it slowly and evenly, keeping the skin pinched.
- When the plunger is pushed to its limit, pull out the needle and let go of the skin.
- When the needle is removed from the skin, some blood may leak from the injection site. This is normal. You can disinfect the injection site by pressing the antiseptic wipe for a few seconds after the injection.
- Place the used syringe in a sharps container. Do not try to put the protective cap back on the needle.
- Never throw used syringes into household waste containers.
Use of the needle protection device
The pre-filled syringe can be equipped with a safety device for the needle that protects against accidental needle stick.
- Carry out the injection according to the technique described above.
- While holding the syringe with your fingers resting on its support edge, apply pressure on the plunger until the injection of the entire dose is complete. The needle guard system will NOT activate if the FULL dose has not been administered.
- Remove the needle from your skin, then release the plunger and the syringe will move forward until the shield has covered the needle and snaps into place.
If you forget to use Retacrit
Do not use a double dose to make up for a forgotten previous dose.
If you stop taking Retacrit
Do not stop treatment without first checking with your doctor.
If you have any further questions on the use of Retacrit, ask your doctor.
Overdose What to do if you have taken too much Retacrit
Retacrit has a large margin of safety and side effects from an overdose of this medicine are unlikely to occur. Tell your doctor or nurse straight away if you think you have too much injected Retacrit.
Side Effects What are the side effects of Retacrit
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately if you have a headache, particularly if it is sudden, sharp, migraine-like headache, if you feel confused or if you have fits. These symptoms may be warning signs of a sudden increase. blood pressure, which requires emergency treatment.
Tell your doctor or nurse if you notice any of the effects on this list.
Very common side effects
These may affect more than 1 in 10 people treated with Retacrit.
- Flu-like symptoms, headache, joint pain, feeling of weakness, tiredness and dizziness.
- In patients with kidney disease not yet undergoing dialysis, respiratory tract congestion, such as stuffy nose and sore throat, has been reported.
Common side effects
These may affect up to 1 in 10 people treated with Retacrit.
- Increased blood pressure. The increase in blood pressure may require treatment with medicines (or adjustment of the medicines you are already being treated for your high blood pressure). Your doctor will check your blood pressure at regular intervals during treatment with Retacrit, especially during treatment with Retacrit. "start of therapy.
- Chest pain, shortness of breath, painful swelling in the legs which could be a symptom of blood clots (pulmonary embolism, deep vein thrombosis).
- Stroke (insufficient blood supply to the brain, which could cause inability to move one or more limbs on one side of the body, inability to understand or speak, or inability to see one side of the visual field).
- Rash and swelling around the eyes (edema), which could be caused by an allergic reaction.
- Coagulation in the artificial kidney.
Uncommon side effects
These may affect up to 1 in 100 people treated with Retacrit.
- Cerebral hemorrhage.
Rare side effects
These may affect up to 1 in 1 000 people treated with Retacrit.
- Hypersensitivity reactions.
Very rare side effects
These may affect up to 1 in 10,000 people treated with Retacrit.
- There may be increases in the levels of platelets, which are normally involved in the formation of blood clots. The doctor will check these values.
Undesirable effects with frequency not known
The frequency of these undesirable effects cannot be calculated from the available data.
- Swelling, especially in the eye and lip area (Quincke's edema) and shock-like allergic reactions with symptoms such as tingling, redness, itching, flushing and rapid pulse.
- Vascular and thrombotic events (blood clots) in blood vessels such as impeded blood supply to the brain, retinal thrombosis, impeded blood supply to the heart, heart attack, arterial thrombosis, dilation of blood vessel walls (aneurysm).
- Red Series Aplasia (PRCA) PRCA has been reported in patients after months to years of subcutaneous (injection under the skin) treatment of erythropoietin. PRCA means the inability to produce an adequate number of red blood cells in the bone marrow (see section "Warnings and precautions").
- Itching.
Other side effects
Patients with kidney disease
- Increase in blood pressure, which may require drug treatment or an adjustment in the dosage of medicines you are already taking for high blood pressure. Your doctor may measure your blood pressure regularly while you are using Retacrit, particularly at the start of therapy.
- An occlusion of the connection between artery and vein (shunt thrombosis) can occur in particular if you have low blood pressure or if you have complications of arteriovenous fistula. Your doctor will be able to check the shunt and prescribe a medicine to prevent thrombosis.
Patients with malignant tumors
- Blood clotting (vascular thrombotic events) (see section "Warnings and precautions").
- Increased blood pressure. For this reason, hemoglobin levels and blood pressure should be monitored.
If you experience any side effects, tell your doctor, pharmacist or nurse. This also applies to any side effects not listed in this leaflet.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton ("EXP" / "EXP").
The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
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).
Keep the pre-filled syringe in the outer carton to protect the medicine from light.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Retacrit contains
The active ingredient is epoetin zeta (produced by recombinant DNA technique in Chinese hamster ovary cell lines).
Retacrit 1 000 IU / 0.3 ml solution for injection in a pre-filled syringe
1 pre-filled syringe with 0.3 ml solution for injection contains 1 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 3 333 IU of epoetin zeta per ml.
Retacrit 2 000 IU / 0.6 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.6 ml solution for injection contains 2,000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 3 333 IU of epoetin zeta per ml.
Retacrit 3,000 IU / 0.9 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.9 ml solution for injection contains 3,000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 3 333 IU of epoetin zeta per ml.
Retacrit 4 000 IU / 0.4 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.4 ml solution for injection contains 4 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 10 000 IU of epoetin zeta per ml.
Retacrit 5 000 IU / 0.5 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.5 ml solution for injection contains 5 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 10 000 IU of epoetin zeta per ml.
Retacrit 6 000 IU / 0.6 ml solution for injection in a pre-filled syringe
1 pre-filled syringe with 0.6 ml solution for injection contains 6 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 10 000 IU of epoetin zeta per ml.
Retacrit 8 000 IU / 0.8 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.8 ml solution for injection contains 8 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 10 000 IU of epoetin zeta per ml.
Retacrit 10 000 IU / 1 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 1.0 ml solution for injection contains 10 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 10 000 IU of epoetin zeta per ml.
Retacrit 20 000 IU / 0.5 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 0.5 ml solution for injection contains 20 000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 40 000 IU of epoetin zeta per ml.
Retacrit 30 000 IU / 0.75 ml solution for injection in a pre-filled syringe
1 pre-filled syringe with 0.75 ml of solution for injection contains 30,000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 40 000 IU of epoetin zeta per ml.
Retacrit 40 000 IU / 1 ml solution for injection in pre-filled syringe
1 pre-filled syringe with 1.0 ml solution for injection contains 40,000 international units (IU) of epoetin zeta (recombinant human erythropoietin). The solution contains 40 000 IU of epoetin zeta per ml. The other ingredients are disodium phosphate dihydrate, monobasic sodium phosphate dihydrate, sodium chloride, calcium chloride dihydrate, polysorbate 20, glycine, leucine, isoleucine, threonine, glutamic acid, phenylalanine and water for injections, sodium hydroxide (for pH adjustment), hydrochloric acid (to adjust the pH).
What Retacrit looks like and contents of the pack
Retacrit is a clear and colorless solution for injection contained in clear colorless glass syringes with a fixed needle.
The pre-filled syringes contain 0.3 ml to 1 ml of solution, depending on the content of epoetin zeta (see section "What Retacrit contains").
One pack contains 1 or 4 or 6 pre-filled syringes with or without a needle guard.
Multipacks contain 4 (4 packs of 1) or 6 (6 packs of 1) pre-filled syringes.
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 -
RETACRIT 1000 IU / 0.3 ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One pre-filled syringe with 0.3 ml solution for injection contains 1 000 international units (IU) of epoetin zeta * (recombinant human erythropoietin). The solution contains 3 333 IU of epoetin zeta per ml.
* Produced by recombinant DNA technique in Chinese Hamster Ovary (CHO) cell lines.
Excipient with known effect:
Each pre-filled syringe contains 0.15 mg of phenylalanine.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Solution for injection in pre-filled syringe.
Clear and colorless solution.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
• Treatment of symptomatic anemia associated with chronic renal failure (CRI) in adult and pediatric patients:
• Treatment of anemia associated with chronic renal failure in adult and pediatric patients on hemodialysis and in adult patients on peritoneal dialysis (see section 4.4).
• Treatment of severe anemia of renal origin with clinical symptoms in adult patients with renal insufficiency not yet undergoing dialysis (see section 4.4).
- Treatment of anemia and reduction of transfusion requirements in adult patients undergoing chemotherapy for solid tumors, malignant lymphoma or multiple myeloma and at risk of blood transfusion as indicated by the patient's general condition (cardiovascular situation, anemia pre-existing at the start of chemotherapy).
- Retacrit can be used to increase the amount of autologous blood in patients who are part of a predonation program. Use in this indication should be evaluated in light of the reported risks of thromboembolic events. Treatment should only be reserved for patients with moderate anemia (in the absence of iron deficiency) if blood storage procedures are unavailable or insufficient when "Planned major elective surgery requires a large volume of blood (4 or more units of blood for women, 5 or more units for men).
- Retacrit can be used to reduce exposure to allogeneic blood transfusions in non-iron deficient adult patients believed to be at high risk of transfusion complications prior to major elective orthopedic surgery. Restrict use to patients with moderate anemia (Hb 10 -13 g / dl) not part of an autologous predonation program and for which moderate blood loss is expected (from 900 to 1 800 ml).
04.2 Posology and method of administration -
Retacrit therapy should be initiated under the supervision of medical personnel experienced in the management of patients with the indications described above.
Dosage
Treatment of symptomatic anemia in adult and pediatric patients with chronic renal failure
Retacrit should be administered either subcutaneously or intravenously.
The desired hemoglobin concentration is between 10 and 12 g / dl (6.2-7.5 mmol / l), except in pediatric patients, where the hemoglobin concentration must be between 9.5 and 11 g / dl (5.9-6.8 mmol / l). The upper limit of the target hemoglobin concentration should not be exceeded. 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. Retacrit should be administered either subcutaneously or intravenously to achieve hemoglobin values not exceeding 12 g / dl (7.5 mmol / l). Due to intra-patient variability, single hemoglobin values above and below the desired hemoglobin concentration may occasionally be observed 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.
Patients should be monitored closely to ensure that the lowest authorized effective dose of Retacrit is used to adequately control the symptoms of anemia by maintaining a hemoglobin concentration of less than or equal to 12g / dl (7.5 mmol / l).
Caution should be exercised in increasing the doses of Retacrit in patients with chronic renal failure. In patients with a poor hemoglobin response to Retacrit, alternative explanations for this poor response should be considered (see sections 4.4 and 5.1). In patients with insufficiency chronic renal disease and clinical evidence of ischemic heart disease or congestive heart failure, maintenance hemoglobin concentration should not exceed the maximum target concentration limit.
Adult patients on hemodialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two phases:
1. Correction phase: 50 IU / kg, 3 times a week. If dosage adjustment is necessary, this should be done gradually, at intervals of at least 4 weeks. With each adjustment, the dose should be increased or decreased by 25 IU / kg, 3 times per week.
2. Maintenance phase: Dosage adjustment aimed at maintaining the desired level of hemoglobin (Hb), between 10 and 12 g / dl (6.2-7.5 mmol / l). The recommended total weekly dose ranges from 75 to 300 IU / kg.
Available clinical data indicate that patients with a very low initial hemoglobin level (8 g / dl or> 5 mmol / l).
Pediatric patients on hemodialysis
The treatment is divided into two phases.
1. Correction phase 50 IU / kg, 3 times per week intravenously. If dosage adjustment is necessary, this should be done in increments of 25 IU / kg 3 times per week, at intervals of at least 4 weeks, until the target is reached.
2. Maintenance phase Dosage adjustment aimed at maintaining the desired level of hemoglobin (Hb), between 9.5 and 11 g / dl (5.9-6.8 mmol / l).
Generally children and adolescents weighing less than 30 kg require higher maintenance doses than children weighing more than 30 kg and adults. In clinical studies, for example, the following maintenance doses were observed after 6 months of treatment:
Available clinical data indicate that patients with a very low initial hemoglobin level (6.8 g / dl or> 4.25 mmol / l).
Adult patients on peritoneal dialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two phases.
1. Correction phase: The starting dose is 50 IU / kg of weight, twice a week.
2. Maintenance phase: Dosage adjustment aimed at maintaining the desired level of hemoglobin (Hb), (between 10 and 12 g / dl [6.2-7.5 mmol / l]. The maintenance dose is between 25 and 50 IU / kg 2 times a week, divided into 2 equal doses.
Adult patients with renal insufficiency not yet on dialysis
Retacrit should be administered either subcutaneously or intravenously.
The treatment is divided into two phases.
1. Correction phase: An initial dose of 50 IU / kg 3 times per week, followed if necessary by an increase in increments of 25 IU / kg (3 times per week) until the desired goal is reached (the increase should occur gradually, at intervals of at least four weeks).
2. Maintenance phase: During the maintenance phase, Retacrit can be administered 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 the desired hemoglobin (Hb) level, (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 a 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 a week. every 2 weeks.
Treatment of patients with chemotherapy-induced anemia
Retacrit should be administered subcutaneously to anemic patients (eg with hemoglobin concentration ≤ 10 g / dl (6.2 mmol / l). The symptoms and consequences of anemia may vary according to age, gender and severity. overall disease; an individual assessment of the clinical course and condition of each individual patient is required by the physician.
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, relative to a target hemoglobin range of 10 g / dL (6.2 mmol / L) to 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.
Patients should be monitored closely to ensure that the lowest authorized dose of Retacrit is used to adequately control the symptoms of anemia.
Retacrit therapy should be continued for another month after the end of chemotherapy. The starting dose is 150 IU / kg, 3 times per week subcutaneously. Alternatively, Retacrit can be administered subcutaneously at the starting dose of 450 IU / kg once weekly. If after 4 weeks of treatment the hemoglobin has increased by at least 1 g / dL (0.62 mmol / L) or the reticulocyte count has increased by ≥ 40,000 cells / μl from baseline, the dose should remain at 450 IU / kg once a week or 150 IU / kg 3 times a week. If the hemoglobin increase is
The recommended dosing regimen is shown in the following table:
Once the therapeutic target for the individual patient is achieved, the dose should be reduced by 25 to 50% to maintain hemoglobin at that level. Appropriate dose titration should be considered.
Dosage adjustment
If the increase in hemoglobin is greater than 2 g / dl (> 1.25 mmol / l) per month, the dose of Retacrit should be reduced by approximately 25-50%. If the hemoglobin value exceeds 12 g / dl (7.5 mmol / L), withhold therapy until it returns to or falls below 12 g / dL (7.5 mmol / L), then resume Retacrit therapy at a 25% lower dose than the previous dose.
Treatment of adult patients who are candidates for surgical interventions that are part of autologous predonation programs
Retacrit must be administered intravenously.
At the time of blood donation, Retacrit must be administered after completing the donation procedure.
Mildly anemic patients (hematocrit 33-39%) requiring predeposit of ≥ 4 units of blood should be treated with 600 IU / kg of Retacrit 2 times per week for 3 weeks prior to surgery.
Throughout the duration of Retacrit therapy, all patients should receive adequate iron supplementation (eg 200 mg / day of oral elemental iron). The administration of iron should be started as soon as possible, even several weeks before performing the autologous predeposit, in order to increase the iron stores before starting therapy with Retacrit.
Treatment of adult patients scheduled for major elective orthopedic surgery
Retacrit should be administered subcutaneously.
A dose of 600 IU / kg body weight should be administered once weekly for three weeks (days 21, 14 and 7) prior to surgery and on the day of surgery (day 0). In cases where it is necessary to reduce the time before surgery to less than three weeks, a daily dose of 300 IU / kg of body weight should be administered for 10 consecutive days before surgery, on the day of surgery and in the four days If the hemoglobin level reaches or exceeds 15 g / dl as part of haematological tests performed in the preoperative period, Retacrit should be discontinued and subsequent doses should not be administered.
Iron deficiencies must be treated before starting treatment with Retacrit. In addition, an adequate amount of iron should be administered to all patients treated with Retacrit (eg 200 mg of iron ions orally per day) for the entire duration of treatment with Retacrit. iron administration prior to Retacrit therapy to obtain adequate deposits.
Method of administration
Intravenous injection
Administration should take at least 1-5 minutes, depending on the total dose. In hemodialysis patients it is possible to administer the bolus dose, during the dialysis session, from a suitable venous access of the dialysis circuit. Alternatively, the substance can be injected at the end of the dialysis session through the fistula and followed by 10 ml of 9 mg / ml (0.9%) NaCl physiological solution to irrigate the circuit and ensure a satisfactory introduction of the product into the circulation. In patients who react to treatment with flu-like symptoms it is preferable to opt for a slower administration.
Retacrit must not be administered by intravenous infusion.
Retacrit must not be mixed with other medicinal products (see section 6.2).
Subcutaneous injection
In general, the maximum volume of 1 ml per injection site should not be exceeded. In case of larger volumes, it is necessary to choose more administration sites.
Injections are given in the limbs or in the anterior abdominal wall.
For instructions on handling of the medicinal product before administration, see section 6.6.
04.3 Contraindications -
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Patients with pure red cell aplasia (PRCA) following treatment with erythropoietin should not undergo therapy with Retacrit or any other types of erythropoietin (see section 4.4).
- Uncontrolled 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.
- In the indication of major elective orthopedic surgery: severe coronary, peripheral arterial, carotid or cerebral vascular diseases, including patients with recent myocardial infarction or cerebrovascular accident.
- Patients who for any reason cannot receive "adequate antithrombotic prophylaxis.
04.4 Special warnings and appropriate precautions for use -
General information
As in all patients receiving erythropoietin, an increase in blood pressure may occur during therapy with Retacrit. Blood pressure should be carefully monitored and adequately controlled before, at the initiation and during the course of therapy with Retacrit, both in all patients undergoing treatment with epoetin for the first time and in patients already treated. It may be necessary to establish or strengthen anti-hypertensive treatment If blood pressure cannot be controlled, treatment with Retacrit should be stopped.
Retacrit should also be used with caution in the presence of epilepsy and chronic liver failure.
A moderate dose-dependent rise in platelet counts within the normal range may occur during treatment with erythropoietin. 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.
All other causes of anemia (iron deficiency, haemolysis, blood loss, vitamin B12 or folate deficiency) should be evaluated and treated before and during treatment with Retacrit. In most cases, the serum ferritin values decrease at the same time as the hematocrit values increase. In order to ensure an optimal response to erythropoietin, adequate iron stores must be ensured:
- in patients with chronic renal failure and serum ferritin levels below 100 ng / ml iron supplementation is recommended, for example 200-300 mg / day orally (100-200 mg / day in pediatric patients);
- In all cancer patients with transferrin saturation values below 20%, an oral iron supplement of 200-300 mg / day is recommended.
All these factors contributing to the onset of anemia must also be carefully considered before deciding to increase the erythropoietin dose in cancer patients.
A paradoxical decrease in hemoglobin and the development of severe anemia associated with low reticulocyte counts should alert them to discontinue treatment with epoetin and perform anti-erythropoietin antibody tests. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin. , when epoetins have been used in combination. Epoetins are not approved for the management of anemia associated with hepatitis C.
In order to improve the traceability of Erythropoiesis Stimulating Agents (Erythropiesis Stimulating Agents (ESA), the name of the ESA that has been prescribed must be clearly recorded (or indicated) in the patient's medical record.
Good blood management practices should always be used in the perioperative.
Patients scheduled for major elective orthopedic surgery
In patients scheduled for major elective orthopedic surgery, the causes of the anemia should be established and treated, possibly before starting treatment with Retacrit. Thrombotic events may pose a risk in this patient population, and this should be carefully considered in relation to the anticipated benefit of treatment.Patients should receive "adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in patients with underlying cardiovascular disease. In addition, particular caution should be exercised in patients predisposed to developing deep vein thrombosis (DVT). Furthermore, in patients with baseline hemoglobin> 13 g / dl, the possibility that Retacrit treatment may be associated with an increased risk of postoperative thrombotic / vascular events cannot be excluded. Therefore, such treatment should not be used in patients with baseline hemoglobin> 13 g / dl.
Patients with chronic renal insufficiency
Hemoglobin concentration
In patients with chronic renal failure, the maintenance hemoglobin concentration should not exceed the upper limit of the target hemoglobin concentration recommended in section 4.2. Increased risk of death, serious cardiovascular events and cerebrovascular events including stroke have been observed in clinical trials when ESA was administered to achieve hemoglobin values greater than 12 g / dl (7.5 mmol / l).
Controlled clinical trials have shown no significant benefit attributable to the administration of epoetins once the hemoglobin concentration has exceeded the levels necessary to control the symptoms of anemia and avoid blood transfusions.
The hemoglobin level should be measured at regular intervals until it reaches a constant value, and thereafter at periodic intervals. The increase in hemoglobin should be approximately 1 g / dl (0.62 mmol / l) per month and should not exceed 2 g / dl (1.25 mmol / l) per month to minimize the risk of developing hypertension or its aggravation.
Chronic renal failure patients treated with Retacrit subcutaneously should be monitored periodically for loss of efficacy, defined as non-response or reduced response to Retacrit treatment in patients who previously responded to such therapy. This is characterized by a sustained decrease in hemoglobin despite an increase in the dose of Retacrit.
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.
Caution should be exercised in increasing doses of Retacrit 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 4.4 and 5.1).
A lack of response to erythropoietin therapy must promptly investigate the responsible factors. These include: iron, folate or vitamin B12 deficiency, aluminum intoxication, intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, bone marrow fibrosis of any origin.
Cases of antibody-mediated PRCA have been reported very rarely in patients with chronic renal failure administered subcutaneous erythropoietin. In patients who exhibit a "sudden loss of efficacy, demonstrated by a decrease in hemoglobin (1-2 g / dl per month) with increased need for transfusions, a reticulocyte count should be performed and typical causes of preventing response to treatment (eg iron, folate or vitamin B12 deficiency, aluminum poisoning, infection or inflammation, blood loss, haemolysis). If no cause is found, consideration should be given to performing a blood test bone marrow to diagnose a PRCA.
If PRCA is diagnosed, Retacrit therapy should be discontinued immediately and a test for the presence of anti-erythropoietin antibodies should be considered. Patients should not be diverted to treatment with another medicinal product, given cross-reactivity between anti-erythropoietin antibodies and other erythropoietins Other causes of PRCA must be excluded and appropriate therapy instituted.
Periodic monitoring of the reticulocyte count is recommended to detect any loss of therapeutic efficacy in patients with chronic renal failure.
Hyperkalaemia has been observed in isolated cases. In patients with chronic renal failure, correction of anemia may lead to an increase in appetite and absorption of potassium and protein. Prescribed parameters for dialysis may need periodic adjustment to keep urea, creatinine and potassium within Desired values. In patients with chronic renal failure serum electrolytes should be monitored. If elevated (or rising) serum potassium values are observed, then consideration should be given to discontinuing erythropoietin administration until hyperkalaemia is corrected.
An increase in the heparin dose is often required during erythropoietin therapy due to an increase in the hematocrit value. Occlusion of the dialysis system may occur if heparinization is not optimal.
Based on the data available to date, correction of anemia with erythropoietin in adult patients with renal insufficiency not yet undergoing dialysis does not accelerate the progression of renal insufficiency.
Adult cancer patients with symptomatic anemia on chemotherapy
In cancer patients receiving chemotherapy, the 2-3 week interval between administration and the appearance of erythropoietin-induced erythrocytes should be considered when assessing the appropriateness of Retacrit therapy (patients at risk of transfusion ). In cancer patients undergoing chemotherapy, if the hemoglobin increases more than 2 g / dl (1.25 mmol / l) per month or if its level exceeds 12 g / dl (7.5 mmol / l), it is The dosage adjustment procedure indicated in section 4.2 must be carefully performed in order to reduce the potential risk factors for thrombotic events (see section 4.2).
Since an increased incidence of thromboembolic events has been observed in cancer patients undergoing treatment with erythropoietic agents (see section 4.8), this risk should be carefully weighed in the light of the benefit of treatment (with Retacrit), particularly in those cancer patients with an increased thromboembolic risk, such as obese subjects or with a history of thrombotic and vascular events (deep vein thrombosis, pulmonary embolism).
Adult patients who are candidates for surgery that are part of an autologous predonation program
All warnings and special precautions associated with autologous predonation programs must be observed, especially by restoring the volume of blood drawn as usual.
Oncogenic potential
Epoetins are growth factors that primarily stimulate the production of erythrocytes. Erythropoietin receptors can be expressed on the surface of a range of neoplastic cells. As with all growth factors, there is a doubt that epoetins can stimulate the growth of all malignant tumors. In several controlled clinical trials this has not been Epoetins have been shown to improve overall survival or decrease the risk of cancer progression in patients with cancer-associated anemia.
Several controlled clinical trials in which epoetins were administered to patients with a number of common malignancies, such as squamous carcinoma of the head and neck, lung cancer and breast cancer, have shown an unexplained increase in the mortality rate. In controlled clinical trials, the use of epoetin alfa and other erythropoiesis stimulating agents (ESAs) showed:
• A reduction in time to tumor progression in patients with advanced head and neck cancer treated with radiotherapy when administered to achieve hemoglobin values greater than 14 g / dl (8.7 mmol / l),
• a reduction in overall survival and an increase in deaths attributed to tumor progression at 4 months in patients with metastatic breast cancer treated with chemotherapy when administered to achieve hemoglobin values of 12-14 g / dl (7.5-8.7 mmol / l),
• an increased risk of death when administered to obtain hemoglobin values of 12 g / dl (7.5 mmol / l) in patients with active malignancies, not treated with chemotherapy or radiotherapy. The use of ESA 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).
This medicine contains phenylalanine, a substance which may be dangerous for people with phenylketonuria.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, which means that it is considered "low in sodium".
04.5 Interactions with other medicinal products and other forms of interaction -
Treatment with erythropoietin has not been shown to alter the metabolism of other medicinal products. However, since cyclosporin binds to erythrocytes, there may be the possibility of an "interaction with other medicinal products. If erythropoietin is administered concomitantly with cyclosporine, blood levels of cyclosporine should be monitored and the dose of this medicinal product it must be corrected according to the increase in the hematocrit value.
There is no evidence to indicate an "interaction between epoetin alfa and G-CSF or GM-CSF with regard to haematological differentiation or proliferation in tumor biopsy specimens. in vitro.
04.6 Pregnancy and breastfeeding -
There are no adequate and well controlled studies in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). It is not known whether exogenous epoetin zeta is excreted in human milk. Therefore, in general, erythropoietin should only be used during pregnancy and lactation if the potential benefits outweigh the potential risks to the fetus.
04.7 Effects on ability to drive and use machines -
Retacrit has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects -
Summary of the safety profile
The results of clinical studies with Retacrit are in line with the safety profile of other authorized erythropoietins. Based on the results of clinical trials with other licensed erythropoietins, approximately 8% of patients treated with erythropoietin are expected to experience adverse reactions. Adverse events during treatment with erythropoietin are mainly observed in patients with chronic renal failure or underlying malignancies and they are mainly represented by headache and a dose-dependent increase in blood pressure. Hypertensive crises with symptoms similar to an "encephalopathy" may occur. Attention should be paid to sudden acute migraine-like headaches, which may be a warning sign.
Respiratory tract congestion, including events of upper tract congestion, nasal congestion and nasopharyngitis, has been reported in some studies in adult patients with renal insufficiency not yet undergoing dialysis treated with extended dosing intervals.
In patients treated with erythropoietic agents, thrombotic / vascular events such as myocardial ischaemia, myocardial infarction, cerebrovascular accidents (cerebral haemorrhage and cerebral infarction), transient ischemic attacks, deep vein thrombosis, arterial thrombosis, pulmonary embolism, aneurysm, retinal thrombosis have been observed coagulation in the artificial kidney.
Antibody-mediated erythroblastopenia (PRCA) has been observed after months or years of treatment with epoetin alfa. Antibodies to erythropoietins have been observed in most of these patients (see sections 4.3 and 4.4).
Adverse events printout
This section defines the frequencies of adverse events as: Very common (> 1/10); common (> 1/100 to 1/1 000 to 1/10 000 a
Within each frequency class, adverse events are presented in descending order of severity.
The frequency may vary depending on the indication
Adult and pediatric hemodialysis patients, adult patients undergoing peritoneal dialysis and adult patients with renal insufficiency not yet on dialysis
The most frequent adverse reaction in the setting of treatment with epoetin alfa is dose-dependent increase in blood pressure or worsening of pre-existing hypertension. This increase in blood pressure can be treated pharmacologically. In addition, monitoring of blood pressure is recommended. particularly at the beginning of therapy. The following reactions have also occurred in isolated cases of patients with normal or low blood pressure: hypertensive crisis with symptoms similar to an encephalopathy (headache and confusional state) and generalized tonicoclonic seizures, requiring immediate medical intervention and intensive treatment. you should pay particular attention to sudden acute migraine-like headaches, which may be a warning sign.
Shunt thrombosis may occur, particularly in patients with a tendency to hypotension or with complications of arteriovenous fistulas (stenosis, aneurysms, etc.). In these patients, early revision of the shunt and antithrombotic prophylaxis, for example with acetylsalicylic acid, are recommended. .
Adult cancer patients on chemotherapy with symptomatic anemia
Hypertension may occur in patients treated with epoetin alfa. Consequently, close monitoring of hemoglobin and blood pressure should be performed.
An increased incidence of vascular thrombotic events has been observed in patients treated with erythropoietic agents (see section 4.4 and section 4.8 - General considerations).
Patient candidates for surgery
Regardless of erythropoietin treatment, thromboembolic events may occur following repeated phlebotomies in surgical patients with underlying cardiovascular disease.
Therefore, such patients should routinely undergo replacement of the collected blood volume. In patients with baseline hemoglobin> 13 g / dl, the possibility that Retacrit treatment may be associated with an increased risk of postoperative thrombotic / vascular events cannot be excluded.
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.
04.9 Overdose -
The therapeutic window of erythropoietin is very broad. Overdose of erythropoietin can produce effects which are extensions of the pharmacological effects of the hormone. If excessively high hemoglobin levels occur, a phlebotomy can be performed. If necessary, additional supportive care should be provided.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Other antianemics, erythropoietin
ATC code: B03XA01
Retacrit is a biosimilar medicinal product. Detailed information is available on the European Medicines Agency website http://www.ema.europa.eu
Pharmacodynamic effects
Erythropoietin is a glycoprotein which, as a mitosis-stimulating factor and differentiation hormone, stimulates the production of erythrocytes from the precursors of the stem compartment. The apparent molecular weight of erythropoietin is 32,000-40,000 daltons. The protein fraction of the molecule constitutes about 58% of its total molecular weight and is composed of 165 amino acids. The four carbohydrate chains are linked to the protein by three N-glycosidic bonds and one oglycoside bond. From the point of view of the amino acid sequence and carbohydrate composition, epoetin zeta is identical to endogenous human erythropoietin isolated from the urine of anemic patients. The biological efficacy of erythropoietin has been demonstrated in various animal models in vivo (normal and anemic rats, polycythemic mice). After erythropoietin administration the erythrocyte count, hemoglobin values and reticulocyte count increase along with the 59Fe incorporation rate. In tests in vitro (mouse splenic cell culture), increased incorporation of 3H-thymidine into nucleated erythroid cells of the spleen was observed after incubation with erythropoietin.
Through cell cultures of human bone marrow it has been shown that erythropoietin specifically stimulates erythropoiesis without altering leukopoiesis. No cytotoxic activity of erythropoietin was observed on bone marrow cells.
Similarly to other hematopoietic growth factors, erythropoietin has been shown in vitro to possess stimulating properties of human endothelial cells.
Adult patients with renal insufficiency not yet undergoing dialysis
In 2 extended dose interval studies of erythropoietin (3 times per week, once per week, once every 2 weeks and once every 4 weeks) some patients with longer dose ranges did not maintain adequate hemoglobin levels and the protocol requirements for discontinuation defined by the hemoglobin value are met (0% in once-weekly dosing, 3.7% in once-every-two-week dosing and 3.3% in once-every-4-week groups).
Clinical efficacy and safety
Three placebo-controlled studies involved 721 cancer patients receiving platinum-free chemotherapy, including 389 with haematological malignancies (221 with multiple myeloma, 144 with non-Hodgkin's lymphoma and 24 with other haematological malignancies) and 332 with solid tumors (172 mammary, 64 gynecological, 23 pulmonary, 22 prostatic, 21 gastrointestinal and 30 other types). Two large open-label studies involved 2 697 cancer patients receiving platinum-free chemotherapy, including 1 895 with solid tumors (683 breast, 260 lung, 174 gynecological, 300 gastrointestinal and 478 other) and 802 with haematological malignancies.
In a prospective, randomized, double-blind, placebo-controlled study conducted on 375 anemic patients with various non-myeloid neoplasms and receiving platinum-free chemotherapy, a significant reduction in the sequelae associated with anemia (such as fatigue, asthenia and reduction activity), measured by the following assessment tools: the general assessment scale FACT-An (Functional Assessment of Cancer Therapy-Anaemia), the fatigue rating scale FACT-An and the Cancer Linear Analogue Scale (CLAS). Two other randomized, placebo-controlled trials involving fewer patients failed to demonstrate a significant improvement in quality of life parameters assessed with EORTC-QLQ-C30 and CLAS, respectively.
Erythropoietin is a growth factor that primarily stimulates the production of erythrocytes. Erythropoietin receptors can be expressed on the surface of various types of tumor cells.
Survival and tumor progression were analyzed in five large controlled studies, which included a total of 2,833 patients, including four double-blind, placebo-controlled studies and one open-label study. These studies enrolled patients who were receiving chemotherapy (two studies) or patient populations in whom erythropoiesis stimulating agents are not indicated: cancer patients with anemia not undergoing chemotherapy and patients with head and neck cancer. , undergoing radiotherapy. In two studies, the target hemoglobin concentration was> 13 g / dL; in the remaining studies it was 12-14 g / dL. In the open-label study, no difference in overall survival was found between patients treated with recombinant human erythropoietin versus controls. In the four placebo-controlled studies, the hazard ratio (hazard ratio) for overall survival was between 1.25 and 2.47, in favor of controls. Compared to controls, these studies observed a statistically significant, constant and unexplained increase in mortality in patients with anemia associated with several common malignancies and treated with recombinant human erythropoietin. The overall survival outcomes of the studies could not be satisfactorily explained by the differences in the incidence of thrombosis and associated complications in subjects treated with recombinant human erythropoietin and in control subjects.
A systematic review was also carried out on over 9,000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data provided an estimated hazard ratio of 1.08 in favor of controls (95% CI: 0.99, 1.18; 42 studies and 8 167 patients). An increased relative risk of thromboembolic events was observed in patients treated with recombinant human erythropoietin (RR 1.67, 95% CI: 1.35, 2.06, 35 studies and 6 769 patients). There is an increased risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin and a negative effect on overall survival cannot be excluded. It is not known to what extent these data are attributable to the administration of recombinant human erythropoietin to cancer patients receiving chemotherapy to achieve hemoglobin concentrations below 13 g / dl, as only a few patients with the described characteristics were included in the reviewed data. .
A single patient data analysis was also performed on over 13,900 cancer patients (chemo-radio-, chemoradium-, or no therapy) who participated in 53 controlled clinical trials with different epoetins. overall survival generated a hazard ratio point estimate of 1.06 in favor of controls (95% CI: 1.00, 1.12: 53 trials and 13 933 patients) and for cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10 441 patients). The meta-analysis also supports a consistent and significant increased relative risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin (see section 4.4).
In a randomized, double-blind, placebo-controlled study of 4,038 non-dialysed CRF patients with type 2 diabetes and hemoglobin values ≤ 11 g / dl, patients were treated with either darbepoetin alfa to achieve hemoglobin levels of 13 g / dl or placebo (see section 4.4). The study did not meet any of the primary objectives in demonstrating to reduce the risk of related mortality, cardiovascular morbidity, and development of end-stage renal disease (ESRD). Analyzes of the individual components of the composite endpoints showed an HR ( 95% CI): death 1.05 (0.92, 1.21), stroke 1.92 (1.38, 2.68), congestive heart failure (CHF) 0.89 (0.74, 1.08 ), myocardial infarction (MI) 0.96 (0.75, 1.23), hospitalization for myocardial ischaemia 0.84 (0.55, 1.27), ESRD 1.02 (0.87, 1.18 ).
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 and 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).
05.2 "Pharmacokinetic properties -
Intravenous route of administration
Measurement of erythropoietin after repeated intravenous administration showed a "half-life of approximately 4 hours in healthy volunteers and a" slightly longer half-life in patients with renal insufficiency (approximately 5 hours). A half-life of approximately 6 hours has been reported in children.
Route of subcutaneous administration
Following subcutaneous injection, serum erythropoietin levels are much lower than intravenous levels, slowly increase and peak between 12 and 18 hours after administration. This peak is always well below that reached intravenously (about 1/20).
There is no accumulation phenomena: the concentrations remain the same, whether they are detected 24 hours after the first injection or 24 hours after the last injection.
The half-life is difficult to assess in case of subcutaneous administration and is estimated to be approximately 24 hours. The bioavailability of subcutaneous injectable erythropoietin is much lower than the intravenous medicinal product: approximately 20%.
05.3 Preclinical safety data -
In some preclinical toxicology studies in dogs and rats, but not in monkeys, erythropoietin therapy has been associated with subclinical bone marrow fibrosis (bone marrow fibrosis is a known complication of chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown factors). In a study conducted in hemodialysis patients treated with erythropoietin for 3 years, the incidence of bone marrow fibrosis was not increased compared to a corresponding group of control patients on dialysis but not treated with erythropoietin.
Studies in animals have shown that erythropoietin decreases fetal body weight, delays the ossification process and increases fetal mortality when given at weekly doses approximately 20 times those recommended for humans. These alterations are interpreted as secondary to the reduced increase in maternal body weight.
Erythropoietin showed no activity in mutagenicity tests on bacterial and mammalian cell cultures and in vivo in a mouse micronucleus test. Long-term carcinogenicity studies have not been conducted. There are conflicting data in the literature regarding the possibility that erythropoietin plays an important role in the proliferation of cancer cells. These data are based on results obtained in vitro from human tumor tissue samples; however, their scope in the clinical setting is unclear.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Disodium phosphate dihydrate
Sodium monobasic phosphate dihydrate
Sodium chloride
Calcium chloride dihydrate
Polysorbate 20
Glycine
Leucine
Isoleucine
Threonine
Glutamic acid
Phenylalanine
Water for injectable solutions
Sodium hydroxide (to adjust the pH)
Hydrochloric acid (to adjust the pH)
06.2 Incompatibility "-
In the absence of incompatibility studies, this medicinal product must not be mixed with other products.
06.3 Period of validity "-
30 months
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
Keep the pre-filled syringe in the outer carton to protect the medicine from light.
During 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 -
0.3 ml solution in type I glass pre-filled syringe with fixed steel needle and PTFE-lined plunger stopper with or without needle guard.
One pack contains 1 or 6 pre-filled syringes.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Instructions for handling Retacrit:
1. After removing a syringe from the blister, check that the solution is clear, colorless and practically free of visible particles.
2. Remove the needle cover and squeeze the air out of the needle and syringe by holding the syringe upright and gently pushing the plunger up.
3. The syringe is ready for use.
Retacrit should not be used if any of the following occur:
• the blister is open or otherwise damaged;
• the solution is not colorless or contains visible particles in suspension;
• c "liquid has leaked from the pre-filled syringe or condensation is visible inside the blister which is still sealed;
• the medicine was accidentally frozen.
This medicine is intended for single use only.
Don't shake.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Hospira UK Limited
Horizon
Honey Lane
Hurley
Maidenhead
SL6 6RJ
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/07/431/001 pre-filled syringe
EU / 1/07/431/002 pre-filled syringe
EU / 1/07/431/026 pre-filled syringe with needle shield
EU / 1/07/431/027 pre-filled syringe with needle shield
038381012
038381024
038381265
038381277
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 18 December 2007
Date of last renewal: November 15, 2012
10.0 DATE OF REVISION OF THE TEXT -
D.CCE September 2016
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -
