Binocrit - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Epoetin alfa

Binocrit 1,000 IU / 0.5 mL solution for injection in a pre-filled syringe
Binocrit 2,000 IU / 1 mL solution for injection in a pre-filled syringe
Binocrit 3,000 IU / 0.3 mL solution for injection in a pre-filled syringe
Binocrit 4,000 IU / 0.4 mL solution for injection in a pre-filled syringe
Binocrit 5,000 IU / 0.5 mL solution for injection in a pre-filled syringe
Binocrit 6,000 IU / 0.6 mL solution for injection in a pre-filled syringe
Binocrit 7,000 IU / 0.7 mL solution for injection in a pre-filled syringe
Binocrit 8,000 IU / 0.8 mL solution for injection in a pre-filled syringe
Binocrit 9,000 IU / 0.9 mL solution for injection in a pre-filled syringe
Binocrit 10,000 IU / 1 mL solution for injection in a pre-filled syringe
Binocrit 20,000 IU / 0.5 mL solution for injection in a pre-filled syringe
Binocrit 30,000 IU / 0.75 mL solution for injection in a pre-filled syringe
Binocrit 40,000 IU / 1 mL solution for injection in a pre-filled syringe

Indications Why is Binocrit used? What is it for?

Binocrit contains the active substance epoetin alfa, a protein that stimulates the bone marrow to produce more red blood cells that carry hemoglobin (a substance that carries oxygen).

Epoetin alfa is a copy of the human protein erythropoietin and works in the same way.

Binocrit is used to treat symptomatic anemia caused by kidney disease:

  • in children undergoing hemodialysis
  • in adults undergoing hemodialysis or peritoneal dialysis,
  • in severely anemic adults not yet on dialysis.

In the case of kidney disease, you may have a shortage of red blood cells if the kidney does not produce enough erythropoietin (necessary for the production of red blood cells). Binocrit is prescribed to stimulate the bone marrow to produce more red blood cells.

Binocrit is used to treat anemia when you are receiving chemotherapy for solid tumors, malignant lymphoma or multiple myeloma (bone marrow cancer) and if your doctor decides you may need a blood transfusion. Binocrit may reduce the need for blood transfusions. blood.

Binocrit is used in moderately anemic people who donate some of their blood before surgery so that the collected blood can be given to them during or after surgery. Because Binocrit stimulates the production of red blood cells, doctors can draw more blood from these people.

Binocrit is used in moderately anemic adults who are about to have major orthopedic surgery (such as hip or knee replacement surgery) to reduce the potential need for blood transfusions.

Contraindications When Binocrit should not be used

Do not use Binocrit

  • if you are allergic to epoetin alfa or any of the other ingredients of this medicine (listed in section 6).
  • if you have been diagnosed with 'pure red blood cell aplasia (the bone marrow cannot make enough red blood cells) following treatment with any medicine that stimulates red blood cell production (including Binocrit). See section 4.
  • if you have high blood pressure which is not sufficiently controlled with medicines.
  • to stimulate the production of red blood cells (so doctors can draw more blood from you) if you cannot receive transfusions with your own blood during or after surgery.
  • if you are about to have major elective orthopedic surgery (such as hip or knee surgery) and:
    • have severe heart disease
    • have severe vein or artery disease
    • have recently had a heart attack or stroke
    • cannot take medicines to thin the blood Binocrit may not be suitable for you. Discuss this with your doctor.

Some people need medicines to reduce the risk of blood clots while being treated with Binocrit. If you cannot take medicines that prevent blood clots, you should not take Binocrit.

Precautions for use What you need to know before you take Binocrit

Talk to your doctor, pharmacist or nurse before using Binocrit.

Binocrit and other products that stimulate the production of red blood cells may increase the risk of 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 if you are overweight, have diabetes, have heart disease or need to lie down for a while. long term due to surgery or illness). Tell your doctor about any such situation. Your doctor will help you decide if Binocrit is right for you.

It is important that you tell your doctor if any of the following apply to you.

You may be able to use Binocrit anyway, but you need to talk to your doctor first.

If you know that you are in pain or have suffered in the past from:

  • high blood pressure;
  • convulsions or seizures;
  • liver disease;
  • anemia from other causes;
  • porphyria (a rare blood disorder).

If you are a cancer patient, be aware that medicines that stimulate the production of red blood cells (such as Binocrit) can act as growth factors and therefore could theoretically affect the progression of the tumor.

Depending on your personal situation, a blood transfusion may be preferable. Discuss this with your doctor.

If you have hepatitis C and receive interferon and ribavirin, you should discuss this with your doctor because the combination of epoetin alfa with interferon and ribavirin has in rare cases caused a reduction in the effect of the treatment and a condition called pure red cell aplasia (PRCA), a severe form of anemia. Binocrit is not approved for the treatment of anemia associated with hepatitis C.

If you are a patient with chronic renal failure, and in particular if you do not respond adequately to Binocrit, your doctor will check the dose of Binocrit you receive because repeatedly increasing the dose of Binocrit if it does not respond to treatment may increase the risk of problems. to the heart or blood vessels and the risk of myocardial infarction, stroke and death.

Take special care with other products that stimulate the production of red blood cells: Binocrit belongs to a group of products which, like the human protein erythropoietin, stimulate the production of red blood cells. Your healthcare professional will always make a note of the specific product you are using. If you are given any medicine from this group, other than Binocrit, during your treatment, talk to your doctor or pharmacist before using it.

Interactions Which drugs or foods may change the effect of Binocrit

Binocrit does not usually react with other medicines, but tell your doctor if you are using, have recently used or might use any other medicines, including those obtained without a prescription.

If you take a medicine called cyclosporine (used, for example, after kidney transplants), your doctor may have blood tests done to measure your cyclosporine levels while you are taking Binocrit.

Iron supplements and other blood stimulants can increase the effectiveness of Binocrit. Your doctor will decide if it is right for you to take them.

If you go to a hospital, clinic or family doctor, tell them that you are being treated with Binocrit. This could 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 apply to you.

You may be able to use Binocrit anyway, but you should first discuss this with your doctor:

  • if you are pregnant or if you suspect a pregnancy.
  • if you are breastfeeding.

Binocrit contains sodium

Binocrit contains less than 1 mmol (23 mg) sodium per dose, ie it is essentially "sodium-free".

Dose, Method and Time of Administration How to use Binocrit: Posology

Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor.

The doctor ran a blood test and decided you need Binocrit.

Binocrit can be given by injection:

  • into a vein or tube that goes into a vein (intravenously)
  • or under the skin (subcutaneously).

Your doctor will decide how Binocrit will be injected. Usually, injections are given by a doctor, nurse, or other healthcare professional. Some people, depending on why they need treatment with Binocrit, may later learn how to inject it under the skin: see Instructions for self-injecting Binocrit at the end of this package leaflet.

Binocrit must not be used:

  • after the expiry date shown on the label and outer packaging
  • if you know or believe that it has been accidentally frozen or
  • if a refrigerator failure has occurred.

The dose of Binocrit that you will be given depends on your body weight in kilograms. The cause of the anemia is also important for the doctor to choose the correct dose.

Your doctor will check your blood pressure regularly during Binocrit therapy.

People with kidney disease

  • Your doctor will keep your hemoglobin level between 10 and 12 g / dL, as a high hemoglobin level could increase the risk of blood clots and death.
  • The usual starting dose of Binocrit in adults and children is 50 International Units (IU) per kilogram (/ kg) of body weight, given three times per week. In patients undergoing peritoneal dialysis, Binocrit can be administered twice a week.
  • In adults and children, Binocrit is given as an injection into a vein (intravenously) or into a tube that goes into a vein. When this access (through a vein or tube) is not readily available, the doctor may decide to inject Binocrit under the skin (subcutaneously). This affects dialysis patients and patients not yet on dialysis.
  • Your doctor will order blood tests on a regular basis to see how the anemia responds to therapy and may adjust the dose, usually every four weeks at the latest.
  • Once the anemia has been corrected, your doctor will continue to check your blood regularly. The dosage and frequency of administration of Binocrit may be further adjusted to maintain your response to treatment. Your doctor will use the lowest effective dose to control your symptoms. anemia.
  • If you do not respond adequately to Binocrit, your doctor will check the dose you are receiving and will inform you if your Binocrit doses need to be changed.
  • If you are using a longer interval (greater than once a week) between doses of Binocrit, you may not be able to maintain adequate hemoglobin levels and may need to increase the dose or frequency of Binocrit administration.
  • You may also receive iron supplementation before and during treatment with Binocrit to increase the effectiveness of the treatment.
  • If you are on dialysis when you start Binocrit treatment, your dialysis schedule may need to be changed. The doctor will decide on this.

Adults on chemotherapy

  • Your doctor may start Binocrit therapy if your hemoglobin is 10 g / dL or less.
  • Your doctor will keep your hemoglobin level between 10 and 12 g / dL, as a high hemoglobin level can increase the risk of blood clots and death.
  • The usual starting dose is 150 IU per kilogram of body weight three times a week or 450 IU per kilogram of body weight once a week.
  • Binocrit is given by injection under the skin.
  • Your doctor will order blood tests and may adjust the dose depending on how your anemia responds to treatment.
  • You may also receive iron supplementation before and during treatment with Binocrit to increase the effectiveness of the treatment.
  • Treatment with Binocrit will usually continue for one month after the end of chemotherapy.

Adults who donate their own blood

  • The usual dose is 600 IU per kilogram of body weight, twice a week.
  • Binocrit is given by injection into a vein, immediately after donating blood, for 3 weeks before surgery.
  • You may also receive iron supplementation before and during treatment with Binocrit to increase the effectiveness of the treatment. Adults scheduled for major orthopedic surgery
  • The recommended dose is 600 IU per kilogram of body weight once a week.
  • Binocrit is given by injection under the skin every week for three weeks prior to surgery and on the day of surgery.
  • If there is a need to shorten the time before surgery, a daily dose of 300 IU / kg is administered for a maximum of ten days before surgery, on the day of surgery and in the following four days.
  • If blood tests show hemoglobin values ​​too high before surgery, treatment will be stopped.
  • You may receive iron supplementation before and during treatment with Binocrit to increase the effectiveness of the treatment.

Instructions for injecting Binocrit under the skin

At the start of treatment, Binocrit is usually injected by medical or paramedical staff. Thereafter, your doctor may suggest that you, or a caregiver, learn how to inject Binocrit under the skin (subcutaneously) on their own.

  • Do not try to inject yourself with this medicine unless your doctor or nurse has shown you how.
  • Always use Binocrit exactly as directed by your doctor or nurse.
  • Be sure to inject only the amount of liquid indicated by your doctor or nurse.
  • Only use Binocrit if it has been stored correctly - see section 5, How to store Binocrit.
  • Before use, let the Binocrit syringe rest until it reaches room temperature. This usually takes 15-30 minutes. Use the syringe within 3 days of taking it out of the refrigerator.

Take only one dose of Binocrit from each syringe.

If Binocrit is injected under the skin (subcutaneously), the injected volume generally does not exceed one milliliter (1 mL) per single injection.

Binocrit is given alone and not mixed with other injectable liquids.

Do not shake the Binocrit syringes. Prolonged vigorous shaking may damage the product. If the product has been shaken vigorously, do not use it.

Binocrit self-injection instructions are provided at the end of this package leaflet.

If you forget to use Binocrit

Give the next injection as soon as you remember. If it is less than a day until the next injection, skip the missed injection and continue with your normal schedule. Do not inject a double dose.

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.

Overdose What to do if you have taken too much Binocrit

Tell your doctor or nurse immediately if you believe that too much Binocrit has been injected. Side effects are unlikely to occur if you overdose with Binocrit.

Side Effects What are the side effects of Binocrit

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately if you notice any of the side effects listed.

Very common side effects

They may affect more than 1 in 10 people using Binocrit.

  • Diarrhea
  • Nausea
  • He retched
  • Fever
  • Respiratory tract congestion, such as stuffy nose and sore throat, has been reported in patients with kidney disease and not yet on dialysis.

Common side effects

These may affect up to 1 in 10 people using Binocrit.

  • Increased blood pressure. The following signs may indicate a sudden increase in blood pressure: headache, particularly if a sudden onset and stabbing type similar to migraine, confusion or seizures. These signs require urgent treatment. The increase in blood pressure blood may need treatment with other medicines (or an adjustment in the dosage of medicines you are already taking for high blood pressure).
  • Blood clots (including deep vein thrombosis and embolism) which may require urgent intervention. Symptoms may include chest pain, breathlessness and swelling with pain and redness, usually in the legs.
  • Cough.
  • Skin rash, which may be due to an allergic reaction.
  • Pain in the bones or muscles.
  • Flu-like symptoms such as headache, aches and pains in the joints, feeling of weakness, chills, tiredness and dizziness. These symptoms may be more common at the start of treatment. If you experience these symptoms while injecting into the vein, a slower injection 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 may affect up to 1 in 100 people using Binocrit.

  • High levels of potassium in the blood, which can lead to abnormal heart rhythms (this is a very common side effect in dialysis patients).
  • Convulsions.
  • Congestion of the nose or airways.

Very rare side effects

These may affect up to 1 in 10,000 people who use Binocrit.

  • Symptoms of Pure Red Cell Aplasia (PRCA) Pure Red Cell Aplasia (PRCA) means that the bone marrow does not make enough red blood cells. PRCA causes "sudden and severe anemia. The symptoms are:
    • unusual tiredness,
    • feeling dizzy,
    • breathlessness.

PRCA has been reported very rarely, especially in patients with kidney disease, after months or years of treatment with epoetin alfa and other medicines that stimulate red blood cell production.

  • Particularly at the beginning of treatment, there may be an increase in the number of some small blood cells (called platelets), which are normally involved in the formation of clots. Your doctor will carry out the relevant checks.

If you are on hemodialysis:

  • Clots (thrombosis) can form in the dialysis fistula. This is more likely to happen if you have low blood pressure or if there are complications with the fistula.
  • Clots can also form in the hemodialysis system. The doctor may decide to increase the dose of heparin during dialysis.

Tell your doctor or nurse immediately if you notice any of these effects or if you notice any other effects while taking Binocrit.

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.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the label after "EXP" and on the carton after "EXP."
  • Store and transport refrigerated (2 ° C - 8 ° C).
  • You can take Binocrit out of the refrigerator and store it at room temperature (up to 25 ° C) for up to 3 days. Once the syringe has been removed from the refrigerator and has reached room temperature (up to 25 ° C) it must be used within 3 days or thrown away.
  • Do not freeze or shake.
  • Store in the original package to protect the medicine from light.

Do not use this medicine if you notice

  • which has been accidentally frozen or
  • that a refrigerator failure has occurred
  • that the liquid is colored or if it sees particles floating in it
  • that the seal is broken.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Binocrit contains

  • The active substance is epoetin alfa (for quantity see table below).
  • The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorbate 80, hydrochloric acid (to adjust pH), sodium hydroxide (to adjust pH), water for injections.

What Binocrit looks like and contents of the pack

Binocrit is presented as a clear and colorless solution for injection in a pre-filled syringe. The syringes are sealed in blisters.

Formulation Corresponding formulations in quantity / volume for each dosage Amount of epoetin alfa Pre-filled syringes * 2,000 IU / mL: 1,000 IU / 0.5 mL 2,000 IU / 1 mL 10,000 IU / mL: 3,000 IU / 0.3 mL 4,000 IU / 0.4 mL 5,000 IU / 0.5 mL 6,000 IU / 0.6 mL 7,000 IU / 0.7 mL 8,000 IU / 0.8 mL 9,000 IU / 0.9 mL 10,000 IU / 1 mL 40,000 IU / mL: 20,000 IU / 0 5 mL 30,000 IU / 0.75 mL 40,000 IU / 1 mL 8.4 micrograms 16.8 micrograms 25.2 micrograms 33.6 micrograms 42.0 micrograms 50.4 micrograms 58.8 micrograms 67.2 micrograms 75.6 micrograms 84.0 micrograms 168.0 micrograms 252.0 micrograms 336.0 micrograms

* Packs of 1, 4 or 6 pre-filled syringes with or without needle safety guard.

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.

Further information on Binocrit can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

BINOCRIT SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Binocrit 1,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each mL of solution contains 2,000 IU of epoetin alfa *, corresponding to 16.8 mcg per mL

One 0.5 mL pre-filled syringe contains 1,000 international units (IU), corresponding to 8.4 mcg of epoetin alfa. *

Binocrit 2,000 IU / 1 mL solution for injection in a pre-filled syringe

Each mL of solution contains 2,000 IU of epoetin alfa *, corresponding to 16.8 mcg per mL

One 1 mL pre-filled syringe contains 2,000 international units (IU), corresponding to 16.8 mcg of epoetin alfa. *

Binocrit 3,000 IU / 0.3 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.3 mL pre-filled syringe contains 3,000 international units (IU), corresponding to 25.2 mcg of epoetin alfa. *

Binocrit 4,000 IU / 0.4 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.4 mL pre-filled syringe contains 4,000 international units (IU), corresponding to 33.6 mcg of epoetin alfa. *

Binocrit 5,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.5 mL pre-filled syringe contains 5,000 international units (IU), corresponding to 42.0 mcg of epoetin alfa. *

Binocrit 6,000 IU / 0.6 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.6 mL pre-filled syringe contains 6,000 international units (IU), corresponding to 50.4 mcg of epoetin alfa. *

Binocrit 7,000 IU / 0.7 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.7 mL pre-filled syringe contains 7,000 international units (IU), corresponding to 58.8 mcg of epoetin alfa. *

Binocrit 8,000 IU / 0.8 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.8 mL pre-filled syringe contains 8,000 international units (IU), corresponding to 67.2 mcg of epoetin alfa. *

Binocrit 9,000 IU / 0.9 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 0.9 mL pre-filled syringe contains 9,000 international units (IU), corresponding to 75.6 mcg of epoetin alfa. *

Binocrit 10,000 IU / 1 mL solution for injection in a pre-filled syringe

Each mL of solution contains 10,000 IU of epoetin alfa *, corresponding to 84.0 mcg per mL

One 1 mL pre-filled syringe contains 10,000 international units (IU), corresponding to 84.0 mcg of epoetin alfa. *

Binocrit 20,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each mL of solution contains 40,000 IU of epoetin alfa *, corresponding to 336.0 mcg per mL

One 0.5 mL pre-filled syringe contains 20,000 international units (IU), corresponding to 168.0 mcg of epoetin alfa. *

Binocrit 30,000 IU / 0.75 mL solution for injection in a pre-filled syringe

Each mL of solution contains 40,000 IU of epoetin alfa *, corresponding to 336.0 mcg per mL

One 0.75 mL pre-filled syringe contains 30,000 international units (IU), corresponding to 252.0 mcg of epoetin alfa. *

Binocrit 40,000 IU / 1 mL solution for injection in a pre-filled syringe

Each mL of solution contains 40,000 IU of epoetin alfa *, corresponding to 336.0 mcg per mL

One 1 mL pre-filled syringe contains 40,000 international units (IU), corresponding to 336.0 mcg of epoetin alfa. *

* Produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology

For the full list of excipients, see section 6.1.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, ie it is essentially "sodium-free".

03.0 PHARMACEUTICAL FORM -

Solution for injection in pre-filled syringe (injection)

Clear and colorless solution

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Binocrit is indicated for the treatment of symptomatic anemia associated with chronic renal failure (CRI):

• in hemodialysis adults and children aged 1 to 18 years and adult patients undergoing peritoneal dialysis (see section 4.4).

• in adult patients with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms (see section 4.4).

Binocrit is indicated in adults 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 transfusion requirements.

Binocrit is indicated in adults who are part of an autologous predonation program to increase the production of autologous blood.Treatment should only be carried out in patients with moderate anemia (hemoglobin [Hb] concentration range between 10 and 13 g / dL [6.2 and 8.1 mmol / L], without iron deficiency), when blood-saving techniques are not available or insufficient and planned major elective surgery requires a large amount of blood (4 or more units of blood for women, 5 or more units for men).

Binocrit is indicated in non-iron deficient adults, believed to be at high risk of transfusion complications, prior to major elective orthopedic surgery, to reduce exposure to allogeneic blood transfusions. Limit use to patients with moderate anemia (concentration range hemoglobin between 10 and 13 g / dL or between 6.2 and 8.1 mmol / L) not part of an autologous predonation program and for which moderate blood loss is expected (900-1,800 mL).

04.2 Posology and method of administration -

Binocrit therapy should be initiated under the supervision of physicians experienced in the treatment of patients with the above indications.

Dosage

All other causes of anemia (iron, 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 therapy. with epoetin alfa and when deciding on a dose increase. To ensure an optimal response to epoetin alfa, it is necessary to ensure that adequate iron stores exist and, if necessary, to administer an iron supplement (see section 4.4).

Treatment of symptomatic anemia in adult patients with chronic renal failure

The symptoms and consequences of anemia may vary according to age, sex and medical comorbidities; an individual assessment of the clinical course and condition of each individual patient is required by the physician.

The recommended desired hemoglobin concentration range is 10 g / dL to 12 g / dL (6.2 to 7.5 mmol / L). Binocrit should be administered so that hemoglobin values ​​do not increase beyond 12 g / dL (7.5 mmol / L). A rise in hemoglobin greater than 2 g / dL (1.25 mmol / L) over a period of weeks should be avoided. If this occurs, dose adjustment should be made. appropriate.

Due to intra-patient variability, individual hemoglobin values ​​above and below the desired hemoglobin concentration range may occasionally be observed. 10 g / dL (6.2 mmol / L) and 12 g / dL (7.5 mmol / L).

Prolonged hemoglobin levels above 12 g / dL (7.5 mmol / L) should be avoided. If hemoglobin increases by more than 2 g / dL (1.25 mmol / L) per month, or if you have sustained hemoglobin levels above 12 g / dL (7.5 mmol / L), reduce the dose of Binocrit by 25%. If hemoglobin exceeds 13 g / dL (8.1 mmol / L), discontinue therapy until values ​​drop below 12 g / dL (7.5 mmol / L) and then resume treatment. with Binocrit at a dose 25% lower than the previous dose.

Patients should be closely monitored to ensure that the lowest approved effective dose of Binocrit is used for adequate control of anemia and symptoms of anemia, while maintaining a hemoglobin concentration below or equal to 12 g / dL (7.45 mmol /L).

Use caution in increasing doses of Binocrit in patients with chronic renal failure. In patients with poor hemoglobin response to Binocrit, alternative explanations for the poor response should be considered (see sections 4.4 and 5.1).

Treatment with Binocrit consists of two phases: the correction phase and the maintenance phase.

Adult hemodialysis patients

In hemodialysis patients where intravenous access is readily available, intravenous administration is preferable.

Correction phase

The starting dose is 50 IU / kg, three times per week.

If necessary, increase or decrease the dose by 25 IU / kg (three times per week) until the desired hemoglobin concentration range is reached, between 10 g / dL and 12 g / dL (between 6.2 and 7.5 mmol / L) (this should happen gradually at intervals of at least four weeks).

Maintenance phase

The recommended total weekly dose is between 75 IU / kg and 300 IU / kg.

Adequate dose adjustment should be made to maintain hemoglobin values ​​within the desired concentration range of 10 g / dL to 12 g / dL (6.2 to 7.5 mmol / L).

Patients with initially very low hemoglobin values ​​(8 g / dL or> 5 mmol / L).

Adult patients with renal insufficiency not yet on dialysis

Where intravenous access is not readily available, Binocrit can be administered subcutaneously.

Correction phase

Initial dose of 50 IU / kg, 3 times per week, followed, if necessary, by increments of 25 IU / kg (3 times per week) until the desired value is reached (this should be done gradually at intervals of at least four weeks).

Maintenance phase

During the maintenance phase, Binocrit can be administered 3 times per week or, in the case of subcutaneous administration, once a week or once every 2 weeks.

Appropriate adjustment of dose and dosage intervals should be made to maintain hemoglobin values ​​at the desired level: hemoglobin between 10 g / dL and 12 g / dL (6.2 to 7.5 mmol / L). Extending the interval between doses may require an increase in dosage.

The maximum dosage 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 undergoing peritoneal dialysis

Where intravenous access is not readily available, Binocrit 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, in 2 equal injections.

Adequate dose adjustment should be made to maintain hemoglobin values ​​at the desired level, between 10 g / dL and 12 g / dL (6.2 to 7.5 mmol / L).

Treatment of adult patients with chemotherapy-induced anemia

The symptoms and consequences of anemia may vary according to age, sex and overall severity of the disease; an individual assessment of the clinical course and condition of each individual patient is required by the physician.

Binocrit should be administered to anemic patients (e.g. with hemoglobin concentration ≤ 10 g / dL (6.2 mmol / L)).

The starting dose is 150 IU / kg subcutaneously, 3 times per week.

Alternatively, Binocrit can be administered at an initial dose of 450 IU / kg subcutaneously once weekly.

Adequate dose adjustment should be made to maintain hemoglobin values ​​within the desired concentration range of 10 g / dL to 12 g / dL (6.2 to 7.5 mmol / L).

Due to intra-patient variability, single hemoglobin concentrations above and below the desired hemoglobin concentration range may occasionally be observed. It is recommended that hemoglobin variability be addressed through optimal dose management, taking into account the hemoglobin concentration range. 10 g / dL (6.2 mmol / L) to 12 g / dL (7.5 mmol / L) desired Prolonged hemoglobin concentrations above 12 g / dL (7.5 mmol / L) should be avoided; guidelines for appropriate dose adjustment for hemoglobin concentrations above 12 g / dL (7.5 mmol / L) are described below.

• If 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 above baseline after four weeks of treatment, a dose of 150 IU / kg three times per week or 450 IU / kg once per week should be maintained.

• If the increase in hemoglobin concentration is

• If the increase in hemoglobin concentration is

Dose adjustment to maintain a hemoglobin concentration between 10 g / dL and 12 g / dL (between 6.2 and 7.5 mmol / L)

If the hemoglobin concentration increases by more than 2 g / dL (1.25 mmol / L) per month, or if the hemoglobin concentration level exceeds 12 g / dL (7.5 mmol / L), reduce the Binocrit dose of about 25-50%.

If the hemoglobin concentration level exceeds 13 g / dL (8.1 mmol / L), discontinue therapy until values ​​drop below 12 g / dL (7.5 mmol / L) and then resume treatment with Binocrit at a dose 25% lower than the previous dose.

The recommended dosing regimen is shown in the following table:

150 IU / kg 3x / week or 450 IU / kg once a week for 4 weeks ↓ ↓ Reticulocyte count increased ≥ 40,000 / mcL or Hb increase ≥ 1 g / dL Increased reticulocyte count ↓ ↓ Target Hb (≤ 12 g / dL) 300 IU / kg 3x / week for 4 weeks ↑ ← ↓ Reticulocyte count increased ≥ 40,000 / mcL or Hb increase ≥ 1 g / dL Increased reticulocyte count ↓ Discontinuation of therapy

Patients should be closely monitored to ensure that the lowest approved dose of the erythropoiesis stimulating agent (erythropoiesis-stimulating agent, ESA) for adequate control of the symptoms of anemia.

Epoetin alfa therapy should continue for up to one month after the end of chemotherapy.

Treatment of adult surgical patients participating in an autologous predonation program

Patients with mild anemia (hematocrit between 33 and 39%), who require pre-deposition of 4 or more units of blood, should be treated with 600 IU / kg of Binocrit intravenously, twice a week, over three weeks. prior to surgery. Binocrit should be administered after the donation procedure has been completed.

Treatment of adult patients scheduled for major elective orthopedic surgery

The recommended dose is 600 IU / kg of Binocrit, administered subcutaneously once weekly for three weeks (days -21, -14 and -7) before surgery and on the day of surgery (day 0).

In cases where, for medical reasons, it is necessary to reduce the time to surgery to less than three weeks, 300 IU / kg of Binocrit should be administered subcutaneously for 10 consecutive days prior to surgery, on the day of surgery and in the four days immediately following.

If the hemoglobin level reaches or exceeds 15 g / dL (9.38 mmol / L) in the preoperative period, Binocrit should be discontinued and subsequent dosages should not be administered.

Pediatric population

Treatment of symptomatic anemia in patients with chronic renal failure on hemodialysis

The symptoms and consequences of anemia may vary according to age, sex and medical comorbidities; an individual assessment of the clinical course and condition of each individual patient is required by the physician.

In pediatric patients, the recommended hemoglobin concentration range is 9.5 g / dL to 11 g / dL (5.9 to 6.8 mmol / L). Binocrit should be administered so that the hemoglobin values do not increase above 11 g / dL (6.8 mmol / L). An increase in hemoglobin of greater than 2 g / dL (1.25 mmol / L) over a four-week period should be avoided. an appropriate dose adjustment should be made.

Patients should be closely monitored to ensure that the lowest approved dose of Binocrit is used for adequate control of anemia and symptoms of anemia.

Treatment with Binocrit consists of two phases: the correction phase and the maintenance phase.

In pediatric patients on hemodialysis where intravenous access is readily available, intravenous administration is preferable.

Correction phase

The starting dose is 50 IU / kg intravenously, 3 times per week.

If necessary, increase or decrease the dose by 25 IU / kg (three times per week) until the desired hemoglobin concentration range is reached, between 9.5 g / dL and 11 g / dL (between 5.9 and 6 , 8 mmol / L) (this should be done gradually at intervals of at least four weeks).

Maintenance phase

Adequate dose adjustment should be made to maintain hemoglobin levels within the desired concentration range of 9.5 g / dL to 11 g / dL (5.9 to 6.8 mmol / L).

Typically, children weighing less than 30 kg need higher maintenance doses than children weighing more than 30 kg and adults.

Pediatric patients with very low baseline hemoglobin values ​​(6.8 g / dL or> 4.25 mmol / L).

Anemia in patients with chronic renal failure before the start of dialysis or undergoing peritoneal dialysis

The safety and efficacy of epoetin alfa in chronic renal failure patients with anemia prior to initiation of dialysis or undergoing peritoneal dialysis have not been established. Currently available data for the subcutaneous use of epoetin alfa in these populations are described in section 5.1, but no recommendation on a posology can be made.

Treatment of pediatric patients with chemotherapy-induced anemia

The safety and efficacy of epoetin alfa in pediatric patients undergoing chemotherapy have not been established (see section 5.1).

Treatment of pediatric surgical patients participating in an autologous predonation program

The safety and efficacy of epoetin alfa in pediatric subjects have not been established. No data are available.

Treatment of pediatric patients awaiting major elective orthopedic surgery

The safety and efficacy of epoetin alfa in pediatric subjects have not been established. No data are available.

Method of administration

Precautions to be taken before handling or administering the medicinal product.

Before use, let the Binocrit syringe rest until it reaches room temperature. This usually takes 15-30 minutes.

As with all other injectable products, check that the solution does not contain particles and does not show discolouration. Binocrit is a sterile but unpreserved product and is for single use only. Administer the required amount.

Treatment of symptomatic anemia in adult patients with chronic renal failure

In chronic renal failure patients where intravenous access is regularly available (hemodialysis patients) intravenous administration of Binocrit is preferable.

Where intravenous access is not readily available, (patients not yet on dialysis and patients undergoing peritoneal dialysis) Binocrit can be administered by subcutaneous injection.

Treatment of adult patients with chemotherapy-induced anemia

Binocrit must be administered by subcutaneous injection.

Treatment of adult surgical patients participating in an autologous predonation program

Binocrit must be administered intravenously.

Treatment of adult patients scheduled for major elective orthopedic surgery

Binocrit must be administered by subcutaneous injection.

Treatment of symptomatic anemia in pediatric patients with chronic renal failure on hemodialysis

In pediatric chronic renal failure patients where intravenous access is regularly available (hemodialysis patients) intravenous administration of Binocrit is preferable.

Intravenous administration

Administer for at least one to five minutes, depending on the total dose. In hemodialysis patients, a bolus can be administered during the dialysis session through a suitable venous access in the dialysis line. Alternatively, the injection can be administered at the end of the dialysis session through the fistula needle tube, followed by 10 mL of isotonic saline to rinse the tube and ensure the product is injected into the circulation (see Posology, "Hemodialysis Adult Patients. ").

In patients reacting to treatment with flu-like symptoms, slower administration is preferable (see section 4.8).

Do not administer Binocrit by intravenous infusion or in combination with other medicinal products in solution (refer to section 6.6 for further information).

Subcutaneous administration

Do not exceed the maximum volume of 1 mL at each injection site. To inject larger volumes, use multiple injection sites.

Administer the injection into the limbs or anterior abdominal wall.

In cases where the physician determines that the patient or their caregiver can safely and effectively administer Binocrit subcutaneously on their own, guidance on the correct dosage and method of administration should be provided.

The "Binocrit self-injection instructions" can be found at the end of the package leaflet.

04.3 Contraindications -

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Do not administer Binocrit or any other erythropoietin to patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin (see section 4.4).

• Uncontrolled hypertension.

• All contraindications associated with autologous blood predonation programs must be respected in patients who are provided with a Binocrit supplement.

The use of Binocrit in patients scheduled for major elective orthopedic surgery, who are not participating in an autologous predonation program, is contraindicated in patients with severe coronary, peripheral arterial, carotid or cerebral vascular disease, including patients with heart attack recent myocardial or cerebrovascular accident.

• Surgical patients who, for whatever reason, cannot receive adequate antithrombotic prophylaxis.

04.4 Special warnings and appropriate precautions for use -

General consideration

In patients treated with epoetin alfa, blood pressure should be carefully monitored and controlled as needed. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or poorly controlled hypertension. Medicinal products may need to be added. o Increase the dose of antihypertensive therapy Discontinue treatment with epoetin alfa if blood pressure cannot be controlled.

Hypertensive crises with encephalopathy and seizures requiring immediate medical attention and intensive care have also occurred during epoetin alfa treatment of patients with previously normal or low blood pressure. migraine-like, which may be a 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 a predisposition to seizure activity, such as CNS infections and brain metastases.

Epoetin alfa should be used with caution in patients with chronic hepatic insufficiency. The safety of epoetin alfa is not established in patients with hepatic dysfunction.

An "increased incidence of vascular thrombotic events (VTE) has been observed in patients treated with ESA (see section 4.8). These include venous and arterial thrombosis and embolisms (including some cases with fatal outcome), such as deep vein thrombosis, pulmonary emboli , retinal thrombosis and myocardial infarction In addition, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and transient ischemic attacks) have been reported.

The reported risk of these VTEs should be carefully weighed against the expected benefits of treatment with epoetin alfa, particularly in patients with pre-existing risk factors for VTE, including obesity and history of VTE (e.g. deep vein thrombosis, pulmonary embolism and cerebrovascular accident).

In all patients, hemoglobin levels should be closely monitored due to the potentially higher risk of thromboembolic events and fatal outcome if patients are treated at hemoglobin levels above the concentration range of the indication.

A moderate dose-dependent increase in platelet counts within the normal range may occur during treatment with epoetin alfa. This increase regresses during continued therapy. In addition, there have been reports of thrombocythaemia above the normal range. It is recommended. to have the platelet count monitored regularly during the first eight weeks of therapy.

All other causes of anemia (iron, 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 therapy. with epoetin alfa and when deciding on a dose increase. In most cases, serum ferritin values ​​decrease at the same time as the hematocrit increases. To ensure an optimal response to epoetin alfa, it is necessary to ensure that adequate iron stores exist and, if necessary, to administer an iron supplement (see section 4.2):

• In chronic renal failure patients, iron administration is recommended (elemental iron, 200 to 300 mg / day orally in adults and 100 to 200 mg / day orally in pediatric subjects) if serum levels of ferritin are less than 100 ng / mL.

• In cancer patients, iron administration (elemental iron, 200 to 300 mg / day orally) is recommended if the transferrin saturation is less than 20%.

• In patients participating in an autologous predonation program, the administration of iron (elemental iron, 200 mg / day orally) must take place several weeks before starting the autologous predonation, in order to form abundant iron deposits before the " initiation of therapy with epoetin alfa, and for the entire duration of therapy with epoetin alfa.

• In patients scheduled for major elective orthopedic surgery, iron administration (elemental iron, 200 mg / day orally) should take place for the entire duration of epoetin alfa therapy. If possible, iron administration it must begin before the start of epoetin alfa therapy in order to form adequate iron stores.

Very rarely, the appearance or exacerbation of porphyria has been observed in patients treated with epoetin alfa. Epoetin alfa should be used with caution in patients with porphyria.

To improve the traceability of erythropoiesis stimulating agents (ESAs), the name of the agent administered must be recorded (or indicated) unambiguously in the patient's health records.

Patients should switch from one ESA to another only under adequate supervision.

Pure Red Cell Aplasia (PRCA)

Antibody-mediated PRCA has been reported after months or years of subcutaneous epoetin treatment, mainly in patients with chronic renal failure. Cases have also been reported in patients with hepatitis C treated with interferon and ribavirin, in the presence of concomitant therapy with ESA. Epoetin alfa is not approved for the treatment of anemia associated with hepatitis C.

In patients in whom there is suddenly a lack of efficacy of therapy, defined by a decrease in hemoglobin (1-2 g / dL or 0.62-1.25 mmol / L per month) with increased transfusion requirements, it should be determined reticulocyte count and typical causes of a non-response should be analyzed (iron, folate or vitamin B12 deficiency, aluminum intoxication, infection or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin).

In the event of paradoxical decrease in hemoglobin and onset of severe anemia associated with low reticulocyte counts, treatment with epoetin alfa should be discontinued and anti-erythropoietin antibodies determined. A bone marrow examination should also be considered for a "possible diagnosis of PRCA.

Other ESA therapies should not be started due to the risk of cross reaction.

Treatment of symptomatic anemia in adult and pediatric patients with chronic renal failure

In chronic renal failure patients treated with epoetin alfa, hemoglobin levels should be measured regularly until a stable level is reached and thereafter at periodic intervals.

In patients with chronic renal failure, 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 worsening of hypertension.

In patients with chronic renal failure, maintenance hemoglobin concentration should not exceed the upper limit of the hemoglobin concentration range, as recommended in section 4.2. An increased risk of death and serious cardiovascular events was observed in clinical trials. of administration of ESA to achieve a hemoglobin concentration level 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.

Caution should be exercised in increasing doses of Binocrit 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 the poor response should be considered (see sections 4.2 and 5.1).

Chronic renal failure patients treated with subcutaneous epoetin alfa should be monitored periodically for loss of efficacy, defined as no or reduced response to epoetin alfa treatment in patients who previously responded to such therapy. This condition is characterized by a prolonged decrease in hemoglobin despite an increase in the dose of epoetin alfa (see section 4.8).

Some patients using longer intervals between epoetin alfa doses (greater than once weekly) may fail to maintain adequate hemoglobin levels (see section 5.1) and may require an increase in the dose of epoetin alfa. Hemoglobin levels should be monitored regularly.

Shunt thrombosis has occurred in hemodialysis patients, particularly in patients with a tendency to hypotension or with complications of arteriovenous fistulas (eg stenosis, aneurysms, etc.). In these patients, early revision of the shunt and an early revision of the shunt are recommended. antithrombotic prophylaxis, for example with acetylsalicylic acid.

Hyperkalaemia has been observed in isolated cases, although a causal link has not been established. In patients with chronic renal failure, serum electrolytes should be monitored. In the presence of an elevated or rising serum potassium level, in addition to appropriate treatment of hyperkalaemia, consideration should be given to discontinuing administration of epoetin alfa until the serum potassium level is corrected.

Due to the increased hematocrit, an increase in the dose of heparin during hemodialysis is often necessary during therapy with epoetin alfa. If the heparinization is not optimal it is possible that an occlusion of the dialysis system occurs.

Based on the information currently available, correction of anemia with epoetin alfa in adult patients with renal insufficiency not yet undergoing dialysis does not accelerate the progression of renal insufficiency.

Treatment of patients with chemotherapy-induced anemia

In cancer patients treated with epoetin alfa, hemoglobin levels should be measured regularly until a stable level is reached and thereafter at periodic intervals.

Epoetins are growth factors that primarily stimulate the production of erythrocytes. Erythropoietin receptors can be expressed on the surface of a variety of cancer cells. As with all growth factors, there is concern that epoetins may stimulate tumor growth. The role of ESAs on tumor progression cannot be ruled out. on reduced progression-free survival. In controlled clinical trials, the use of epoetin alfa and other ESAs was associated with a reduction in locoregional tumor control or a reduction in overall survival:

• reduced locoregional control in patients with advanced head and neck cancer treated with radiotherapy, when administered to achieve a hemoglobin concentration level above 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 a hemoglobin concentration range of 12-14 g / dL (7.5- 8.7 mmol / L),

• an increased risk of death when administered to achieve a hemoglobin concentration level of 12 g / dL (7.5 mmol / L) in patients with active malignancies, not treated with either chemotherapy or radiotherapy. The use of ESA is not indicated in this patient population.

• a 9% increased risk of disease progression (PD) or death in the epoetin alfa and standard therapy (SOC) group and a 15% increased risk, which cannot be statistically excluded in patients with metastatic breast cancer treated with chemotherapy when administered to achieve a hemoglobin concentration range of 10-12 g / dL (6.2-7.5 mmol / L).

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 treat with recombinant erythropoietin should be based on an assessment of the benefit-balance. risk with the involvement of the individual patient and should take into account the specific clinical context. Factors to be considered in this assessment should include the type of cancer and its stage, the degree of anemia, the "life expectancy," environment in which the patient is treated and the patient's preferences (see section 5.1).

In cancer patients receiving chemotherapy, the 2-3 week interval between ESA administration and the appearance of erythropoietin-induced erythrocytes should be taken into account when assessing the appropriateness of epoetin alfa therapy (patients at risk for transfusion).

Surgical patients participating in autologous predonation programs

All special warnings and precautions relating to autologous predonation programs must be observed; in particular, volume replacement must be performed routinely.

Patients scheduled for major elective orthopedic surgery

Always follow good blood management practices in the perioperative period.

Patients scheduled for major elective orthopedic surgery should receive "adequate antithrombotic prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in patients with underlying cardiovascular disease. Special attention should also be paid. caution in patients predisposed to developing DVT (deep vein thrombosis). Furthermore, in patients with baseline hemoglobin> 13 g / dL (> 8.1 mmol / L), the possibility cannot be excluded that treatment with epoetin alfa may be associated with an increased risk of post-operative thrombotic / vascular events. Therefore, epoetin alfa should not be used in patients with baseline hemoglobin> 13 g / dL (> 8.1 mmol / L).

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per pre-filled syringe, ie it is essentially "sodium-free".

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 medicinal products.

Medicines that reduce erythropoiesis may reduce the response to epoetin alfa.

Since cyclosporine is bound by erythrocytes, the potential for drug interactions exists. If epoetin alfa is administered concomitantly with ciclosporin, blood levels of ciclosporin should be monitored and the dose of ciclosporin adjusted as the hematocrit increases.

There is no evidence to indicate an "interaction between epoetin alfa and granulocyte colony stimulating factor (G-CSF) or granulocyte and macrophage colony stimulating factor (GM-CSF) with respect to haematological differentiation or proliferation in tumor biopsy specimens. in vitro.

In adult patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU / mL epoetin alfa with 6 mg / kg of trastuzumab had no effect on the pharmacokinetics of trastuzumab.

04.6 Pregnancy and breastfeeding -

Pregnancy

There are no or limited data from the use of epoetin alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Therefore, epoetin alfa should only be used in pregnancy if the potential benefit outweighs the potential risk to the fetus. The use of epoetin alfa is not recommended in pregnant surgical patients who are part of an autologous predonation program.

Feeding time

It is not known whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should be used with caution in breastfeeding women. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from epoetin alfa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

The use of epoetin alfa is not recommended in lactating surgical patients participating in an autologous predonation program.

Fertility

There are no studies to determine 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 and use machines have been performed. Binocrit has no or negligible influence on the ability to drive or use machines.

04.8 Undesirable effects -

Summary of the safety profile

The most frequent adverse drug reaction during treatment with epoetin alfa is dose-dependent increases in blood pressure or worsening of pre-existing hypertension.Blood pressure should be monitored, particularly at the initiation of therapy (see section 4.4).

The most frequent adverse drug reactions observed in clinical studies with epoetin alfa are the following: diarrhea, nausea, vomiting, pyrexia and headache. Influenza-like illness can occur particularly at the start of treatment.

Respiratory tract congestion, including events of upper respiratory tract congestion, nasal congestion and nasopharyngitis, has been reported in studies with extended dose intervals in adult patients with renal insufficiency and not yet undergoing dialysis.

An "increased incidence of vascular thrombotic events (TVE) has been observed in patients treated with ESA (see section 4.4).

Table of adverse reactions

Out of a total of 3,262 subjects included in 23 randomized, double-blind, placebo- or standard-care-controlled studies, the overall safety profile of epoetin alfa was evaluated in 1,992 anemic subjects. 228 subjects with chronic renal failure treated were included. with epoetin alfa in 4 chronic renal failure studies (2 studies in pre-dialysis [N = 131 exposed subjects with chronic renal insufficiency] and 2 on dialysis [N = 97 exposed subjects with chronic renal insufficiency]; 1,404 cancer subjects exposed in 16 studies on anemia due to chemotherapy; 147 subjects exposed in 2 autologous blood donation studies and 213 subjects exposed in 1 perioperative study. Adverse drug reactions reported by ≥ 1% of subjects treated with epoetin alfa in these studies are shown in the table below.

Frequency estimate: very common (≥ 1/10); common (≥ 1/100,

System and organ classification Frequency Very common common Uncommon Rare Very rare Not known Disorders of the blood and lymphatic system Pure red cell aplasia mediated by anti-erythropoetin antibodies1,4, thrombocythaemia¹ Metabolism and nutrition disorders Hyperkalemia² Disorders of the immune system Anaphylactic reaction4, hypersensitivity4 Nervous system disorders Headache Convulsions Vascular pathologies Venous and arterial thrombosis³, hypertension Hypertensive crisis 4 Respiratory, thoracic and mediastinal disorders Cough Respiratory congestion Gastrointestinal disorders Diarrhea, nausea, vomiting Skin and subcutaneous tissue disorders Rash Angioneurotic edema4, urticaria4 Musculoskeletal and connective tissue disorders Arthralgia, bone pain, myalgia, pain in extremities Congenital, familial and genetic disorders Porphyria 4 General disorders and administration site conditions Pyrexia Chills, flu-like illness, injection site reactions, peripheral edema Ineffective drug 4

1 Identified in experience post-marketing and frequency category estimated based on spontaneous reporting rates

² Common in dialysis

³ Includes arterial and venous events, both fatal and non-fatal, such as deep vein thrombosis, pulmonary emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular accidents (including cerebral infarction and cerebral haemorrhage), transient ischemic attacks, shunt thrombosis ( including dialysis equipment) and thrombosis in arteriovenous shunt aneurysms

4 Discussed in subsection below and / or section 4.4.

Description of selected adverse reactions

Hypersensitivity reactions including cases of rash (including urticaria), anaphylactic reactions and angioneurotic edema have been reported (see section 4.4).

Hypertensive crises with encephalopathy and seizures requiring immediate medical attention and intensive care have also occurred during epoetin alfa treatment of patients with previously normal or low blood pressure. migraine-like, which may be a warning sign (see section 4.4).

Antibody-mediated pure red cell aplasia (in

Pediatric population with chronic renal failure on hemodialysis

Exposure of pediatric chronic renal failure patients on hemodialysis in clinical trials and experience post-marketing it is limited. No pediatric-specific adverse reactions were reported in this population that are not mentioned in the table above or that are inconsistent with the underlying disease.

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 www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

The therapeutic margin of epoetin alfa is very wide. An overdose of epoetin alfa can cause effects that represent an extension of the pharmacological effects of the hormone. In the presence of excessively high hemoglobin levels, phlebotomy can be used. must resort to additional supportive treatments.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: antianemics, erythropoietin, ATC code: B03XA01

Binocrit is a biosimilar medicinal product. More detailed information is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

Mechanism of action

Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the central regulator of erythrocyte production. "EPO is involved in all phases of erythroid development and its main effect is expressed at the level of the erythroid precursors. After binding to its receptor on the cell surface, EPO activates the transmission pathways of signals that interfere with" apoptosis and stimulates the proliferation of erythroid cells.

Recombinant human EPO (epoetin alfa), expressed in Chinese hamster ovary cells, has a sequence of 165 amino acids identical to that of human urinary EPO; the two substances are indistinguishable from functional analyzes. 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 red blood cells. Erythropoietin receptors can be expressed on the surface of different types of cancer cells.

Pharmacodynamic effects

Healthy volunteers

After single doses (20,000 to 160,000 IU subcutaneously) of epoetin alfa, a dose-dependent response was observed for the pharmacodynamic markers studied, including reticulocytes, erythrocytes and hemoglobin. A defined concentration-time profile, with peak and return to baseline, was observed for changes in the percentage of reticulocytes. A less defined profile was observed for erythrocytes and hemoglobin. In general, all pharmacodynamic markers increased in linear proportion to dose and maximal response was achieved at higher dose levels.

Additional pharmacodynamic studies looked at 40,000 IU once weekly compared to 150 IU / kg 3 times per week. Despite the differences in concentration-time profiles, the pharmacodynamic response (as measured by changes in percentage of reticulocytes, hemoglobin and total red blood cells) was similar between these regimens. In further studies, the 40,000 IU regimen of epoetin alfa once weekly was compared with doses ranging from 80,000 to 120,000 IU subcutaneously given every two weeks. Overall, based on the results of these pharmacodynamic studies in healthy subjects, the 40,000 IU once weekly regimen appears to be more effective in terms of erythrocyte production compared to the biweekly regimens, although similar reticulocyte production was observed in the once weekly and every two week regimens.

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 noticeable response to epoetin alfa is an increase in the reticulocyte count within 10 days, followed by an increase in the erythrocyte count, hemoglobin and hematocrit, usually within 2 to 6 weeks. The hemoglobin response it varies from patient to patient and can be influenced by iron deposits and the presence of concomitant diseases.

Chemotherapy induced anemia

Epoetin alfa, given 3 times per week or once per week, has been shown to increase hemoglobin and reduce the need for transfusions after the first month of therapy in anemic cancer patients undergoing chemotherapy.

In a study to compare the therapeutic regimen with 150 IU / kg 3 times per week and the therapeutic regimen with 40,000 IU once a week in healthy subjects and in anemic cancer subjects, the temporal profiles of changes in the percentage of reticulocytes, Hemoglobin and total erythrocytes were similar in both regimens in both healthy subjects and anemic cancer subjects. The AUCs of the respective pharmacodynamic parameters were similar in the 150 IU / kg 3 times per week regimen and the 40,000 IU regimen. once a week in healthy subjects and also in anemic cancer subjects.

Adult surgical patients participating in an autologous predonation program

Epoetin alfa has been shown to stimulate erythrocyte production, allowing increased autologous blood collection and limiting hemoglobin reduction in adult patients awaiting major elective surgery, for whom predeposit is believed does not fully meet the perioperative need for blood. The most evident effects are observed in patients with low hemoglobin values ​​(≤ 13 g / dL).

Treatment of adult patients scheduled for major elective orthopedic surgery

In patients scheduled for major elective orthopedic surgery with pretreatment hemoglobin values> 10 and ≤ 13 g / dL, epoetin alfa has been shown to reduce the risk of receiving allogeneic transfusions and accelerate erythroid recovery (increased hemoglobin levels, hematocrit levels and reticulocyte counts).

Clinical efficacy and safety

Chronic renal failure

Epoetin alfa has been investigated in clinical studies in anemic adult patients with chronic renal failure, including patients on hemodialysis and pre-dialysis, for the treatment of anemia and maintenance of hematocrit over a target concentration range of 30 and 36%.

In clinical trials with starting doses ranging from 50 to 150 IU / kg three times per week, approximately 95% of patients responded with a clinically significant increase in hematocrit. After approximately two months of therapy, nearly all patients were independent of Transfusions. Once the target hematocrit was reached, the maintenance dose was set individually for each patient.

In the three largest clinical trials conducted in adult dialysis patients, the median maintenance dose required to maintain hematocrit between 30 and 36% was approximately 75 IU / kg administered 3 times per week.

In a double-blind, placebo-controlled, multicenter, quality of life study in chronic renal failure patients on hemodialysis there was a clinically and statistically significant improvement in patients treated with epoetin alfa compared to placebo in terms of fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients in the epoetin alfa group were also enrolled in an open-label extension study which showed improvements in quality of life that were maintained for an additional 12 months.

Adult patients with renal insufficiency not yet on dialysis

In clinical studies conducted in chronic renal failure 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. A prolonged and dose-dependent increase in hematocrit was observed in chronic renal failure patients not on dialysis following intravenous or subcutaneous administration of epoetin alfa. The rates of hematocrit increase were similar with both routes of administration of epoetin alfa. In addition, doses of epoetin alfa between 75 and 150 IU / kg per week have been shown to maintain hematocrit at values ​​between 36 and 38% for up to six months.

In two studies with prolonged dosing intervals for epoetin alfa (3 times per week, once per week, once every 2 weeks and once every 4 weeks), some patients with longer dosing intervals did not maintain adequate hemoglobin levels and met protocol withdrawal criteria for hemoglobin (0% in the once weekly group, 3.7% in the once every 2 weeks group, and 3.3% in the once every 4 weeks group).

In a prospective randomized study 1,432 anemic patients with chronic renal failure who were not dialyzed were evaluated. Patients were assigned to epoetin alfa treatment to maintain a hemoglobin level of 13.5 g / dL (above the recommended hemoglobin concentration level) or 11.3 g / dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 (18%) of the 715 patients in the group with higher hemoglobin levels compared to 97 (14%) of the 717 patients in the group. with lower hemoglobin levels (hazard ratio [HR] 1.3; 95% CI: 1.0, 1.7; p = 0.03).

Pooled post-hoc analyzes of clinical studies of ESAs in patients with chronic renal failure (on dialysis, not on dialysis, diabetic and non-diabetic) were conducted. A trend was observed for an increase in the estimated risk of all-cause mortality and cardiovascular and cerebrovascular events associated with higher cumulative doses of ESA, regardless of the presence or absence of diabetes or dialysis (see section 4.2 and section 4.4).

Treatment of patients with chemotherapy-induced anemia

Epoetin alfa has been investigated in clinical studies in anemic cancer patients with lymphoid and solid tumors and in patients undergoing various chemotherapy regimens, including platinum and platinum-free regimens. In these studies it was shown that epoetin alfa, administered 3 twice a week and once a week, increases hemoglobin and reduces 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.

The available evidence indicates 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 similar 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 in patients treated with placebo, as well as by a similar proportion of patients in the epoetin alfa and placebo groups whose absolute neutrophil counts were less than 1,000 and 500 cells / mcL.

In a prospective, randomized, double-blind, placebo-controlled study conducted with 375 anemic patients with various non-myeloid malignancies and treated with non-platinum-based chemotherapy, a significant reduction in anemia-related sequelae (fatigue) was observed. , energy and reduced activity) based on the following instrumental measurements and rating scales: General Functional Assessment of Cancer Therapy-Anaemia (FACT-An) scale, FACT-An fatigue scale and Cancer Linear Analogue Scale (CLAS). two smaller, randomized, placebo-controlled studies, no significant improvement in quality of life parameters was observed on the EORTC-QLQ-C30 or CLAS scales, respectively.

Survival and tumor progression were analyzed in five large controlled studies involving a total of 2,833 patients, including four double-blind placebo-controlled studies and one open-label study. These studies enrolled patients on chemotherapy (two studies) or patient populations in whom ESAs are not indicated: cancer patients with anemia not undergoing chemotherapy and patients with head and neck cancer undergoing radiotherapy. In two studies, the desired hemoglobin concentration level was> 13 g / dL (8.1 mmol / L); in the remaining studies it ranged from 12 to 14 g / dL (7.5 to 8.7 mmol / L). In the open-label study, there was no difference in the overall survival of patients treated with recombinant human erythropoietin and controls.In the four placebo-controlled studies, the overall survival risk ratio ranged from 1.25 to 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 outcome was not sufficiently explained by the differences in the incidence of thrombosis and associated complications in subjects treated with recombinant human erythropoietin and in control subjects.

An "analysis of individual patient data was also conducted in over 13,900 cancer patients (receiving chemotherapy, radiotherapy, chemo-radiotherapy or not undergoing any treatment) participating in 53 controlled clinical trials involving various epoetins. The meta-analysis of the epoetins. overall survival data provided a point estimate of the hazard ratio (hazard ratio) of 1.06 in favor of controls (95% CI: 1.00; 1.12; 53 studies and 13,933 patients) and for cancer patients treated with chemotherapy the risk ratio for overall survival was 1.04 (95% CI: 0.97, 1.11; 38 studies and 10,441 patients). Meta-analyzes have also consistently shown a significantly increased relative risk of thromboembolic events in cancer patients treated with recombinant human erythropoietin (see section 4.4).

An open-label, randomized, multicenter study was conducted of 2,098 women with anemia with metastatic breast cancer who received first or second-line chemotherapy. This was a non-inferiority study designed to exclude a 15% increased risk of tumor progression or death for epoetin alfa plus standard therapy (SOC) compared to SOC alone. Median progression-free survival (progression free survival, PFS) according to the investigator's assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating that the study objective was not achieved cut-off clinical 1337 deaths were reported. Median overall survival in the group receiving epoetin alfa plus SOC was 17.2 months compared with 17.4 months in the group receiving SOC alone (HR 1.06, 95% CI: 0.95, 1.18). In the arm receiving epoetin alfa plus SOC, significantly fewer patients received erythrocyte transfusions (5.8% vs. 11.4%); however, in the arm receiving epoetin alfa plus SOC, significantly more patients (2.8% vs. 1.4%) experienced thrombotic vascular events.

Autologous predonation program

The effect of epoetin alfa on the facilitation of autologous blood donation in patients with low hematocrit (≤ 39% in the absence of underlying iron deficiency anemia) awaiting major orthopedic surgery was evaluated in a double-blind study. placebo-controlled study conducted in 204 patients and a single-blind, placebo-controlled study conducted 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 (for a total of 6 doses). On average, patients treated with epoetin alfa were able to donate significantly more units of blood for predeposit (4.5 units) compared to 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 (for a total of 6 doses). These patients treated with epoetin alfa were also able to donate significantly more units of blood to the predeposit (epoetin alfa 300 IU / kg = 4.4 units; epoetin alfa 600 IU / kg = 4.7 units) in comparison to patients treated with placebo (2.9 units).

Epoetin alfa therapy reduced the risk of exposure to allogeneic blood by 50% compared to patients not receiving 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 non-ironopenic adult patients awaiting a elective major hip or knee orthopedic surgery. Epoetin alfa was administered subcutaneously within 10 days prior to surgery, on the day of surgery, and for four days following surgery. Patients were stratified by 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 transfusion in patients with pretreatment hemoglobin ranging from> 10 to ≤13 g / dL. Sixteen percent of patients treated with epoetin alfa 300 IU / kg, 23% of patients treated with epoetin alfa 100 IU / kg and 45% of patients treated with placebo required transfusions.

In an open-label, parallel-group study in non-iron deficient adult subjects with pretreatment hemoglobin ranging from ≥10 to ≤13 g / dL awaiting major hip or knee orthopedic surgery, epoetin alfa was compared. 300 IU / kg per day subcutaneously in the 10 days prior to surgery, the day of surgery and in the four days following surgery with epoetin alfa 600 IU / kg subcutaneously once a week for the 3 weeks prior to surgery. intervention and the day of the intervention.

From the pre-treatment phase to the pre-operative phase, the mean increase in hemoglobin in the 600 IU / kg per week group (1.44 g / dL) was double that of the 300 IU / dL group. kg per day (0.73 g / dL). Mean hemoglobin levels were similar in the two treatment groups throughout the postoperative period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates (16% in the 600 IU / kg per week group and 20% in the 300 IU / kg per day group).

Pediatric population

Chronic renal failure

Epoetin alfa was evaluated in an open-label, non-randomized, open-range, 52-week clinical study in pediatric chronic renal failure patients undergoing hemodialysis. The median age of patients enrolled in the study was 11.6 years (range from 0.5 to 20.1 years).

Epoetin alfa was administered at doses of 75 IU / kg / week intravenously, divided into 2 or 3 doses after dialysis, titrated to 75 IU / kg / week at 4-week intervals (up to a maximum of 300 IU / kg / week) to obtain an increase in hemoglobin of 1 g / dL / month. The desired hemoglobin concentration range was 9.6 to 11.2 g / dL. Eighty-one percent of patients achieved this hemoglobin concentration level. Median time to goal was 11 weeks and median dose to goal was 150 IU / kg / week. Of the patients who achieved the goal, 90% achieved it on the 3 times per week regimen.

After 52 weeks, 57% of patients remained in the study, receiving a median dose of 200 IU / kg / week.

Clinical data relating to subcutaneous administration in children are limited. In 5 open-label, uncontrolled studies with a small number of patients (the number of patients ranged from 9-22, for a total N = 72), epoetin alfa was administered subcutaneously to children with a single dose starting from 100 IU / kg / week to 150 IU / kg / week, with the possibility of increasing it up to 300 IU / kg / week. In these studies, the majority of patients were pre-dialysed (N = 44), 27 patients were on peritoneal dialysis and two were on hemodialysis; the age of the patients ranged from 4 months to 17 years. Overall, these studies have methodological limitations, but treatment has been associated with positive trends towards higher hemoglobin levels. No unexpected adverse events were reported (see section 4.2).

Chemotherapy induced anemia

Epoetin alfa 600 IU / kg (administered intravenously or subcutaneously once weekly) was evaluated in a 16-week randomized, double-blind, placebo-controlled study and in a randomized, controlled, open-label and duration of 20 weeks in pediatric patients with anemia undergoing myelosuppressive chemotherapy for the treatment of various childhood non-myeloid malignancies.

In the 16-week study (n = 222), in patients treated with epoetin alfa there was no significant effect on the Quality of Life in pediatric patients reported by the patients themselves or by their parents or in the Cancer Module scores compared to placebo (primary efficacy endpoint). Furthermore, there was no statistical difference between the percentage of patients who required red blood cell transfusions in the group receiving epoetin alfa and that receiving placebo.

In the 20-week study (n = 225), there was no significant difference in the primary efficacy endpoint, i.e. in the proportion of patients who required red blood cell transfusion after day 28 (62% of patients who received epoetin alfa vs. 69% of patients receiving standard therapy).

05.2 "Pharmacokinetic properties -

Absorption

Following subcutaneous injection, serum levels of epoetin alfa peaked between 12 and 18 hours post-dose. There was no accumulation after administration of multiple doses of 600 IU / kg subcutaneously once weekly.

The absolute bioavailability of subcutaneous injectable epoetin alfa is approximately 20% in healthy subjects.

Distribution

The mean volume of distribution was 49.3 mL / kg after intravenous doses 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 to 107 mL / kg after single doses (12 IU / kg) and from 42 to 64 mL / kg after multiple doses, respectively. (48-192 IU / kg). Therefore, the volume of distribution is slightly greater than the plasma space.

Elimination

The half-life of epoetin alfa following multiple dose intravenous administration is approximately 4 hours in healthy subjects.

The half-life after subcutaneous administration is estimated to be approximately 24 hours in healthy subjects.

The mean CL / F 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 for the 150 IU / kg 3 times per week and 40,000 IU once weekly regimens in cancer anemic subjects was 45.8 and 11.3 mL / h / kg, respectively. In most anemic cancer subjects undergoing 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 values ​​observed in 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. Administration of single doses of 300 to 2,400 IU / kg of epoetin alfa subcutaneously resulted in a linear correlation between mean Cmax and dose and between mean AUC and dose. An inverse correlation between apparent clearance and dose. dose was observed in healthy subjects.

In studies to examine the lengthening of the dosing interval (40,000 IU once a week and 80,000, 100,000, and 120,000 IU every two weeks), a linear, but not dose-proportional, correlation was observed between mean Cmax and dose and between mean AUC and steady-state dose.

Pharmacokinetic / pharmacodynamic relationships

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 to 8.7 hours has been observed in pediatric subjects with chronic renal failure following multiple dose intravenous administration of epoetin alfa. The pharmacokinetic profile of epoetin alfa in children and adolescents appears similar to that of adults.

Pharmacokinetic data in neonates are limited.

A study in 7 preterm infants with very low birth weight and 10 healthy adults given i.v. suggested that the volume of distribution was approximately 1.5 to 2 times higher in preterm infants than in healthy adults and that clearance was approximately 3 times higher in preterm infants than in healthy adults.

Renal impairment

In patients with chronic renal failure, the half-life of intravenously administered epoetin alfa is slightly longer, approximately 5 hours, compared to healthy subjects.

05.3 Preclinical safety data -

In repeat dose toxicology studies in dogs and rats, but not monkeys, epoetin alfa 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. The incidence of bone marrow fibrosis was not increased in a study conducted with hemodialysis patients treated for 3 years with epoetin alfa compared to a compatible control group of dialysis patients not treated with epoetin alfa.

Epoetin alfa does not induce gene mutation in bacteria (Ames test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.

Long-term carcinogenicity studies have not been conducted. Discordant data existing in literature, based on results obtained in vitro with human tumor samples, suggest a possible role of erythropoietins in tumor proliferation. The clinical significance is uncertain.

In human bone marrow cell cultures, epoetin alfa specifically stimulates erythropoiesis and does not affect leukopoiesis. There were no cytotoxic effects of epoetin alfa on bone marrow cells.

In animal studies, epoetin alfa has been shown to induce a reduction in fetal body weight, a delay in ossification and an increase in fetal mortality when administered at weekly doses approximately 20 times the recommended weekly dose in humans. they are considered secondary to the mother's reduced body weight gain and their significance to humans is unknown at therapeutic dose levels.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Sodium monobasic phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Glycine

Polysorbate 80

Water for injections

Hydrochloric acid (to adjust the pH)

Sodium hydroxide (to adjust the pH)

06.2 Incompatibility "-

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

06.3 Period of validity "-

2 years

06.4 Special precautions for storage -

Store and transport refrigerated (2 ° C - 8 ° C). This temperature range must be strictly observed until administration to the patient.

For outpatient use, the medicine can be removed from the refrigerator, without putting it back, 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 discarded. .

Do not freeze or shake.

Store in the original package to protect the medicine from light.

06.5 Nature of the immediate packaging and contents of the package -

Pre-filled syringes (type I glass), with or without needle safety device, with plunger stopper (Teflon rubber) sealed in blister packs.

Binocrit 1,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.5 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 2,000 IU / 1 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 1 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 3,000 IU / 0.3 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.3 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 4,000 IU / 0.4 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.4 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 5,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.5 ml of injectable solution.

Packs of 1 or 6 syringes.

Binocrit 6,000 IU / 0.6 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.6 ml of injectable solution.

Packs of 1 or 6 syringes.

Binocrit 7,000 IU / 0.7 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.7 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 8,000 IU / 0.8 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.8 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 9,000 IU / 0.9 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.9 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 10,000 IU / 1 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 1 ml of solution for injection.

Packs of 1 or 6 syringes.

Binocrit 20,000 IU / 0.5 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.5 ml of solution for injection.

Packs of 1, 4 or 6 syringes.

Binocrit 30,000 IU / 0.75 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 0.75 ml of solution for injection.

Packs of 1, 4 or 6 syringes.

Binocrit 40,000 IU / 1 mL solution for injection in a pre-filled syringe

Each pre-filled syringe contains 1 ml of solution for injection.

Packs of 1, 4 or 6 syringes.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

Binocrit must not be used and must be discarded

• if the liquid is colored or if you see particles floating in it

• if the seal is broken

• if it is known or suspected that it may have been accidentally frozen or

• if a refrigerator failure has occurred

The pre-filled syringes are ready for use (see section 4.2). The pre-filled syringe must not be shaken. The syringes are marked with raised graduations; this allows for partial use if necessary. Each graduation corresponds to a volume of 0, 1 mL. The product is for single use only. Withdraw only one dose of Binocrit from each syringe and discard any unnecessary solution before injecting.

Using the pre-filled syringe with needle safety guard

The needle safety guard covers the needle after injection and prevents the operator from injuring himself. The device does not interfere with normal use of the syringe. Push slowly and evenly on the plunger until the full dose is released and the plunger cannot be pushed further. While continuing to push down on the plunger, pull the syringe away from the patient. The safety device covers the needle as soon as the plunger is released.

Using the pre-filled syringe without a needle safety guard

Administer the dose according to the standard procedure.

Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Sandoz GmbH

Biochemiestr. 10

A-6250 Kundl

Austria

08.0 MARKETING AUTHORIZATION NUMBER -

Binocrit 1,000 IU / 0.5 mL solution for injection in a pre-filled syringe

EU / 1/07/410/001 - 1000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.5 ml (2000 IU / ml) 1 pre-filled syringe - AIC n. 038190017 / E

EU / 1/07/410/002 - 1000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.5 ml (2000 IU / ml) 6 pre-filled syringes - AIC n. 038190029 / E

EU / 1/07/410/027 - 1000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.5 ml (2000 IU / ml) 1 0.5 ml pre-filled syringe with device safety for needle - AIC n. 038190272 / E

EU / 1/07/410/028 - 1000IU / 0.5 ml solution for injection in pre-filled syringe (glass) - intravenous subcutaneous use - 0.5 ml (2000 IU / ml) - 6 pre-filled syringes of 0.5 ml with device needle safety - AIC N. 038190284 / E

Binocrit 2,000 IU / 1 mL solution for injection in a pre-filled syringe

EU / 1/07/410/003 - 2000 IU / 1.0 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 1.0 ml (2000 IU / ml) 1 pre-filled syringe - AIC n. 038190031 / E

EU / 1/07/410/004 - 2000 IU / 1.0 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 1.0 ml (2000 IU / ml) 6 pre-filled syringes - AIC n. 038190043 / E

EU / 1/07/410/029 - 2000IU / 1ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 1ml (2000IU / ml) 1 1ml pre-filled syringe with needle safety device - AIC No. 038190296 / E

EU / 1/07/410 / 030- 2000IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 1 ml (2000 IU / ml) - 6 pre-filled syringes of 1 ml with safety device for needle - AIC N. 038190308 / E

Binocrit 3,000 IU / 0.3 mL solution for injection in a pre-filled syringe

EU / 1/07/410/005 - 3000 IU / 0.3 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.3 ml (10000 IU / ml) 1 pre-filled syringe - AIC n. 038190056 / E

EU / 1/07/410/006 - 3000 IU / 0.3 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.3 ml (10000 IU / ml) 6 pre-filled syringes - AIC n. 038190068 / E

EU / 1/07/410 / 031- 3000IU / 0.3ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.3ml (10000IU / ml) 1 0.3ml pre-filled syringe with safety device per needle - AIC N. 038190310 / E

EU / 1/07/410/032 - 3000IU / 0.3ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.3ml (10000 IU / ml) - 6 prefilled 0.3ml syringes with device needle safety - AIC N. 038190322 / E

Binocrit 4,000 IU / 0.4 mL solution for injection in a pre-filled syringe

EU / 1/07/410/007 - 4000 IU / 0.4 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.4 ml (10000 IU / ml) 1 pre-filled syringe - AIC n. 038190070 / E

EU / 1/07/410/008 - 4000 IU / 0.4 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.4 ml (10000 IU / ml) 6 pre-filled syringes - AIC n. 038190082 / E

EU / 1/07/410/033 - 4000IU / 0.4ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.4ml (10000IU / ml) 1 0.4ml pre-filled syringe with safety device per needle - AIC N. 038190334 / E

EU / 1/07/410/034 - 4000IU / 0.4 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.4 ml (10000 IU / ml) - 6 pre-filled syringes of 0.4 ml with device safety needle - AIC N. 038190346 / E

Binocrit 5,000 IU / 0.5 mL solution for injection in a pre-filled syringe

EU / 1/07/410/009 - 5000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.5 ml (10000 IU / ml) 1 pre-filled syringe - AIC n. 038190094 / E

EU / 1/07/410/010 - 5000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0.5 ml (10000 IU / ml) 6 pre-filled syringes - AIC n. 038190106 / E

EU / 1/07/410/035 - 5000IU / 0.5 ml solution for injection in pre-filled syringe (glass) - intravenous subcutaneous use - 0.5 ml (10000 IU / ml) - 1 0.5 ml pre-filled syringe with device safety needle - AIC N. 038190359 / E

EU / 1/07/410/036 - 5000IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.5 ml (10000 IU / ml) - 6 pre-filled syringes of 0.5 ml with device safety for needle -AIC N. 038190361 / E

Binocrit 6,000 IU / 0.6 mL solution for injection in a pre-filled syringe

EU / 1/07/410/011 - 6000 IU / 0,6 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0,6 ml (10,000 IU / ml) 1 pre-filled syringe - AIC n. 038190118 / E

EU / 1/07/410/012 - 6000 IU / 0,6 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0,6 ml (10,000 IU / ml) 6 pre-filled syringes - AIC n. 038190120 / E

EU / 1/07/410/037 - 6000IU / 0.6 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.6 ml (10000 IU / ml) - 1 pre-filled syringe of 0.6 ml with device safety needle - AIC N. 038190373 / E

EU / 1/07/410/038 - 6000IU / 0,6 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0,6 ml (10,000 IU / ml) - 6 pre-filled syringes of 0,6 ml with device safety needle - AIC N. 038190385 / E

Binocrit 7,000 IU / 0.7 mL solution for injection in a pre-filled syringe

EU / 1/07/410/017 - 7000IU / 0.7 ml solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 0.7 ml (10000IU / ml) 1 pre-filled syringe - AIC No. 038190171 / AND

EU / 1/07/410/018 - 7000IU / 0.7 ml solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 0.7 ml (10000IU / ml) 6 pre-filled syringes - AIC No. 038190183 / AND

EU / 1/07/410/039 - 7000IU / 0.7ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.7ml (10000IU / ml) 1 pre-filled syringe of 0.7ml with safety device per needle - AIC N. 038190397 / E

EU / 1/07/410/040 - 7000IU / 0.7 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.7 ml (10000IU / ml) 6 pre-filled syringes of 0.7 ml with safety device per needle - AIC N. 038190409 / E

Binocrit 8,000 IU / 0.8 mL solution for injection in a pre-filled syringe

EU / 1/07/410/013 - 8000 IU / 0,8 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0,8 ml (10,000 IU / ml) 1 pre-filled syringe - AIC n. 038190132 / E

EU / 1/07/410/014 - 8000 IU / 0,8 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 0,8 ml (10,000 IU / ml) 6 pre-filled syringes - AIC n. 038190144 / E

EU / 1/07/410/041 - 8000IU / 0.8 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.8 ml (10000 IU / ml) - 1 pre-filled syringe of 0.8 ml with device safety needle - AIC N. 038190411 / E

EU / 1/07/410/042 - 8000IU / 0.8 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 0.8 ml (10000 IU / ml) - 6 pre-filled syringes of 0.8 ml with device safety needle - AIC N. 038190423 / E

Binocrit 9,000 IU / 0.9 mL solution for injection in a pre-filled syringe

EU / 1/07/410/019 - 9000IU / 0.9 ml solution for injection in pre-filled syringe - subcutaneous or intravenous use pre-filled syringe (glass) 0.9 ml (10000IU / ml) 1 pre-filled pre-filled syringe - AIC No. 038190195 / AND

EU / 1/07/410/020 - 9000IU / 0.9 ml solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 0.9 ml (10000IU / ml) 6 pre-filled syringes - AIC No. 038190207 / AND

EU / 1/07/410/043 - 9000IU / 0.9 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.9 ml (10000IU / ml) 1 pre-filled syringe of 0.9 ml with safety device per needle - AIC N. 038190435 / E

EU / 1/07/410/044 - 9000IU / 0.9 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.9 ml (10000IU / ml) 6 pre-filled syringes of 0.9 ml with safety device per needle - AIC N. 038190447 / E

Binocrit 10,000 IU / 1 mL solution for injection in a pre-filled syringe

EU / 1/07/410/015 - 10000 IU / 1.0 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 1.0 ml (10000 IU / ml) 1 pre-filled syringe - AIC n. 038190157 / E

EU / 1/07/410/016 - 10000 IU / 1.0 ml solution for injection in pre-filled syringe (glass) subcutaneous or intravenous use 1.0 ml (10000 IU / ml) 6 pre-filled syringes - AIC n. 038190169 / E

EU / 1/07/410/045 - 10000IU / 1 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 1 ml (10000 IU / ml) - 1 pre-filled syringe of 1 ml with safety device for needle - AIC N . 038190450 / E

EU / 1/07/410/046 - 10000IU / 1 ml solution for injection in pre-filled syringe (glass) - subcutaneous intravenous use - 1 ml (10000 IU / ml) - 6 pre-filled syringes of 1 ml with safety device for needle - AIC N . 038190462 / E

Binocrit 20,000 IU / 0.5 mL solution for injection in a pre-filled syringe

EU / 1/07/410/021 - 20,000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use 0.5 ml (40,000 IU / ml) 1 pre-filled syringe - AIC n. 038190219 / E

EU / 1/07/410/022 - 20,000 IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use 0.5 ml (40,000 IU / ml) 6 pre-filled syringes - AIC n. 038190221 / E

EU / 1/07/410/047 - 20000IU / 0.5ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.5ml (40000IU / ml) 1 0.5ml pre-filled syringe with safety device per needle - AIC N. 038190474 / E

EU / 1/07/410/053 - 20,000 IU / 0.5 ML - solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 0.5 ML (40,000 IU / ML) - 4 pre-filled syringes with device safety for needle AIC: 038190536 / E

EU / 1/07/410/048 - 20000IU / 0.5 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.5 ml (40000IU / ml) 6 pre-filled syringes of 0.5 ml with safety device per needle - AIC N. 038190486 / E

Binocrit 30,000 IU / 0.75 mL solution for injection in a pre-filled syringe

EU / 1/07/410/023 - 30,000 IU / 0.75 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use 0.75 ml (40,000 IU / ml) 1 pre-filled syringe - AIC n. 038190233 / E

EU / 1/07/410/024 - 30,000 IU / 0.75 ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use 0.75 ml (40,000 IU / ml) 6 pre-filled syringes - AIC n. 038190245 / E

EU / 1/07/410/049 - 30000IU / 0.75ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.75ml (40000IU / ml) 1 pre-filled syringe of 0.75ml with safety device for August - AIC N. 038190498 / E

EU / 1/07/410/054 - 30,000 IU / 0.75 ML - solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 0.75 ML (40,000 IU / ML) - 4 pre-filled syringes with device safety for needle AIC: 038190548 / E

EU / 1/07/410/050 - 30000IU / 0.75ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 0.75ml (40000UI / ml) 6 pre-filled syringes of 0.75ml with safety device per needle - AIC N. 038190500 / E

Binocrit 40,000 IU / 1 mL solution for injection in a pre-filled syringe

EU / 1/07/410/025 - 40,000 IU / 1.0 ml - solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 1.0 ml (40,000 IU / ml) 1 pre-filled syringe - AIC n. 038190258 / E

EU / 1/07/410/026 - 40,000 IU / 1.0 ml - solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 1.0 ml (40,000 IU / ml) 6 pre-filled syringes - AIC n. 038190260 / E

EU / 1/07/410/051 - 40000IU / 1ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 1ml (40000IU / ml) 1 1ml pre-filled syringe with needle safety device - AIC N. 038190512 / E

EU / 1/07/410/055 - 40,000 IU / 1.0 ML - solution for injection in pre-filled syringe - subcutaneous or intravenous use - pre-filled syringe (glass) 1.0 ML (40,000 IU / ML) - 4 pre-filled syringes with device safety needle for AIC needle: 038190551 / E

EU / 1/07/410/052 - 40000UI / 1ml solution for injection in pre-filled syringe (glass) - subcutaneous or intravenous use - 1ml (40000UI / ml) 6 1ml pre-filled syringes with needle safety device - AIC N. 038190524 / E

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

From the first authorization: 28 August 2007

Date of most recent renewal: June 18, 2012

10.0 DATE OF REVISION OF THE TEXT -

10/2016

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 -

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